Palladium-catalyzed diastereo- and enantioselective Wagner-Meerwein shift: Control of absolute stereochemistry in the C-C bond migration event

Article abstract of DOI:10.1021/ja7111299

Inducing absolute stereochemistry in Wagner-Meerwein shifts was examined in a ring expansion protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities. The results demonstrate that, during the C-C bond migration process, our chiral catalysts can control the stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover, the stereochemical outcome of the reaction can be rationalized very well with the working model of the chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones with an α-chiral O-tertiary center which has various synthetic applications.

Full text of DOI:10.1021/ja7111299

Published on Web 04/23/2008
Palladium-Catalyzed Diastereo- and Enantioselective
Wagner-Meerwein Shift: Control of Absolute Stereochemistry
in the C-C Bond Migration Event
Barry M. Trost* and Jia Xie
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received December 24, 2007; E-mail: bmtrost@stanford.edu
Abstract: Inducing absolute stereochemistry in Wagner-Meerwein shifts was examined in a ring expansion
protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring
expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities.
The results demonstrate that, during the C-C bond migration process, our chiral catalysts can control the
stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover,
the stereochemical outcome of the reaction can be rationalized very well with the working model of the
chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones
with an R-chiral O-tertiary center which has various synthetic applications.
Scheme 1. Palladium-Catalyzed Enantioselective
Wagner-Meerwein Shift of Cyclobutanols
Introduction
The Wagner-Meerwein shift is a classical intramolecular
rearrangement that involves first the generation of a carbocation
which is then followed by a 1,2 C-C bond migration.1 Inducing
absolute stereochemistry in such a process is a formidable
objective in that it requires the differentiation of the prochiral
faces of the carbocation (eq 1).2
Asymmetric metal complex cations as in the case of π-al-
lylmetal cations offer a strategy to achieve this objective, as
shown in Scheme 1.3 For substrates such as I, the π-allylpal-
ladium intermediate was generated by the ionization of the
allylic leaving group in a process analogous to the palladium-
catalyzed asymmetric allylic alkylation (AAA) reactions.4 With
our chiral ligands L1-L4(Scheme 1), the first enantioselective
Wagner-Meerwein shift was developed in a ring expansion
protocol.2
Scheme 2. Palladium-Catalyzed AAA Reaction with the Allene by
Hydropalladation
Recently, utilizing the hydropalladation of allenes to generate
the π-allylpalladium intermediates has allowed the development
(1) For an overview of Wagner–Meerwein shift and related reactions, see:
ComprehensiVe Organic Synthesis, Vol. 3; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Hanson, J. R., Chapter
3.1, pp 705–720; Rickborn, B., Chapter 3.2, pp 721–732 and Chapter
3.3, pp 733–776; Coveney, D. J., Chapter 3.4, pp 777–802.
(2) Trost, B. M.; Yasukata, T. J. Am. Soc. Chem. 2001, 123, 7162–7163.
(3) Leading reviews of reactions involving chiral π-allylmetal cations.
For Pd, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996,
96, 395–422. (b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14.
For Mo, see: (c) Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37,
159–167. For Cu, see: (d) Yorimitsu, H.; Oshima, K. Angew Chem.,
Int. Ed. 2005, 44, 4435–4439. For Rh, see: (e) Evans, P. A.; Leahy,
D. K Chemtracts 2003, 16, 567–578.
of Pd AAA reactions with allenes (Scheme 2).5–7 With catalytic
amounts of palladium and acid, this reaction is marked with
simplicity, synthetic efficiency, and high level of atom
economy.8
The ease of metalation of the allene 1, which then provides
easy access to the carbinols II (Scheme 3), suggested the
feasibility of a ring expansion protocol.9 Given our success in
asymmetric intermolecular allylations, the intriguing question
(4) For reviews of Pd AAA reactions, see: (a) Trost, B. M. J. Org. Chem.
2004, 69, 5813–5837. (b) Trost, B. M.; Crawley, M. L. Chem. ReV.
2003, 103, 2921–2943.
9
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 6231–6242 6231

A R T I C L E S
Trost and Xie
Scheme 3. Palladium-Catalyzed Asymmetric Wagner-Meerwein Shift of Allenylcyclobutanols
Scheme 4. Designed Reaction Scope
of whether such a method of generating the π-allylpalladium
complex could induce an asymmetric Wagner-Meerwein shift
arises.
types of allenylcyclobutanols, A and B (Scheme 4). Ring
expansion of type A substrates allowed us to examine the
enantioselectivity, the functional group compatibility on the
allene side chain, and the effect of substituents on the ring. A
number of issues arise with type B substrates, the first being
the question of cis/trans isomers. Further, the ring expansion
creates two stereogenic centers; therefore, both the diastereo-
selectivity and the enantioselectivity must be examined.
To synthesize type A substrates, we first prepared allenes with
different alkoxy groups, 1a-1h, by the isomerization of
propargyl ethers catalyzed by t-BuOK at room temperature
(Scheme 5). Cyclobutanone is commercially available. Substi-
In the case of substrates such as II, where R′ * H, the two
bonds that can undergo migration are diastereotopic in nature,
and, as a result, a second stereogenic center can be generated
in the product. To the best of our knowledge, there are very
limited literature examples of diastereo- and enantioselective
bond migration events mediated by asymmetric catalysis.10 Since
the bond migration occurs outside the coordination sphere of
the metal, the ability for chiral ligands on the palladium to affect
the stereochemistry with respect to the prochiral migrating
groups seems remote. Nevertheless, our success in inducing
stereochemistry of prochiral nucleophiles motivated us to
consider such a possibility.11 However, given that the exact
nature of the ion pair plays an important role in the chiral
recognition, the question arises whether this analogy to a
migrating event which lacks such ion pair character and structure
is appropriate.
With this challenge in mind, we decided to fully explore the
diastereoselectivity and enantioselectivity of the process not only
because of the uniqueness of the mechanism but also because
of potential synthetic applications that may arise from this
methodology. The ring expansion reaction will provide an
efficient way to synthesize highly substituted chiral cyclopen-
tanones with R-chiral O-tertiary centers.
(6) For generation of hydriometal species from protonation, see: Trost,
B. M. Chem. Eur. J. 1998, 4, 2405–2412.
(7) For hydropalladation of allenes, see: (a) Yamamoto, Y.; Al-Masum,
M.; Asao, N. J. Am. Soc. Chem. 1994, 116, 6019–20. (b) Yamamoto,
Y.; Al-Masum, M. Synlett 1995, 969–970. (c) Yamamoto, Y.; Al-
Masum, M.; Fujiwara, N. Chem. Commun. 1996, 381–382. (d) Meguro,
M.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 7453–
7456. (e) Trost, B. M.; Michellys, P.-Y.; Gerusz, V. J. Angew. Chem.,
Int. Ed. 1997, 36, 1750–1753. (f) Trost, B. M.; Jaekel, C.; Plietker,
B. J. Am. Soc. Chem. 2003, 125, 4438–4439. (g) Trost, B. M.; Simas,
A. B. C.; Plietker, B.; Jakel, C.; Xie, J. Chem. Eur. J. 2005, 11, 7075–
7082. (h) Trost, B. M.; Xie, J. J. Am. Soc. Chem. 2006, 128, 6044–
45.
(8) For reviews of atom economy, see: (a) Trost, B. M. Science 1991,
254, 1471–7. (b) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–
81. (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
(9) For references of ring expansion reactions involving π-allylpalladium
intermediates with achiral ligands, see: (a) Jeong, I.-Y.; Nagao, Y.
Tetrahedron Lett. 1998, 39, 8677–8680. (b) Jeong, I.-Y.; Shiro, M.;
Nagao, Y. Heterocycles 2000, 52, 85–89. (c) Nagao, Y.; Tanaka, S.;
Hayashi, K.; Sano, S.; Shiro, M. Synlett 2004, 481–484. (d) Nagao,
Y.; Tanaka, S.; Ueki, A.; Jeong, I.-Y.; Sano, S.; Shiro, M. Synlett
2002, 480–482. (e) Nagao, Y.; Ueki, A.; Asano, K.; Tanaka, S.; Sano,
S.; Shiro, M. Org. Lett. 2002, 4, 455–457. (f) Nemoto, H.; Yoshida,
M.; Fukumoto, K. J. Org. Chem. 1997, 62, 6450–6451. (g) Yoshida,
M.; Nemoto, H.; Ihara, M. Tetrahedron Lett. 1999, 40, 8583–8586.
(h) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron Lett. 2000, 41,
5089–5092. (i) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron
2002, 58, 7839–7846. (j) Yoshida, M.; Sugimoto, K.; Ihara, M. Org.
Lett. 2004, 6, 1979–1982.
Results and Discussion
Synthesis of Cyclobutanols. To examine the scope and the
different types of selectivities of the reaction, we prepared two
(5) For a recent book and reviews of allene, see: (a) Zimmer, R.; Dinesh,
C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067–3125.
(b) Hashimi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590–3593.
(c) Sydnes, L. K. Chem. ReV. 2003, 103, 1133–1150. (d) Wei, L.-L.;
Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773–782. (e) Tius,
M. A. Acc. Chem. Res. 2003, 36, 284–290. (f) Ma, S. Acc. Chem.
Res. 2003, 36, 701–712. (g) Krause, N.; Hashmi, A. S. Modern Allene
Chemistry; Wiley-VCH: Weinheim, 2004. (h) Hoffmann-Ro¨der, A.;
Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196–1216. (i) Ohno,
H. Chem. Pharm. Bull. 2005, 53, 1211–1226. (j) Ma, S. Chem. ReV.
2005, 105, 2829–2872. (k) Ma, S. Aldrichim. Acta 2007, 40 (4), 91–
102.
(10) For an enantioselective 1,2 C–C bond migration, see: (a) Brunner,
H.; Stohr, F. Eur. J. Org. Chem. 2000, 2777–2786. (b) Reference 2.
(c) Reference 7f. (d) Ooi, T.; Saito, A.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 3220–3221. (e) Ohmatsu, K.; Maruoka, K. J. Am.
Chem. Soc. 2007, 129, 2410–2411.
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Inducing Absolute Stereochemistry in Wagner-Meerwein Shifts
Scheme 5. Preparation of Alkoxyallenes
A R T I C L E S
Table 1. Preparation of 3-Monosubstituted Allenylcyclobutanols
Scheme 6. Preparation of Substituted Cyclobutanones
Scheme 7. Preparation of Allenylcyclobutanols A
tuted cyclobutanones 2a-2n were synthesized via a classical
zinc-catalyzed [2+2] ketene cycloaddition reaction (Scheme 6).
Finally, the addition of allenyllithiums generated from allenes
1a-1h to cyclobutanone and substituted cyclobutanones 2a-2d
furnished the desired type A allenylcyclobutanols 3a-3h and
4a-4d (Scheme 7).
Type B allenylcyclobutanols were prepared via the same
addition reaction. However, the addition of allenes to the
cyclobutanones generated cis/trans isomers. Since it was
anticipated that the cis/trans stereochemistry of the substrates
B might also affect the overall stereochemical outcome (eq 2),
the first challenge became the diastereoselective formation of
the ring expansion substrates B, which were not known in the
literature. However, a couple of examples indicated that
diastereoselective nucleophilic additions to 3-substituted cy-
clobutanones were possible.12
a Method X: Benzyloxyallene was deprotonated with n-BuLi at
-78 °C, followed by addition of cyclobutanones. Method Y:
Benzoxyallene was deprotonated with n-BuLi at -78 °C, followed by
the addition of 1 equiv of Et2Zn at 0 °C, and the reaction was stirred at
0 °C for 15 min. The solution was then cooled to -78 °C, followed by
the addition of cyclobutanones. b Isolated yield of the mixture of
diastereomers. c The diastereomer ratio (d.r.) values were determined by
1H NMR.
tion of lithiated benzoxyallene 1 with a variety of differently
substituted cyclobutanones 2e-2n (Table 1).
Our results indicated that when bulky substituents were
present at the 3-position of the cyclobutanones (entries 1–5),
addition of the allenyllithium (method X) led to reactions with
high diastereoselectivity (10:1–14:1). On the other hand, less
sterically demanding groups at the 3-position (entries 6–10) gave
(11) (a) Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174–184.
(b) Trost, B. M.; Xu, J. J. Am. Soc. Chem. 2005, 127, 17180–17181.
(c) Trost, B. M.; Xu, J. J. Am. Soc. Chem. 2005, 127, 2846–2847.
(12) (a) Lampman, G. M.; Hager, G. D.; Couchman, G. L. J. Org. Chem.
1970, 35, 2398–402. (b) Sieja, J. B. J. Am. Soc. Chem. 1971, 93, 130–
136. (c) Elgomati, T.; Gasteiger, J.; Lenoir, D.; Ugi, I. Chem. Ber.
1976, 109, 826–832. (d) Jain, R.; Sponsler, M. B.; Coms, F. D.;
Dougherty, D. A. J. Am. Soc. Chem. 1988, 110, 1356–1366. (e)
Dehmlow, E. V.; Bueker, S. Chem. Ber 1993, 126, 2759–2763. (f)
Gil, R.; Fiaud, J.-C. Bull. Soc. Chim. Fr. 1994, 131, 584–589.
To begin these studies, we chose 3-monosubstituted cyclobu-
tanones 2e-2n because we believed they would result in better
diastereoselectivity in the addition reaction. The 3-monosub-
stituted allenylcyclobutanols 4e-4n were synthesized by reac-
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A R T I C L E S
Trost and Xie
Table 2. Control Experimentsa
Table 4. Enantioselective Wagner-Meerwein Shifta
Pd2dba3 ·
CHCl3
temp
(°C)
ee
(%)c
entry
(R,R)-L1
additives
conv (%)b
1
2
3
4
none
none
none
none
none
10 mol% HOAc
60 <5
60 ∼10
60 ∼10
60 100
n.d.
n.d.
n.d.
74
5 mol% 7.5 mol% none
5 mol% 7.5 mol% 10 mol% HOAc
(85% yield)
30 ∼50
(20% yield)
5 mol% 7.5 mol% 10 mol% PhCO2H + 60 100
5
6
5 mol% 7.5 mol% 10 mol% HOAc
n.d.
83
10 mol% Et3N
(95% yield)
7d 5 mol% 7.5 mol% 10 mol% PhCO2H + 30 ∼70
85
10 mol% Et3N
(35% yield)d
a Unless otherwise indicated, all reactions were performed in
dichloroethane on a 0.2 mmol scale at 0.1 M for 24 h. b Determined by
1H NMR. c The enantiomeric excess (ee) values were determined by
chiral HPLC. d Isolated 35% desired product with other possible
products from hydrolysis of 3a.
Table 3. Optimization of Ring Expansion Reactionsa
entry
ligand
solvent
temp (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
DCE
DCE
DCE
DCE
DMSO
DMF
CH3CN
dioxane
THF
DME
DCE
DCE
60
60
60
60
60
60
60
60
60
60
40
30
23
30
95
86
90
75
41
85
63
40
90
89
90
75
60
96
83
57
87
84
64
79
82
80
80
81
88
92
94
92
9
10
11
12
13d
14d
DCE
DCE
a Unless otherwise indicated, all reactions were performed on a 0.5
mmol scale at 0.1 M for 12 h at 23 °C using L3. b Method A:
performed at 30 °C using L3. Method B: performed at 60 °C using L4.
c Isolated yield. d Unless otherwise indicated, ee values were determined
by chiral HPLC. e Ee values were determined by chiral GC.
a Unless otherwise indicated, all reactions were performed on a 0.2
mmol scale at 0.1 M for 2-24 h. b Isolated yield. c The ee values were
determined by chiral HPLC. d Adding 4 Å molecular sieves.
reactions of moderate diastereoselectivity (∼4.0:1) with method
X. In all cases, diastereomerically enriched compounds could
be accessed via the removal of the minor diastereomers by silica
gel chromatography. Although the yields of these addition
reactions were generally high, significantly lower yields were
encountered with substrates bearing ester functionality, presum-
ably due to its susceptibility to nucleophilic attack by the
allenyllithium.
able. To the best of our knowledge, this reaction is the first
example utilizing a lithium zincate complex to improve the
chemo- and diastereoselectivity of nucleophilic addition to
substituted cyclobutanones.13
Rearrangement of Type A Cyclobutanols (R1 ) R2).
To mitigate the reactivity of the nucleophile, the allenyllithium
was replaced with a lithium zincate complex generated from
the allenyllithium and diethylzinc. We were pleased to find that
the addition reaction to cyclobutanones with this zincate
complex (method Y) had greater tolerance for ester groups as
well as provided greater diastereoselectivities (entries 6–10,
method Y) than the analogous reactions with allenyllithium
(method X).
The enhancement of the diastereoselectivity in the addition
was presumably due to the greater steric demands of the
allenyllithium zincate complexes compared to the simple
allenyllithium reagent, which made trans addition more favor-
To study the enantioselectivity of the ring expansion reaction,
we began with the optimization of the reaction conditions by
using benzyloxyallenylcyclobutanol 3a. Control experiments in
Table 2 showed the lack of a background reaction even at 60 °C
(entry 1). Furthermore, with either the palladium catalyst or the
acid, the reaction times were very long and resulted in low
(13) For a review of lithium zincate complexes, see: Wheatley, A. E. H.
New. J. Chem. 2004, 28, 435–443.
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Inducing Absolute Stereochemistry in Wagner-Meerwein Shifts
A R T I C L E S
Scheme 8. Assignment of the Absolute Configuration and Synthetic Applications
Scheme 9. Ligand Control vs Substrate Control
conversion (entries 2 and 3). Gratifyingly, when both palladium
and acid were present (entry 4), the reaction proceeded to full
conversion at elevated temperature, which is consistent with
the hydropalladation mechanism which requires both the pal-
ladium and the acid.14
Interestingly, the combination of acid and base, for example
benzoic acid and triethylamine, gave the best reactivity and
enantioselectivity compared to other additives (entries 6 and
7). This result is consistent with our earlier results on the
intermolecular nucleophilic addition of benzyloxyallene 1a,
where controlling the pH is essential for good reactivity and
selectivity.7g With benzoic acid and triethylamine as the
additives, we further optimized the reaction conditions by
varying ligands, solvents, and reaction temperatures (Table 3).
The optimized reaction conditions afforded the ring expansion
product 5a in a rather impressive 96% yield and 92% ee (entry
14).
We subjected substrates 3a-3f to the optimized reaction
conditions. As summarized in Table 4, the reaction was shown
to be very general and gave excellent enantioselectivities as well
as great functional group tolerance, including benzyl (entry 1),
4-methoxybenzyl (entry 2), alkyl (entry 3), alkene (entries 4
and 5), and alkyne (entry 6). These results potentially provide
several approaches for further functionalization, and thereby the
ability to access different synthetic targets. For example, ring
expansion products 5e and 5f were utilized to prepare chiral
[4,5] and [4,6] spiro-ring systems such as 5 and 6 via a ring-
closing metathesis (eq 3).
that of the unsubstituted cyclobutanols, and lower conversions
were obtained at 30 °C. Raising the reaction temperature to
60 °C drove the reaction to completion, albeit with 10–20%
decrease in ee using L3. Switching to ligand L4 allowed the
ring expansion of 3,3-disubstituted allenylcyclobutanols 4a-4d
to be performed at 60 °C with increased reactivity and excellent
enantioselectivities. It can be postulated that the rigid backbone
of L4 compared to L3 makes the enantioselectivity less
dependent on the reaction temperature (entries 7–10).
The absolute configuration of the benzyloxy stereocenter was
assigned by converting ring expansion product 5b to 9 (Scheme
8), a known compound whose asymmetric synthesis depended
upon a chiral auxiliary. This compound can serve as a useful
intermediate for synthesizing natural products, for example,
bisabolangelone and trans-kumausyne.15,16
In order to examine the concept of ligand control vs substrate
control, we synthesized allenylcyclobutanol substrates 3g and
3h, both of which had a chiral alkoxy group on the allene side
chain. As shown in Scheme 9, the stereochemical induction in
the ring expansion was controlled by our chiral ligands with
both enantiomers 3g and 3h. Consequently, the chiral side chains
had only a slight impact on the stereochemical induction; for
example, enantiomer 3g, which had an alkoxy group with the
(R) configuration on the side chain, reacted with (R,R)-L3 to
give a 15:1 dr, compared to a 12:1 dr when (S,S)-L3 was
employed (Scheme 9). Enantiomer 3h, which had an alkoxy
group with (S) configuration on the side chain, gave identical
results. For comparison, use of rac-L3 gave a 1.2:1 dr.
Rearrangement of Type B Cyclobutanols (R1 * H, R2 ) H).
We also studied substrates with substituents on the cyclobu-
tanol rings, such as 3,3-disubstituted allenylcyclobutanols 4a-4d
(entries 7–10). It was found that their reactivity was poorer than
After examining the enantioselectivity in the ring expansion
reaction, we moved toward examining both diastereo- and
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A R T I C L E S
Trost and Xie
Table 5. Diastereo- and Enantioselective Wagner-Meerwein
6), and ester (entries 5, 7–10), and gave high diastereoselec-
tivities and enantioselectivities in most cases.
Shifta
Since the diastereomeric mixtures resulting from allene
additions were not completely separable, the subsequent ring
expansions were conducted with the enriched diastereomeric
ratio of allenylcyclobutanols obtained after silica gel chroma-
tography. Although the enantioselectivities were independent
of the ratio of starting material isomers, the diastereomeric ratios
were generally lower than those of the starting materials. This
phenomenon could be understood more easily by examining
the ring expansion of each diastereomer individually. Toward
this end, diastereomers 4j and 4j′ were fully separated and
subjected to the reaction conditions. The ring expansion of the
major isomer 4j gave a 10:1 dr, favoring diastereomer 6j (Table
5, entry 6), whereas the ring expansion of the minor isomer 4j′
gave a 20:1 dr, favoring diastereomer 6j′ (eq 5). The rationale
for a different diastereomeric ratio and diastereomeric outcome
will be discussed in the section on mechanism.
The ester side chains in cyclopentanones 6i and 6m were
utilized in a Claisen condensation to produce 5,5-cis and 5,6-
cis bicyclic products 11 and 12. Methylation of 12 from the
convex face led to cis product 13 (Scheme 10). The structures
of the bicyclic products were assigned on the basis of NOE
study and X-ray single-crystal analysis of product 11, which
also confirmed the absolute configuration of the ring expansion
products (Figure 1).
Figure 1. X-ray structure of 11 showing relative configuration. The standard
deviation of an observation of unit weight (S)7 was 0.962. Disorder was
encountered with vinyl group (C12a and C12b). Hydrogen on C11 could
not be located due to disorder.
a Reactions were performed on a 0.2–0.5 mmol scale at 0.1 M
overnight. b Reactions were run with mixture of diastereomers, the ration
of which are shown following the substituents. Structures shown are the
major diastereomers. c Isolated yield of the major isomers. d The dr
values were determined by 1H NMR. e Ee values were determined by
chiral HPLC analysis.
Scheme 10. Formation of 5,5- and 5,6-Bicyclic Compounds
enantioselectivity in the reaction with the 3-monosubstituted
allenylcyclobutanols, as shown in eq 4. The reaction scope of
the ring expansion reaction was examined with substrates 4e-4n
as listed in Table 5. The reaction tolerated a variety of structural
types, including aryl (entries 1–3), alkyl (entry 4), ether (entry
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Inducing Absolute Stereochemistry in Wagner-Meerwein Shifts
A R T I C L E S
Scheme 11. Proposed Working Model for the Enantioselectivity
Chart 1
Mechanistic Considerations. The absolute stereochemistry we
obtained with our chiral catalyst could be rationalized very well
on the basis of our proposed working model in Scheme 11.17,18
The hydropalladation of the allenylcyclobutanol (Chart 1) can
occur from either the top or the bottom face of the allene, leading
to the formation of η1 π-allylpalladium intermediate 14 or 15,
respectively. Coordination of the palladium to the two π-faces
of the double bond will lead to the formation of either the
matched or mismatched π-allylpalladium intermediate. Inter-
mediate 14 can lead to the formation of syn π-allylpalladium
intermediates 16 and 17. Alternatively, 15 can lead to anti
π-allylpalladium intermediates 18 and 19. Among the four
possible π-allylpalladium intermediates, 16 and 18 are disfa-
vored due to the unfavorable steric interactions between the
bulky cyclobutyl groups and the phenyl ring of the chiral ligand.
Instead, 17 and 19 are preferred because the cyclobutyl groups
are under the flap, thus avoiding the unfavorable steric interac-
tions. Ring expansion of both intermediates 17 and 19 would
lead to the major enantiomer with (R) configuration. However,
according to our previous results, when bulky groups such as a
cyclobutyl group are present on the terminal position, they
preferred to adopt the anti position relative to the C2-H to avoid
1,2-steric interactions.2 This suggests that intermediate 19 is
the favored intermediate overall. Therefore, intermediate 19
should primarily be responsible for the stereochemical outcome
of the reaction. As a result, the enantiomer obtained from the
reaction indeed had an (R) configuration, which was consistent
with the prediction of our working model.
For the 3-monosubstituted cyclobutanol substrates, the dias-
tereoselectivity could also be rationalized by the working model
shown in Scheme 12. As discussed in Scheme 11, four possible
π-allylpalladium intermediates could be generated in the hy-
dropalladation step. The most favored one is intermediate 17,
in which the bulky cyclobutyl group possessed the anti
arrangement relative to the C2-H and located under the flap.
Therefore, hydropalladation of substrates 20 and 21should lead
to intermediates analogous to those shown in Scheme 11.
Because of the 3-substituents, the bonds a and b undergoing
migration are now diastereotopic. Stereoelectronic consideration
suggests that the migration event should occur in an antiperipla-
nar fashion such that the bond that undergoes migration should
be anti relative to the palladium, i.e., bond a in 22 and 25 and
bond b in 23and 24. Only two orientations of the cyclobutanol
(14) Reaction can proceed with Lewis Acid catalysis; for example, Au can
catalyze similar reactions, see: Yeom, H.-S.; Yoon, S.-J.; Shin, S.
Tetrahedron Lett. 2007, 48, 4817–4820.
(15) Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.;
Hutchinson, K. D.; Overman, L. E.; Mishra, P. J. Am. Soc. Chem.
1991, 113, 5365–5378.
(16) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Soc. Chem. 1991,
113, 5378–5384.
(17) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,
39, 747–760.
(18) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545–4554.
9
J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008 6237

A R T I C L E S
Trost and Xie
Scheme 12. Proposed Working Model for the Diastereo- and Enantioselectivity
Chart 2
will then lead to the migration of bonds a and b. For the major
addition isomer 20, the favored π-allylpalladium intermediate
can adopt orientations, such as 22 and 23, where they will lead
to the migration of bonds a and b, respectively. However, in
orientation 23, the bulky cyclobutyl group has a strongly
disfavored interaction with the C3-H which is absent in
orientation 22. Thus, 22 is the favored orientation which leads
to the migration of bond a and the major diastereomer 26.
Similarly, for the minor addition isomer 21, 25 would be the
favored orientation and would lead to the migration of bond a,
thus leading to the minor diastereomer 27.
diastereoselectivity and led to the creation of two new stereo-
genic centers in the products. The method provides a general
way to synthesize highly substituted chiral cyclopentanones
which should have useful synthetic applications. By incorporat-
ing an ester side chain in the ring expansion products, 5,5-cis
and 5,6-cis bicyclic compounds were readily accessed as single
diastereomers by an intramolecular condensation reaction. The
rationalization for diastereoselectivity and enantioselectivity of
the reaction using our proposed working model were consistent
with experimental results.
Experimental Section22,23
Not only are the major diastereomers from different cis/trans
isomers 20 and 21 different (Chart 2), but also the diastereomeric
ratio of the products would be different. For the disfavored
orientations 23 and 24, the latter should be a higher energy
intermediate than the former due to stronger steric interaction
between the R group (R * H) and C3-H. The favored
orientations 22 and 25 should have similar stabilities due to
the absence of significant steric interactions. Therefore, the
energy difference between 24 and 25 should be higher than the
one between 22 and 23. As a result, the diastereomeric ratio
for the ring expansion of the minor isomer 21 should be higher
than for the major addition isomer 20. Indeed, this is observed
in the independent ring expansions of 4j and 4j′, wherein ring
expansion of the major isomer 4j gave a 10:1 dr, favoring
diastereomer 6j (Table 4, entry 6), and ring expansion of the minor
isomer 4j′ gave a 20:1 dr, favoring diastereomer 6j′ (eq 5).
General Procedure for Preparation of Allenyl Ethers
1a-1g. Propa-1,2-dienyloxymethyl-benzene (1a).7g
At room temperature, KOtBu (4.3 g, 38.3 mmol) was added into
a solution of benzylpropargyl ether (22 g, 130 mmol) in THF (10
mL). The suspension was stirred at room temperature for 3 h,
filtered through a Celite pad, and washed with Et2O (50 mL). The
combined solution was concentrated in vacuo and purified by flash
chromatography (1% diethyl ether in petroleum ether) to afford 1a
as a light yellowish liquid. Yield: 18 g (82%).
Rf (5% ether/petroleum ether): 0.84. IR (neat): 3034, 2925, 2868,
1953, 1726, 1454, 1442, 1349, 1190, 1043, 893, 737, 698 cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.85 (dd, J )
6.3 Hz, 1H), 5.48 (d, J ) 6.1 Hz, 2H), 4.62 (s, 2H). 13C NMR (75
MHz, CDCl3): δ 132.0, 128.2, 123.5, 123.3, 123.1, 118.3, 101.1,
81.8, 66.1, 48.1, 24.8, 23.9, 17.0.
Conclusion
In summary, by applying hydropalladation of allenes, we were
able to develop the first asymmetric Wagner-Meerwein shift
of allenylcyclobutanol substrates with our palladium catalysts.
Diastereoselective preparation of 3-monosubstituted substrates
via a novel lithium zincate addition allowed us to examine the
((R)-1-Propa-1,2-dienyloxy-ethyl))-benzene (1g).
9
6238 J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008

Inducing Absolute Stereochemistry in Wagner-Meerwein Shifts
A R T I C L E S
Allenyl ether 1g was prepared according to the general procedure
starting from (R)-1-(prop-2-ynyloxy)-ethyl benzene (2.0 g, 12.5
mmol). Yield: 1.4 g (70%, 80% brsm), recovered 0.20 g of starting
material.
the purification was done with flash chromatography. Yield: 3.0 g
(55%, 70% brsm), recovered starting material 0.63 g.
Rf (50% ether/petroleum ether): 0.58. IR (neat): 2963, 1785, 1735,
1469, 1438, 1391, 1326, 1288, 1239, 1210, 1156, 1112, 1047, 1015,
885, 856, 760 cm-1. 1H NMR (500 MHz, CDCl3): δ 3.55 (s, 3H),
2.84–2.74 (m, 4H), 2.43–2.38 (m, 1H), 2.15 (s, 2H), 0.94 (s, 6H).
13C NMR (125 MHz, CDCl3): δ 206.6, 171.8, 51.1, 47.3, 44.7,
34.1, 33.1, 23.1. HRMS (EI+): m/z calcd for C10H16O3, 184.1099
([M]+); found, 183.1013 (M - H]+), 169.0867 ([M - CH3]+).
3-Benzyloxymethyl-cyclobutanone (2j).21
Rf (10% ether/petroleum ether): 0.80. IR (neat): 3064, 3031, 2977,
1953, 1494, 1449, 1273, 1349, 1196, 1068, 1028, 890, 854, 760,
1
697, 668 cm-1. H NMR (500 MHz, CDCl3): δ 7.34-7.24 (m,
5H), 6.22 (t, J ) 6.0 Hz, 1H), 5.34 (m, 1H), 5.21 (m, 1H), 4.80 (q,
J ) 6.5 Hz, 1H), 1.51 (m, 3H). 13C NMR (125 MHz, CDCl3): δ
201.9, 143.1, 128.3, 127.4, 126.0, 120.1, 90.1, 76.6, 23.3, [R]D24.1
) 218.8 (c ) 1.40, CH2Cl2). Anal. Calcd for C14H16O2: C, 82.46;
H, 7.55. Found: C, 82.59; H, 7.52.
General Procedure for Preparation of Substituted
Cyclobutanones 2a-2n. The general procedure involved a zinc-
catalyzed ketene [2+2] reaction followed by zinc-catalyzed deha-
logenation reduction.19
Cyclobutanone 2j was prepared according to the general
procedure for preparation of substituted cyclobutanones staring from
allyloxymethyl-benzene (5.50 g, 37.1 mmol). Yield: 6.0 g (58%)
over two steps.
3,3-Diphenyl-cyclobutanone (2a).20
Rf (25% ether in petroleum ether): 0.40. IR (neat): 3031, 2857,
1782, 1496, 1454, 1383, 1365, 1206, 1093, 1028, 738, 698 cm-1
.
1H NMR (500 MHz, CDCl3): δ 7.37–7.25 (m, 5H), 4.55 (s, 2H),
3.58 (d, J ) 6.5 Hz, 2H), 3.15–3.08 (m, 2H), 2.90–2.84 (m, 2H),
2.72–2.64 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 207.4, 137.9,
128.4, 127.7, 127.6, 73.1, 72.8, 49.9, 23.5.
Zinc-Catalyzed Ketene [2+2] Reaction. To a stirred suspension
of activated Zn-Cu19 (4.90 g, 75 mmol) and ethene-1,1-diyldiben-
zene (5.41 g, 30 mmol) in dry Et2O (70 mL) was added dropwise
through an addition funnel, during 2 h at reflux, a solution of
trichloroacetic chloride (6.7 mL, 60 mmol) and phosphorus oxy-
chloride (5.7 mL, 60 mmol) in Et2O (30 mL). The suspension was
stirred overnight at reflux. The mixture was cooled to room
temperature and then filtered through a pad of Celite. The residue
was washed with Et2O (3 × 15 mL). The combined solution was
concentrated and then distilled in a Kugelrohr short-path distillation
apparatus (200-250 °C, 0.2 mTorr). The collected liquid was
directly taken to the next step.
Zinc-Catalyzed Dehalogenation Reduction. The solution of the
previous liquid in acetic acid (25 mL) was added dropwise to a
vigorously stirred suspension of zinc dust (7.84 g, 120 mmol) in
acetic acid (25 mL) at 0 °C. After the addition, the reaction mixture
was heated at 70 °C for 2 h. The mixture was allowed to cool to
room temperature and then evacuated to get rid of most of the acetic
acid. The residue was dissolved in Et2O (50 mL) and then poured
into a separation funnel containing water (50 mL) and Et2O (50
mL). The organic layer was washed with water (3 × 25 mL),
saturated sodium bicarbonate solution (2 × 30 mL), and brine (50
mL) and dried over MgSO4. The solution was then filtered and
concentrated, followed by purification with flash chromatography
(15% ether in petroleum ether). Yield: 3.5 g (61%) over two steps;
white solid; mp ) 76-78 °C.
General Procedure for Preparation of Allenylcyclobutanols
3a-3h. 1-(1-Benzyloxy-propa-1,2-dienyl)-cyclobutanol (3a).
To a stirred solution of benzyloxyallene 3a (1.46 g, 10.0 mmol)
in THF (40 mL) was added dropwise a 2.70 M solution of n-BuLi
(3.70 mL, 10.0 mmol) in hexane at -78 °C. After stirring was
continued for 1 h at -78 °C, cyclobutanone (0.75 mL, 10.0 mmol)
was added dropwise to this solution, and stirring was continued
for 2 h at -78 °C. The solution was then warmed to room
temperature. The reaction mixture was diluted with water (20 mL)
and extracted with diethyl ether (3 × 15 mL). The combined
extracts were washed with brine, dried over Mg2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (15% diethyl ether in petroleum ether, silica gel) to give
allenylcyclobutanol 3a as a white solid. Yield: 2.05 g (95%); mp
) 43-45 °C.
Rf (25% ether/petroleum ether): 0.30. IR (neat): 3420, 3089, 3062,
3035, 2981, 2936, 2864, 1952, 1495, 1450, 1374, 1244, 1177, 1136,
1
1096, 1024, 980, 953, 885, 850, 809, 728, 693 cm-1. H NMR
(400 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 5.58 (s, 2H), 4.67 (s,
2H), 2.67 (s, 1H), 2.37-2.37 (m, 2H), 2.22-2.14 (m, 2H),
1.82-1.73 (m, 1H), 1.61-1.50 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 196.3, 137.5, 135.8, 128.4, 127.9, 127.8, 92.6, 73.8, 71.0,
34.6, 12.8. HRMS (EI+): m/z calcd for C14H16O2, 216.1150 ([M]+);
found, 216.1148.
Rf (25% ether/petroleum ether): 0.53. IR (neat): 3082, 3026, 2972,
2924, 1787, 1595, 1580, 1493, 1449, 1375, 1239, 1127, 1084, 1022,
888, 777, 750, 710, 660, 584, cm-1. 1H NMR (500 MHz, CDCl3):
δ 7.35-7.26 (m, 8H), 7.24-7.21 (m, 2H), 3.82 (s, 4H). 13C NMR
(125 MHz, CDCl3): δ 205.6, 147.2, 130.3, 128.6, 126.6, 60.5, 42.0.
3-Methyl-3-(3-oxo-cyclobutyl)-butyric Acid Methyl Ester
(2i).
1-[1-(1-(R)-Phenyl-ethoxy)-propa-1,2-dienyl]-cyclobutanol
(3g).
Allenylcyclobutanol 3g was prepared according to the general
procedure for preparation of allenylcyclobutanols starting from
allenyl ether 1g (0.65 g, 4.06 mmol) and cyclobutanone (1.5 mL,
4.05 mmol). Yield: 0.85 g (92%).
(21) Rammeloo, T.; Stevens, C. Chem. Commun. 2002, 3, 250.
(22) Some experimental details have been described: Trost, B. M.; Xie, J.
J. Am. Soc. Chem. 2006, 129, 6044–6045.
(23) Crystallographic data for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC-655683 (7). Copies of the data can
be obtained free of charge on application to CCDC, 12 Union Rd.,
Cambridge CB21EZ, UK (fax +44 1223-336-033; E-mail
data_request@ccdc.cam.ac.uk).
Cyclobutanone 2i was prepared according to the general proce-
dure for preparation of substituted cyclobutanones starting from
methyl 3,3-dimethylpent-4-enoate (4.21 g, 29.6 mmol), except that
(19) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879.
(20) Cao, W.; Erden, I.; Grow, R. H.; Keeffe, J. R.; Song, J.; Trudell, M. B.;
Wadsworth, T. L.; Xu, F.; Zheng, J. Can. J. Chem. 1999, 77, 1009.
9
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A R T I C L E S
Trost and Xie
3-Benzyloxymethyl-1-(1-benzyloxy-propa-1,2-dienyl)-cyclo-
butanol (4j). Method B. To a stirred solution of benzyloxyallene
(146 mg, 1.0 mmol) in THF (7 mL) was added dropwise a 2.50 M
solution of n-BuLi (0.40 mL, 1.0 mmol) in hexane at -78 °C.
Stirring was continued for 1 h at -78 °C, and then the solution
was warmed to 0 °C and a 1.0 M solution of Et2Zn in hexane (1.0
mL, 1.0 mmol) was added. The resulting solution was stirred at
0 °C for 15 min and cooled to -78 °C, followed by the addition of
a solution of cyclobutanone 2j (190 mg, 1.0 mmol) in THF (3 mL),
and stirring was continued for 2 h at -78 °C. The solution was
then warmed to room temperature. The reaction mixture was diluted
with saturated NH4Cl (10 mL) and extracted with diethyl ether (3
× 5 mL). The combined extracts were washed with brine (10 mL),
dried over Mg2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (30% diethyl ether in
petroleum ether, silica gel) to give allenylcyclobutanol 4j as a
yellowish oil. Reaction dr ) 10:1 (by 1H NMR). Isolated yield of
Rf (25% ether/petroleum ether): 0.35. IR (neat): 3424, 3086, 3063,
3031, 2977, 2943, 1954, 1494, 1450, 1372, 1244, 1206, 1181, 1133,
1
1091, 1028, 956, 910, 885, 760, 731, 699, 546 cm-1. H NMR
(500 MHz, CDCl3): δ7.33-7.23 (m, 5H), 5.47 (d, J ) 7.8 Hz,
1H), 5.30 (d, J ) 7.8 Hz, 1H), 4.85 (q, J ) 6.5 Hz, 1H), 2.70
(broad, 1H), 2.32-2.26 (m, 2H), 2.20-2.14 (m, 2H), 1.77-1.71
(m, 1H), 1.52 (d, J ) 6.5 Hz, 3H), 1.54-1.46 (m, 1H). 13C NMR
(125 MHz, CDCl3): δ 196.9, 143.3, 134.2, 128.2, 127.3, 125.8,
91.9, 76.1, 73.6, 34.5, 34.2, 23.2, 12.6. [R]2D4.8 ) 154.6 (c ) 2.30,
CH2Cl2). HRMS (EI+): m/z calcd for C15H18O2, 230.1307 ([M]+);
found, 230.1310.
1-(1-Benzyloxy-propa-1,2-dienyl)-3-phenyl-cyclobutanol (4e).
1
the major isomer 4j: 269 mg (80%), dr > 20:1 (by H NMR).
Major diastereomer 4j.
Method A. To a stirred solution of benzyloxyallene (161 mg,
1.1 mmol) in THF (7 mL) was added dropwise a 2.43 M solution
of n-BuLi (0.45 mL, 1.1 mmol) in hexane at -78 °C. After stirring
was continued for 1 h at -78 °C, a solution of cyclobutanone 2e
(146 mg, 1.0 mmol) in THF (3 mL) was added dropwise, and
stirring was continued for 2 h at -78 °C. The solution was then
warmed to room temperature. The reaction mixture was diluted
with water (10 mL) and extracted with diethyl ether (3 × 5 mL).
The combined extracts were washed with brine, dried over Mg2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (20% diethyl ether in petroleum ether, silica
gel) to give the desired allenylcyclobutanol as a yellowish liquid.
Reaction dr ) 14:1 (by 1H NMR). Isolated yield of the major isomer
Rf (50% ether/petroleum ether): 0.53. IR (neat): 3448, 3065, 3033,
2962, 2934, 2875, 1954, 1744, 1498, 1456, 1377, 1287, 1222, 1185,
1130, 1080, 1008, 887, 734, 696 cm-1 1H NMR (500 MHz,
.
CDCl3): δ 7.34–7.26 (m, 10H), 5.57 (s, 2H), 4.67 (s, 2H), 4.51 (s,
2H), 3.47 (d, J ) 6.5 Hz, 2H), 2.98 (s, 1H), 2.54–2.50 (m, 2H),
2.20–2.14 (m, 1H), 1.99–1.95 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 196.1, 138.3, 137.3, 135.7, 128.3, 127.8, 127.7, 127.6,
127.5, 92.7, 74.5, 73.0, 70.9, 70.6, 38.0, 25.9. HRMS (EI+): m/z
calcd for C22H24O3, 336.1725 ([M]+), 245.1178 ([M - Bn]+);
found, 245.1185 ([M - Bn]+). LRMS (ESI+): m/z calcd for
C22H24O3, 359.1 ([M + Na]+); found, 359.1 ([M + Na]+).
Minor diastereomer 4j′.
1
4e: 260 mg (85%), dr ) 15:1 (by H NMR).
Major diastereomer 4e. Rf (50% ether/petroleum ether): 0.60.
IR (neat): 3416, 3028, 2934, 1954, 1603, 1496, 1454, 1378, 1238,
1155, 1094, 1029, 892, 751, 697 cm-1 1H NMR (500 MHz,
.
CDCl3): δ7.38–7.15 (m, 10H), 5.63 (s, 2H), 4.71 (s, 2H), 3.03 (m,
1H), 2.87(s, 1H), 2.82–2.77 (m, 2H), 2.37–2.32 (m, 1H), 0.82 (s,
9H). 13C NMR (125 MHz, CDCl3): δ 196.1, 144.8, 137.2, 135.5,
128.4, 128.2, 127.9, 127.8, 126.6, 125.9, 92.7, 71.0, 69.7, 42.4,
30.6. HRMS (EI+): m/z calcd for C20H20O2, 292.1463 ([M]+);
found, 292.1467. Anal. Calcd for C20H20O2: C, 82.16; H, 6.89.
Found: C, 81.91; H, 7.03.
Rf (50% ether/petroleum ether): 0.45. IR (neat): 3448, 3065, 3033,
2962, 2934, 2875, 1954, 1744, 1498, 1456, 1377, 1287, 1222, 1185,
1130, 1080, 1008, 887, 734, 696 cm-1 1H NMR (500 MHz,
.
CDCl3): δ 7.35–7.26 (m, 10H), 5.51 (s, 2H), 4.64 (s, 2H), 4.48 (s,
2H), 3.42 (d, J ) 7.2 Hz, 2H), 2.73–2.67 (m, 1H), 2.49 (s, 1H),
2.29–2.25 (m, 2H), 2.21–2.17 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 196.3, 138.5, 137.3, 136.6, 128.4, 128.3, 127.8, 127.7,
127.6, 127.5, 93.2, 74.1, 72.9, 72.3, 70.9, 36.5, 26.4. HRMS (EI+):
m/z calcd for C22H24O3, 336.1725 ([M]+); found, 336.1728.
General Procedure for Palladium-Catalyzed Ring Expansion
Reactions. 2-Benzyloxy-2-vinyl-cyclopentanone (5a).
3-[3-(1-Benzyloxy-propa-1,2-dienyl)-3-hydroxy-cyclobutyl]-
3-methyl-butyric Acid Methyl Ester (4i).
Allenylcyclobutanol 4i was prepared according to the general
procedure Method A, starting from the benzoxyallene (715 mg,
4.89 mmol) and cyclobutanone 2i (900 mg, 4.89 mmol). Reaction
1
dr ) 10:1 (by H NMR). Isolated yield of the major isomer 4i:
Dichloroethane (DCE) (25 mL, which was dried and freez-
e–pump–thaw degassed) was added into the mixture of
Pd2(dba)3 ·CHCl3 (65.8 mg, 63.6 µmol) and (R,R)-stilbene ligand
L3 (150.3 mg, 0.191 mmol) within a flask which was three times
evacuated and flushed with argon. The mixture was stirred under
argon at room temperature for 15 min. It was then cannulated into
the allenylcyclobutanol 3a (550 mg, 2.54 mmol) with 4 Å molecular
sieves, three times evacuated and flushed with argon, followed by
addition of PhCO2H (0.2 5 mL, 1 M in CH2Cl2, 0.25 mmol) and
Et3N (0.25 mL, 1 M in CH2Cl2, 0.25 mmol) respectively via syringe.
After stirring under argon at 30 °C for 12 h, the mixture was filtered
through a Celite pad, concentrated, and purified by direct flash
1
1.20 g (75%), dr ) 16:1 (by H NMR).
Major diastereomer 4i. Rf (50% ether/petroleum ether): 0.46.
IR (neat): 3449, 3032, 2954, 1954, 1735, 1452, 1369, 1324, 1235,
1124, 1015, 889, 826, 737, 697 cm-1. 1H NMR (500 MHz, CDCl3):
δ 7.36–7.26 (m, 5H), 5.58 (s, 2H), 4.67 (s, 2H), 3.62 (s, 3H), 2.77
(broad, 1H), 2.27–2.23 (m, 2H), 2.12 (s, 1H), 1.96–1.92 (m, 2H),
1.85–1.79 (m, 2H), 0.95 (s, 6H). 13C NMR (125 MHz, CDCl3): δ
196.1, 172.7, 137.2, 135.6, 128.3, 127.8, 127.7, 92.4, 70.9, 68.8,
51.1, 44.6, 35.8, 35.5, 34.0, 23.6. HRMS (EI+): m/z calcd for
C20H26O4, 330.1831 ([M]+); found, 330.1840. Anal. Calcd for
C20H26O4: C, 72.70; H, 7.93. Found: C, 72.56; H, 7.72.
9
6240 J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008

Inducing Absolute Stereochemistry in Wagner-Meerwein Shifts
A R T I C L E S
chromatography (5% diethyl ether in petroleum ether, silica gel)
to give the desired product 5a (530 mg, 96%). Racemic product
was prepared using the same procedure with racemic standard Trost
ligand L1.
Major diastereomer 6i. Rf (25% ether in petroleum ether): 0.43.
IR (neat): 3089, 3031, 2963, 2877, 1738, 1632, 1610, 1453, 1372,
1328, 1232, 1095, 940, 826, 735, 698 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.34–7.24 (m, 5H), 6.00 (dd, J1 ) 18.2 Hz, J2 ) 10.8
Hz, 1H), 5.45–5.42 (m, 2H), 4.50 (d, J ) 11.6 Hz, 1H), 4.36 (d, J
) 11.4 Hz, 1H), 3.64 (s, 3H), 2.57–2.44 (m, 2H), 2.30–2.25 (m,
1H), 2.22 (s, 2H), 2.04 (dd, J1 ) 18.2 Hz, J2 ) 10.6 Hz, 1H), 1.66
(m, 1H), 1.00 (s, 3H), 0.99 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 212.1, 172.1, 138.3, 134.5, 128.2, 127.43, 127.40, 119.2, 83.5,
66.3, 51.3, 45.0, 41.2, 38.5, 37.2, 34.3, 24.0, 23.9. HRMS (EI+):
m/z calcd for C20H26O4, 330.1831 ([M]+); found, 330.1845. Anal.
Calcd for C20H26O4: C, 72.70; H, 7.93. Found: C, 72.58; H, 8.05.
[R]2D5.2 ) -21.12 (c ) 1.10, CH2Cl2). Enantiomeric excess was
determined to be 88% ee by chiral HPLC (Chiralpak AD, 220 nm,
heptane/i-PrOH ) 99.5:0.5, 220 nm, 1.0 mL/min, t1 ) 21.28 min
(major), t2 ) 24.67 min).
Rf (25% ether/petroleum ether): 0.50. IR (neat): 3085, 3058, 3022,
2958, 2913, 2877, 1746, 1492, 1451, 1401, 1379, 1157, 1130, 1080,
1053, 931, 808, 736, 695, 659 cm-1. 1H NMR (500 MHz, CDCl3):
δ 7.35–7.20 (m, 5H), 5.92 (dd, J ) 17.5 Hz, 11 Hz, 1H), 5.46 (dd,
J ) 11 Hz, 0.9 Hz, 1H), 5.41 (dd, J ) 17.5 Hz, 0.9 Hz 1H), 4.52
(d, J ) 11.5 Hz, 1H), 4.48 (d, J ) 11.5 Hz, 1H), 2.41-2.25 (m,
2H), 2.24-2.18 (m, 1H), 2.14-2.02 (m, 2H), 1.88-1.79 (m, 1H).
13C NMR (125 MHz, CDCl3): δ 196.3, 137.5, 135.8, 128.4, 127.9,
127.8, 92.6, 73.8, 71.0, 34.6, 12.8. [R]2D4.8 ) -68.58 (c ) 1.70,
CH2Cl2). Enantiomeric excess was determined to be 92% ee by
chiral HPLC (Chiralpak OD, heptane/i-PrOH ) 99.5:0.5, 1.0 mL/
min, t1 ) 17.22 min (major), t2 ) 20.25 min). Anal. Calcd for
C14H16O2: C, 77.75; H, 7.46. Found: C, 77.90; H, 7.36.
2-Benzyloxy-4-phenyl-2-vinyl-cyclopentanone (6e).
2-Benzyloxy-4-benzyloxymethyl-2-vinyl-cyclopentanone (6j). Cy-
clopentanone 6j was prepared from allenylcyclobutanol 4j (168 mg,
0.50 mmol) according to the general procedure for ring expansion
with (R,R)-anthracene ligand L4 (30.5 mg, 0.0375 mmol) at 60
1
°C. d.r. ) 10:1 (by H NMR). Isolated yield of the major isomer
6j149 mg (88%), 88% ee.
Major diastereomer 6j.
DCE (2 mL, which was dried and freeze–pump–thaw degassed)
was added into the mixture of Pd2(dba)3 ·CHCl3 (5.2 mg, 5.0 µmol)
and (R,R)-stilbene ligand L3 (11.8 mg, 0.015 mmol) within a flask
which was three times evacuated and flushed with argon. The
mixture was stirred under argon at room temperature for 15 min.
It was then cannulated into a flask charged with allenylcyclobutanol
4e (58.5 mg, 0.20 mmol) and 4 Å molecular sieves, three times
evacuated and flushed with argon, followed by addition of PhCO2H
(20 µL, 1.0 M in CH2Cl2, 0.020 mmol) and Et3N (20 µL, 1.0 M in
CH2Cl2, 0.020 mmol) respectively via syringe. After stirring under
argon at 60 °C for 6 h, the mixture was filtered through a Celite
pad, concentrated, and purified by direct flash chromatography (10%
diethyl ether in petroleum ether, silica gel) to give the desired
Rf (25% ether in petroleum ether): 0.45. IR (neat): 3088, 3064,
3031, 2929, 2858, 1740, 1654, 1622, 1496, 1454, 1366, 1346, 1211,
1187, 1104, 1027, 992, 936, 736, 697 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.40–7.23 (m, 10H), 6.01 (dd, J1 ) 18.0 Hz, J2 ) 10.8
Hz, 1H), 5.46–5.41 (m, 2H), 4.52 (s, 2H), 4.50 (d, J ) 11.0 Hz,
1H), 4.36 (d, J ) 11.0 Hz, 1H), 3.52–3.43 (m, 2H), 2.84–2.74 (m,
1H), 2.64–2.57 (m, 1H), 2.40–2.34 (m, 1H), 2.13 (dd, J1 ) 19.1
Hz, J2 ) 10.8 Hz, 1H), 1.80 (dd, J1 ) 14.0 Hz, J2 ) 10.8 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ 212.4, 138.3, 138.2, 134.5, 129.0,
128.40, 128.38, 128.32, 127.7, 127.6, 127.5, 119.4, 83.2, 73.1, 72.7,
66.4, 40.4, 39.3, 32.4. HRMS (EI+): m/z calcd for C22H34O3,
336.1725 ([M]+); found, 336.1726. Anal. Calcd for C14H16O2: C,
78.23; H, 7.88. Found: C, 78.41; H, 7.70. [R]2D6.3 ) -43.97 (c )
1.60, CH2Cl2). Enantiomeric excess was determined to be 88% ee
by chiral HPLC (Chiralpak AD, 220 nm, heptane/i-PrOH ) 99:1,
0.8 mL/min, t1 ) 12.13 min (major), t2 ) 13.84 min).
1
product 6e: dr ) 8.3:1 (by H NMR). Isolated yield of the major
isomer 6e: 47 mg (89%); 88% ee.
Major diastereomer 6e. Rf (25% ether in petroleum ether): 0.69.
IR (neat): 3030, 2924, 2855, 1741, 1652, 1497, 1455, 1274, 1215,
1058, 994, 930, 803, 761, 698 cm-1. 1H NMR (500 MHz, CDCl3):
δ 7.37–7.28 (m, 10H), 6.08 (dd, J1 ) 18.0 Hz, J2 ) 10.8 Hz, 1H),
5.49 (dd, J1 ) 18.0 Hz, J2 ) 1.0 Hz, 1H), 5.47 (dd, J1 ) 10.8 Hz,
J2 ) 1.0 Hz, 1H), 4.58 (d, J ) 11.6 Hz, 1H), 4.44 (d, J ) 11.6 Hz,
1H), 2.91 (ddd, J1 ) 19.0 Hz, J2 ) 7.9 Hz, J3 ) 2.7 Hz, 1H), 2.66
(ddd, J1 ) 13.8 Hz, J2 ) 6.0 Hz, J3 ) 2.7 Hz, 1H), 2.41 (dd, J1 )
19.0 Hz, J2 ) 11.1 Hz, 1H), 2.05 (dd, J1 ) 13.9 Hz, J2 ) 12.1 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 211.9, 142.7, 138.2, 134.3,
129.7, 128.7, 128.4, 127.6, 126.8, 126.7, 119.6, 83.5, 66.6, 44.7,
44.3, 37.3. HRMS (EI+): m/z calcd for C18H24O2, 272.1776 ([M]+);
found, 272.1781. [R]2D2.0) -64.17 (c ) 1.56, CH2Cl2). Enantiomeric
excess was determined to be 88% ee by chiral HPLC (Chiralpak
ODH, 220 nm, heptane/i-PrOH ) 99:1, 0.8 mL/min, t1 ) 20.28
min (major), t2 ) 22.03 min).
Minor diastereomer 6j′.
1
Rf (25% ether in petroleum ether): 0.31. H NMR (500 MHz,
CDCl3): δ 7.36–7.26 (m, 10H), 5.87 (dd, J1 ) 17.7 Hz, J2 ) 10.6
Hz, 1H), 5.46 (dd, J1 ) 10.7 Hz, J2 ) 0.9 Hz, 1H), 5.40 (dd, J1 )
17.7 Hz, J2 ) 0.9 Hz, 1H), 4.65 (d, J ) 11.4 Hz, 1H), 4.52 (s,
2H), 4.45 (d, J ) 11.4 Hz, 1H), 3.50 (dd, J1 ) 6.0 Hz, J2 ) 1.5
Hz, 2H), 2.54–2.36 (m, 3H), 2.19 (dd, J1 ) 18.5 Hz, J2 ) 8.7 Hz,
1H), 1.99 (dd, J1 ) 12.8 Hz, J2 ) 10.1 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ 214.2, 138.4, 138.1, 135.3, 128.4, 128.3, 127.7,
127.6, 127.5, 125.5, 119.9, 85.2, 73.3, 73.2, 66.8, 40.0, 37.3, 31.2,
30.3.
3-(3-Benzyloxy-4-oxo-3-vinyl-cyclopentyl)-3-methyl-butyric
Acid Methyl Ester (6i).
(2R,7R,8S)-2-Benzyloxy-4,4-dimethyl-2-vinyl-hexahydro-
pentalene-1,6-dione (11).
Cyclopentanone 6i was prepared from allenylcyclobutanol 6i
(132.2 mg, 0.40 mmol) according to the general procedure for ring
expansion with (R,R)-anthracene ligand L4 (24.4 mg, 0.030 mmol)
1
at 60 °C: dr ) 7.2:1 (by H NMR). Isolated yield of the major
isomer 6i: 106 mg (80%); 88% ee.
9
J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008 6241

A R T I C L E S
Trost and Xie
Cyclopentanone 6i (49.6 mg, 0.15 mmol) was dissolved in 15
mL of Et2O, followed by addition of NaOMe (12.2 mg, 0.225
mmol). The solution was heated at reflux under N2 overnight,
quenched with aqueous saturated NaHCO3, and extracted with
EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, filtered, concentrated, and purified by silical gel flash
chromatography (25% Et2O in petroleum ether) to give a white
solid. Reaction dr > 10:1. A single isomer was isolated. Yield: 38
mg (85%). The solid was dissolved in Et2O. Slow evaporation of
solvent afforded the white crystal which was used for X-ray
analysis.
Rf (50% ether in petroleum ether): 0.59. IR (neat): 3032, 2959,
2927, 2869, 1767, 1719, 1454, 1374, 1267, 1116, 1060, 948, 876,
741, 699 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.35–7.26 (m, 5H),
6.00 (dd, J1 ) 18.1 Hz, J2 ) 10.8 Hz, 1H), 5.46 (dd, J1 ) 10.8 Hz,
J2 ) 1.0 Hz, 1H), 5.45 (dd, J1 ) 18.0 Hz, J2 ) 1.0 Hz, 1H), 4.53
(d, J ) 11.5 Hz, 1H), 4.29 (d, J ) 11.5 Hz, 1H), 3.38 (dd, J1 )
7.8 Hz, J2 ) 2.6 Hz, 1H), 2.94 (m, 1H), 2.42 (ddd, J1 ) 14.3 Hz,
J2 ) 7.0 Hz, J3 ) 2.8 Hz, 1H), 2.28 (d, J ) 18.4 Hz, 1H), 2.13 (d,
J ) 18.4 Hz, 1H), 1.64 (dd, J1 ) 14.4 Hz, J2 ) 12.0 Hz, 1H), 1.16
(s, 3H), 1.09 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 207.9, 202.1,
137.8, 133.3, 128.4, 127.7, 127.6, 120.1, 85.2, 66.9, 62.8, 49.2,
46.2, 38.2, 35.9, 30.2, 23.5. HRMS (EI+): m/z calcd for C19H22O3,
298.1569 ([M]+), 207.1022 ([M - Bn]+); found, 207.1028 ([M -
Bn]+). LRMS (ESI+): m/z calcd for C19H22O3, 299.2 ([M + H]+),
321.2 ([M + Na]+); found, 299.2 ([M + H]+), 321.2 ([M + Na]+).
[R]2D2.8 ) -73.55 (c ) 1.50, CH2Cl2).
Acknowledgment. We thank the National Science Foundation
and National Institutes of Health (GM-13598) for their generous
support of our programs. Mass spectra were provided by the
Mass Spectrometry Regional Center of the University of
California-San Francisco, supported by the NIH Division of
Research Resources. We thank Johnson Matthey for their
generous gift of palladium salts.
Supporting Information Available: Complete experimental
details, spectra, X-ray structure report, and X-ray crystal-
lographic data (CIF) for 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA7111299
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6242 J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008