Transition-metal-mediated cascade reactions: The water-accelerated carboalumination-Claisen rearrangement-carbonyl addition reaction

Article abstract of DOI:10.1021/jo051211v

A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene functionalities that are readily cyclized to substituted cyclopentenes. An extension of this methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl vinyl ether substrate.

Full text of DOI:10.1021/jo051211v

Transition-Metal-Mediated Cascade Reactions:
The Water-Accelerated Carboalumination-Claisen
Rearrangement-Carbonyl Addition Reaction
Peter Wipf,* David L. Waller, and Jonathan T. Reeves
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
pwipf+@pitt.edu
Received June 14, 2005
A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen
rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers
into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric
quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well
as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene
functionalities that are readily cyclized to substituted cyclopentenes. An extension of this
methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl
vinyl ether substrate.
Introduction
clobutanes,7 oxazolines, and thiazolines.8 Many of these
methods utilize alkenylzirconocenes, derived from in situ
hydrozirconation9 of alkynes, for subsequent C,C-bond
formation.10 In addition, we have reported other cascade
processes in connection with our studies of water-acceler-
ated zirconium-catalyzed carboalumination,5,11 includ-
ing water-accelerated aromatic Claisen rearrangements,12
and a cascade aromatic Claisen rearrangement-asym-
The development of multicomponent, domino, and
cascade reaction technology has dramatically increased
the level of molecular complexity that can be introduced
during a single synthetic operation.1-3 Cascade reactions
often integrate modern synthetic methods, such as metal-
based catalysis, with classical synthetic bond construc-
tions.4 The ability to create new synthetic manifolds by
merging compatible methodologies offers significant op-
portunities for optimizing synthetic efficiency.
(4) For recent examples, see: (a) Suffert, J.; Salem, B.; Klotz, P. J.
Am. Chem. Soc. 2001, 123, 12107. (b) MacMillan, D. W. C.; Dong, V.
M. J. Am. Chem. Soc. 2001, 123, 2448. (c) May, J. A.; Stoltz, B. M. J.
Am. Chem. Soc. 2002, 124, 12426. (d) Lampropoulou, M.; Herrmann,
R.; Wagner, G. Tetrahedron 2004, 60, 4635. (e) Wipf, P.; Coleman, C.
M.; Janjic, J. M.; Iyer, P. S.; Fodor, M. D.; Shafer, Y. A.; Stephenson,
C. R. J.; Kendall, C.; Day, B. W. J. Comb. Chem. 2005, 7, 322.
(5) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2001, 123, 5122. (b) Wipf, P.; Nunes, R. L.; Ribe, S. Helv. Chim. Acta
2002, 85, 3478. (c) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am.
Chem. Soc. 2003, 125, 761.
We have previously reported several cascade reactions
leading to diverse functionality, including allylic5 and
homoallylic6 amines, C-cyclopropyl alkylamines,5 bicy-
(1) (a) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (c) Nair, V.;
Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (d) Weber, L. Curr. Med.
Chem. 2002, 9, 2085. (e) Mayer, S. F.; Kroutil, W.; Faber, K. Chem.
Soc. Rev. 2001, 30, 332.
(2) (a) Pulici, M.; Cervi, G.; Martina, K.; Quartieri, F. Comb. Chem.
High Throughput Screen. 2003, 6, 693. (b) Tietze, L. F. Chem. Rev.
1996, 96, 115. (c) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168.
(6) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
(7) Wipf. P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc.
2003, 125, 14964.
(8) Wipf, P.; Wang, X. J. Comb. Chem. 2002, 4, 656.
(9) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Wipf, P.;
Kendall, C. In Topics in Organometallic Chemistry. Metallocenes in
Regio- and Stereoselective Synthesis; Takahashi, T., Ed.; Springer-
Verlag: Heidelberg, 2004; Vol. 8, Chapter 1, p 1-25.
(3) For a review of recent applications of cascade reactions to natural
product synthesis, see: Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551.
(10) For a review of carbon-carbon bond formation with alkenylzir-
conocenes, see: Wipf, P.; Nunes, R. Tetrahedron 2004, 60, 1269.
10.1021/jo051211v CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/08/2005
8096
J. Org. Chem. 2005, 70, 8096-8102

Water Accelerated Cascade Reactions
TABLE 1. Optimization of Reaction Conditions for the
Conversion of 1 to 3
SCHEME 2. Cascade Conversion of Alkyne to
Allylic Alcohol
entry AlMe3 (equiv) H2O (equiv)
solvent
CH2Cl2
yield of 3 (%)
1
2
3
4
5
6
7
8
9
2.2
1.1
56
60
0
2.05
1.5
1.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
toluene
0.75
0.5
1.0
0
2.5
1.25
2.25
0.56
1.0
60
25
61
60
48
2.2
2.25
2.0
2.25
1.2
SCHEME 1. Cascade Process with Cinnamyl Vinyl
Ether 2
the yield substantially (entry 6). Interestingly, good yields
were obtained with substoichiometric amounts of H2O
(entry 7); however, this was unique to simple unfunc-
tionalized allylic vinyl ethers. The optimum stoichiometry
was found to be 2 equiv of AlMe3 and 1 equiv of H2O,
yielding approximately 60% of the desired material. The
reaction was also sensitive to the choice of solvent.
Conducting the entire process in dichloroethane showed
no benefit over dichloromethane (entry 8). When toluene
was used as a solvent, the rearrangement/addition step
was very slow and gave a yield of only 48% (entry 9).
Therefore, dichloromethane was chosen as the preferred
solvent for this transformation.
Mechanistically, 1,6-diene 8 arises from an initial
water-accelerated zirconium-assisted alkyne carboalum-
ination11-13 (Scheme 2).15 The intermediate vinylalane 5
can act as a Lewis acid12,16 to promote the [3,3] sigma-
tropic rearrangement of the allylic vinyl ether 6 to the
aldehyde 7, which undergoes rapid attack by the viny-
lalane to generate the final allylic alcohol 8 bearing up
to three contiguous stereocenters. It is possible that in
the presence of water partially hydrolyzed alane acts as
bidentate or oligodentate Lewis17 or Brønsted12 acid and
enhances the rate of all three distinctive C,C-bond-
forming steps in this sequence.
Preparation of Allyl Vinyl Ethers. To explore the
scope and limitations of this new cascade reaction, a
straightforward access to allyl vinyl ethers had to be
identified.18 Hg(II)-catalyzed alcohol exchange of cinna-
myl alcohol with 2-methoxypropene generated isoprope-
nyl ether 919 in 45% yield (Scheme 3). The n-butyl-sub-
stituted vinyl ether 11 was synthesized using Buchwald’s
coupling protocol (CuI, Cs2CO3, and phenanthroline 14)20
with vinyl iodide 10.21 After a 24 h reaction time, only a
low 17% yield of the (E,E)-vinyl ether 11 was obtained.
Alternatively, we considered Frauenrath’s allylic ether
isomerization methodology for the preparation of a (Z)-
metric carboalumination leading to branched alkanols in
high enantiomeric excess.13 We now report an aliphatic
Claisen rearrangement-based methodology encompassing
a three-step cascade process with allyl vinyl ethers.14
Results and Discussion
Optimization of Cascade Alkyne Carboalumina-
tion-Claisen Rearrangement-Carbonyl Addition.
Treatment of a solution of 1-hexyne (1) with AlMe3 (5
equiv), H2O (2.5 equiv), and Cp2ZrCl2 (10 mol %) in CH2-
Cl2 followed by addition of cinnamyl vinyl ether 2 pro-
vided allylic alcohol 3 in 42% yield as a 1:1 mixture of
diastereomers after only 10 min reaction time as the
reaction mixture was warmed from -78 to +25 °C
(Scheme 1). In addition to the desired 3, a major side
product (∼30%) was formed and subsequently identified
as the secondary alcohol 4. Suppressing the formation
of this methyl transfer product was our primary goal in
optimizing this model reaction (Table 1). Reduction of the
equivalents of both AlMe3 and H2O to 2.2 and 1.1, re-
spectively (entry 1), suppressed the undesired methyl
addition to nearly undetectable levels. Further variation
in the stoichiometry to 2 equiv of AlMe3 and 1 equiv of
H2O (entry 2) furnished the desired product 3 in 60%
yield with no evidence of the methyl transfer byproduct
4; however, some hydrolysis of the starting vinyl ether
was observed. Reduction of the amount of AlMe3 to levels
below 2 equiv resulted in no reaction or only a trace of
product (entries 3 and 4). An increase in the amount of
AlMe3 to 2.5 equiv and of H2O to 1.25 equiv had little
effect on the yield (entry 5). Equimolar amounts of AlMe3
and H2O resulted in a very slow reaction and lowered
(15) Negishi, E.-I. Dalton Trans. 2005, 827.
(16) (a) Schneider, C.; Brauner, J. Eur. J. Org. Chem. 2001, 4445.
(b) Abe, N.; Hanawa, H.; Maruoka, K.; Sasaki, M.; Miyashita, M.
Tetrahedron Lett. 1999, 40, 5369. (c) Hanawa, H.; Abe, N.; Maruoka,
K. Tetrahedron Lett. 1999, 40, 5365.
(17) (a) Ooi, T.; Takahashi, M.; Yamada, M.; Tayama, E.; Omoto,
K.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 1150. (b) Maruoka, K.;
Banno, H.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 7791. (c) Takai,
K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984, 57,
446.
(11) (a) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1068. (b) Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713. (c) Ribe, S.; Kondru,
R. K.; Beratan, B. N.; Wipf, P. J. Am. Chem. Soc. 2000, 122, 4608.
(12) Rodriguez, S.; Wipf, P. Adv. Synth. Catal. 2002, 344, 434.
(13) Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503.
(14) For an example of a Lewis acid mediated Claisen rearrange-
ment-aldehyde methylation, see: Ooi, T.; Takahashi, M.; Maruoka,
K. J. Am. Chem. Soc. 1996, 118, 11307.
(18) Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp
827-874.
(19) Yamamoto, H.; Banno, H.; Maruoka, K. Tetrahedron: Asym-
metry 1991, 2, 647.
(20) Buchwald, S. L.; Nordmann, G. J. Am. Chem. Soc. 2003, 125,
4978.
(21) Whitney, G. C.; Zweifel, G. J. Am. Chem. Soc. 1967, 89, 2753.
J. Org. Chem, Vol. 70, No. 20, 2005 8097

Wipf et al.
TABLE 2. Reaction Scope with Cinnamyl Derivatives
SCHEME 3. Synthetic Routes to Allyl Vinyl
Ethers
SCHEME 4. Synthesis of Cinnamyl Alcohol
Derived Vinyl Ethers
vinyl ether.22 Bisallyl ether 1223 was obtained by alkyl-
ation of the sodium salt of cinnamyl alcohol with allyl
iodide. Treatment of catalytic NiCl2(dppb) with Li(Et)3-
BH generated the Ni-H catalyst necessary to effect
terminal olefin isomerization of 12, furnishing vinyl ether
13 in 50% yield as a 94:6 ratio of alkenes favoring the
desired (Z)-isomer.
More highly substituted allyl vinyl ethers were acces-
sible from acrylic acid 15.24 Esterification of 15 with
TMSCHN2 proceeded in excellent yield to generate 16
(Scheme 4).25 Reduction of this ester to the primary
alcohol proved difficult, since conjugate addition with
concomitant loss of cinnamyl alcohol predominated under
a range of reducing conditions. Nevertheless, DIBAL
a Shown as major (top)/minor (bottom). b Determined by inte-
gration of the 1H NMR spectrum of the product mixture; dr )
diastereomeric ratio. c Major and minor diastereomers are unas-
signed. d Minor diastereomers are unassigned as indicated.
reduction provided a 29% yield of allylic alcohol 17, which
could be easily converted in excellent yield to the corre-
sponding methyl or TIPS ethers 18 or 19, respectively.
Conversely, amide coupling of dimethylamine to 15 with
EDCI26 furnished dimethyl amide 20 in 48% yield.
Reaction Scope. Most cinnamyl vinyl ether sub-
strates were converted in variable yield but in good
diastereoselectivity to the corresponding allylic alcohols
under the optimized cascade reaction conditions (Table
2).
(22) Wille, A.; Tomm, S.; Frauenrath, H. Synthesis 1998, 305.
(23) Serra, A. C.; da Silva Correa, C. M. M.; do Vale, M. L. C.
Tetrahedron 1991, 47, 9463.
(24) Bu¨chi, G. H.; Vogel, D. E. Org. Synth. 1988, 66, 29.
(25) Shioiri, T. J. Pharm. Soc. Jpn. 1993, 113, 760.
(26) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem.
1961, 26, 2525.
8098 J. Org. Chem., Vol. 70, No. 20, 2005

Water Accelerated Cascade Reactions
TABLE 3. Reaction Scope with Phenethyl Alcohol
Derived Allyl Vinyl Ethers32
SCHEME 5. Synthesis of Phenethyl Alcohol
Derived, Alkyl-Substituted Vinyl Ethers
Isopropenyl ether 9 furnished the tertiary allylic alco-
hols 21 and 22 in 75% yield as a 10:6.7 mixture of
diastereomers. A higher yield and an improved diaster-
eoselectivity were accomplished with butyl-substituted
vinyl ether 11, which provided the stereochemical triad
in allylic alcohols 23 and 24 as a 10:1:0.8 mixture of
diastereomers. The (Z)-vinyl ether 13 led to allylic
alcohols anti,syn-25 and anti,anti-26 in 65% yield as a
10:1 mixture of diastereomers (entry 3). Not unexpect-
edly, the presence of an ester functionality in the Claisen
precursors was problematic. Rapid conjugate addition of
vinyl aluminoxane to 16 led to the fragmentation product
27 (37%) and cinnamyl alcohol (47%, entry 4). The
dienoate 27 is likely derived from a conjugate addition
of the vinyl organometallic to the R,â-unsaturated ester
16, followed by â-elimination of cinnamyl alcohol. Allylic
alcohol 17 was better suited for the desired conversion
and produced diols 28 and 29 in a modest 30% yield but
in excellent diastereoselectivity (10:1, entry 5). Methyl
ether 18 decomposed via elimination pathways, giving
only trace amounts of byproducts (entry 6). In contrast,
the more strongly shielded TIPS ether 19 rearranged
smoothly to give syn,syn-30 and syn,anti-31 in 60% yield
and 10:1 diastereoselectivity (entry 7). The relative
stereochemistry of 30 and 31 was confirmed to be
identical to 28 and 29 by desilyation (TBAF, THF) of the
monoprotected substrates. Amide 20 proved most resis-
tant to rearrangement, requiring 10 equiv of water-
activated alane to generate a low yield of hydroxyl amides
32 and 33 (10:2, entry 8). Most likely, coordination of the
Lewis acidic alanes to the amide group interferes with
the desired rearrangement.
a Shown as major (top)/minor (bottom). b Determined by inte-
1
gration of the H NMR spectrum of the product mixture. c Major
and minor diastereomers are unassigned. d Minor diastereomers
are unassigned as indicated.
SCHEME 6. X-ray Analysis of Ester 46 Confirmed
the Syn,Syn-Configuration for the Major
Diastereomer
The cascade reaction is not limited to conjugated allylic
ethers. In addition to the cinnamyl alcohol derived
substrates, a series of alkyl-substituted allyl vinyl ethers
were prepared from allylic alcohol 34 (Scheme 5).27 These
substrates gave very similar results to their phenyl-
substituted counterparts (Table 3). Again, absence of
additional heteroatoms in the Claisen precursor provided
a higher yield of allylic alcohols (entry 1), whereas amide
37 and allylic alcohol 38 led to low yields but higher
diastereomeric ratios in the cascade conversion (entries
2 and 3).
tion (Scheme 6). In addition to monobenzoate 46, a 75%
yield of the bis-benzoate was also obtained, but the latter
was not diastereomerically pure and therefore unsuitable
for analysis. The configuration of the major diastereomer
formed in the cascade process can be explained by a
chairlike transition state for the accelerated Claisen
rearrangement (Scheme 7).18,28,29 The resulting aldehyde
(or ketone) is then subjected to a highly selective Felkin-
To assign the relative configuration of the major
diastereomers, diol 45, the product of the cascade reaction
of 17 with phenylacetylene, was derivatized to its mono-
p-bromobenzoyl ester 46 and analyzed by X-ray diffrac-
(27) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc.
2001, 123, 12168.
J. Org. Chem, Vol. 70, No. 20, 2005 8099

Wipf et al.
SCHEME 7. Proposed Mechanism
SCHEME 8. Control Reactions for Test of
Stereochemical Integrity of the Aldehyde
Intermediate
intermediate is a ketone, which is known to exhibit
diminished, substituent dependent complexation to alu-
minum Lewis acids compared to aldehydes.35
We were concerned that the intermediate aldehyde 47
might epimerize under the reaction conditions, leading
to decreased product diastereomeric ratio (dr); therefore,
we attempted to isolate this intermediate and compare
it to the product of a thermal Claisen rearrangement with
a substrate of known configuration. Allyl vinyl ether 13,
when subjected to microwave heating,36 underwent a [3,3]
sigmatropic rearrangement in 10 min to yield aldehyde
49 in 60% yield as a 10:1 mixture of diastereomers
(Scheme 8).37 Conversely, attempts to quench a cascade
carboalumination-Claisen rearrangement-vinylalane
addition reaction before the allyl vinyl ether was con-
sumed resulted only in recovered starting material and
final cascade reaction products. Presumably, nucleophilic
addition to the intermediate aldehyde was too rapid for
preparative isolation. However, the addition of alkyla-
lanes to carbonyl groups is slower than vinyl transfer,
and when the reaction with an alkyl aluminoxane was
quenched prematurely, we were able to isolate aldehyde
49 in 55% yield. A 9:1 diastereoselectivity was observed
in this reaction, and the configuration of 49 was identical
to the aldehyde obtained by thermal rearrangement, thus
indicating that R-epimerization during the cascade reac-
tion was unlikely.
Since the addition of water to mixtures of alane and
zirconocene leads to a significant rate increase in the
alkyne carboalumination,11a we also probed the potential
accelerating effect of water in the aldehyde addition.11c
Treatment of aldehyde 49 at -78 °C with vinylalane 50,
prepared via Negishi carboalumination38 in the absence
of water, led in less than 1 min to addition product 25 as
a modest 3:1 mixture of diastereomers. In the presence
of stoichiometric quantities of water, the vinylalane also
rapidly added to this aldehyde, but now in 8:1 diaster-
eocontrol (Scheme 9). These results indicate that, while
Anh addition30 of the vinylalane, directed by the R-ster-
eocenter. After aldehyde 47 is formed, addition takesplace
with the most bulky substituent orthogonal to the car-
bonyl π-bond. This conformation follows the Felkin-Anh
model and allows the nucleophile to assume a Bu¨rgi-
Dunitz trajectory31 for attack onto the carbonyl group.
In the addition of alkylaluminum reagents to alde-
hydes, a six-membered transition state is generally
preferred over a four-membered transition state when
more than 1 equiv of AlR3 is employed.33 In our case,
chelation control in the addition can be ruled out since
substrates 17 and 19 gave identical diastereomers (vide
supra). The stereodirecting effect of the newly formed
aldehyde R-stereocenter, in combination with the steric
demand of the oligomeric alane nucleophile,34 leads to a
high overall induction in the carbonyl addition step.
Further support for the significance of steric effects is
provided by the poor diastereoselectivity of substrates
that lack an R-stereocenter or, as in the case of 9, if the
(28) (a) Wunderli, A.; Zsindely, J.; Hansen, H.-J.; Schmid, H. Helv.
Chim. Acta 1973, 56, 989. (b) Vance, R. L.; Rondan, N. G.; Houk, K.
N.; Jensen, F.; Borden, W. T.; Komomicki, A.; Wimmer, E. J. Am.
Chem. Soc. 1988, 110, 2314. (c) Ireland, R. E.; Wipf, P.; Xiang, J. N. J.
Org. Chem. 1991, 56, 3572. (d) Khaledy, M. M.; Kalani, M. Y. S.;
Khuong, K. S.; Houk, K. N.; Aviyente, V.; Neier, R.; Soldermann, N.;
Velker, J. J. Org. Chem. 2003, 68, 572-577.
(34) It is well-accepted that aluminoxanes are highly aggregated
species, forming clusters which have average molecular weights of
about 1100 amu (in the case of methyl aluminoxane). Additionally,
some of these clusters have been observed by X-ray crystallography.
For reviews on this general topic, see: (a) Chen, E. Y.-X.; Marks, T. J.
Chem. Rev. 2000, 100, 1391. (b) Roesky, H. W.; Walawalkar, M. G.;
Murugavel, R. Acc. Chem. Res. 2001, 34, 201.
(29) Sterically hindered Lewis acids tend to increase the dr in
Claisen rearrangements. See, for example: Boeckman, R. K., Jr.; Neeb,
M. J.; Gaul, M. D. Tetrahedron Lett. 1995, 36, 803.
(30) Anh, N. T.; Maurel, F.; Lefour, J.-M. New J. Chem. 1995, 19,
353.
(35) Maruoka, K.; Nagahara, S.; Yamamoto, H. Tetrahedron Lett.
1990, 31, 5475.
(31) Buergi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron
1974, 30, 1563.
(36) (a) Martinez, I.; Alford, P. E.; Ovaska, T. V. Org. Lett. 2005, 7,
1133. (b) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945.
(32) Resubjecting a mixture of 41 and 42, or 43 and 44, to the
reaction conditions for
2 h did not lead to any change in the
diastereomeric ratio or the yield of recovered material. Therefore, we
conclude that the dr is not influenced by selective distruction of the
minor isomer.
(37) Configuration is based on a chairlike transition state: (a)
Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (b) Reference 18. (c) Reference
28.
(33) (a) Ashby, E. C.; Smith, R. S. J. Org. Chem. 1977, 42, 425. (b)
Evans, D. A. Science 1988, 240, 420.
(38) Negishi, E.; Van Horn, D. E.; King, A. O.; Okukado, N. Synthesis
1979, 501.
8100 J. Org. Chem., Vol. 70, No. 20, 2005

Water Accelerated Cascade Reactions
SCHEME 9. Control Experiments Establish the
Beneficial Effect of Water on the
Diastereoselectivity of the Addition Process
SCHEME 11. [1,3] Rearrangement of
Cyclopropylmethyl Vinyl Ether
SCHEME 10. Preparation of Cyclopentenes by
Ring-Closing Metathesis
conversion of 54 to 56 appears to be the first case of a
[1,3] sigmatropic rearrangement of a cyclopropane ana-
logue of an allyl vinyl ether.43 Starting material 54 was
prepared in high yield from alcohol 53 by a Hg(II)-
mediated vinyl ether exchange.
Conclusions
We have developed a rapid diastereoselective three-
step cascade carboalumination-Claisen rearrangement-
carbonyl addition process leading to 1,6-diene function-
alities containing allylic alcohols with up to three
contiguous stereocenters. The stoichiometric quantities
of water that are used as an additive increase the rate
of the [3,3] sigmatropic rearrangement as well as the
diastereoselectivity of the carbonyl addition. The result-
ing products are readily converted to substituted cyclo-
pentenes. The cascade reaction strategy can also be
extended to a sequence involving a [1,3] sigmatropic shift,
as demonstrated with cyclopropane containing substrate
54.
no measurable rate enhancement in the already fast 1,2-
addition is gained at -78 °C from the addition of water,
the larger aluminoxane cluster acting as a bulky nucleo-
phile in the 1,2-addition or a tighter transition state leads
indeed to improved facial selectivity in the carbonyl
addition step.
Conversion of 1,6-Diene to Cyclopentene. As a
practical demonstration of the synthetic potential of this
new cascade reaction, we converted a 10:1:0.8 mixture
of the 1,6-dienes 23 and 24 in the presence of ruthenium
catalyst 5139 to the cyclopentenols 52 (Scheme 10). These
substituted cyclopentenes have found use in the prepara-
tion of carbocyclic nucleosides, some of which are potent
antiviral agents lacking the labile anomeric linkage that
increases susceptibility to degradative enzymes such as
phosphorylases.40,41
Experimental Section
(E)-7-Methyl-3-phenylundeca-1,6-dien-5-ol (3). General Pro-
tocol A. To a -30 °C solution of AlMe3 (540 mg, 7.35 mmol)
and Cp2ZrCl2 (85.8 mg, 0.294 mmol) in CH2Cl2 (6 mL) was
added H2O (66.1 µL, 3.67 mmol) dropwise. The reaction
mixture was warmed to ambient temperature and then cooled
to 0 °C and treated with 1-hexyne (676 µL, 5.88 mmol). The
mixture was stirred for 30 min, cooled to -78 °C, and treated
with vinyl ether 2 (470 mg, 2.94 mmol) in CH2Cl2 (1.5 mL).
The mixture was warmed to ambient temperature over 10 min
and quenched with 1 M Rochelle’s salt (3 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. The residue was purified by chromatography on
SiO2 (hexanes/EtOAc, 5:1) to furnish alcohol 3 as a colorless
oil which was a 1:1 mixture of inseparable diastereomers as
indicated by 1H NMR analysis: IR (neat) 3334, 2956, 2929,
1452, 996, 913, 700 cm-1; 1H NMR δ 7.34-7.18 (m, 5 H), 6.03-
5.92 (m, 1 H), 5.22-5.17 (m, 1 H), 5.11-5.02 (m, 2 H), 4.31-
4.26 (m, 1 H), 3.49-3.39 (m, 1 H), 2.09-1.96 (m, 3 H), 1.88-
1.74 (m, 1 H), 1.54 (2 br s, 3 H), 1.42-1.20 (m, 4 H), 0.94 (t,
[1,3] vs [3,3] Rearrangement. The [1,3] sigmatropic
rearrangement of allyl vinyl ethers can compete with the
[3,3] sigmatropic shift,18 especially in the presence of
strong Lewis acids and with substrates that favor allyl
cation intermediates.42 While we have not specifically
observed reaction products in our cascade processes that
are derived from [1,3] rearrangements, this process is
feasible under our typical reaction conditions, as dem-
onstrated by the facile conversion of cyclopropylmethyl
vinyl ether 54 into the allylic alcohol 56 (Scheme 11). The
(39) Grubbs, R. H.; Scholl, M.; Ding, S.; Lee, C. W. Org. Lett. 1999,
1, 953.
(40) (a) Marquez, V.; Lim, M. Med. Res. Rev. 1986, 6, 1. (b) Roberts,
S.; Biggadike, K.; Borthwick, A.; Kirk, B. In Topics in Medicinal
Chemistry; Leeming, P. R., Ed.; Royal Society of Chemistry: London,
1988; p 172.
(41) Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A. L. J.
Org. Chem. 2000, 65, 8499.
(42) (a) Nasveschuk, C. G.; Rovis, T. Org. Lett. 2005, 7, 2173. (b)
Gansaeuer, A.; Fielenbach, D.; Stock, C.; Geich-Gimbel, D. Adv. Synth.
Catal. 2003, 345, 1017. (c) Grieco, P. A.; Clark, J. D.; Jagoe, C. T. J.
Am. Chem. Soc. 1991, 113, 5488. (d) Nonoshita, K.; Banno, H.;
Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316.
(43) For the [1,3] sigmatropic rearrangement of the corresponding
allyl vinyl ether, see: Maruoka, K.; Nonoshita, K.; Banno, H.; Yama-
moto, H. J. Am. Chem. Soc. 1988, 110, 7922.
J. Org. Chem, Vol. 70, No. 20, 2005 8101

Wipf et al.
1.5 H, J ) 4.7 Hz), 0.91 (t, 1.5 H, J ) 4.5 Hz); 13C NMR δ
143.8 (2 C), 142.3, 141.9, 139.5, 139.0, 128.4 (4 C), 127.6 (5
C), 127.2, 126.2 (2 C), 114.2, 114.0, 66.6, 66.4, 46.2, 46.1, 43.0,
42.9, 39.2 (2 C), 29.9 (2 C), 22.3 (2 C), 16.5 (2 C), 13.9 (2 C);
MS (EI) m/z (rel intensity) 240 ([M - H2O]+, 34), 201 (30), 183
(62), 155 (16), 117 (100); HRMS (EI) m/z calcd for C18H26O
258.1984, found 258.1982.
Merck Research Laboratories. We thank Dr. Steve Geib
(University of Pittsburgh) for X-ray crystallographic
analysis of 46.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C NMR spectra for all new compounds, and
crystallographic data (CIF) for 46. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work has been supported
by the National Science Foundation (CHE-0315205) and
JO051211V
8102 J. Org. Chem., Vol. 70, No. 20, 2005