Catalytic diastereoselective reductive Claisen rearrangement

Article abstract of DOI:10.1021/ol026273b

(Matrix presented) A catalytic amount of [(cod)RhCl]₂ and MeDuPhos initiates an ester enolate Claisen rearrangement with good yields and diastereocontrol. Reaction conditions are mild and tolerant of base-sensitive functionality.

Full text of DOI:10.1021/ol026273b

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2743-2745
Catalytic Diastereoselective Reductive
Claisen Rearrangement
Steven P. Miller and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of
North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received May 31, 2002
ABSTRACT
A catalytic amount of [(cod)RhCl]2 and MeDuPhos initiates an ester enolate Claisen rearrangement with good yields and diastereocontrol.
Reaction conditions are mild and tolerant of base-sensitive functionality.
The ester enolate Claisen rearrangement is a particularly
powerful method for stereocontrolled carbon-carbon bond
formation from simple achiral materials.1 The transition state
for the reaction is well understood such that prediction of
the major product diastereomer is usually straightforward.
One of the drawbacks to the ester enolate Claisen rearrange-
ment is the requirement for enolate generation, which often
requires treatment with strong base. As an alternative,
investigations in our laboratories have centered on catalytic
enolate generation techniques for use in carbon-carbon
bond-forming reactions, specifically under mild conditions.2
One example of this is the rhodium-MeDuPhos3 catalyzed
diastereoselective reductive aldol reaction, which we have
determined proceeds through the intermediacy of E-
silylketene acetals (eq 1, Scheme 1).4b,e We considered that
Scheme 1
(1) For excellent reviews, see: (a) Chai, Y.; Hong, S.; Linday, H. A.;
McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905. (b) Wipf, P.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol. 5, p 827. (c) Blechert, S. Synthesis 1989, 71. (d) Ziegler, F. E.
Acc. Chem. Res. 1977, 589. For examples of enantioselective ester enolate
Claisen rearrangements, see: (e) Corey, E. J.; Lee, D. H. J. Am. Chem.
Soc. 1991, 113, 4026. (f) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2012. (g) Kazmaier, U.; Mues, H.; Krebs, A. Chem. Eur.
J. 2002, 8, 1850. For an example of an enantioselective acyl-Claisen
rearrangement, see: (h) Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 2911. For an example of a catalytic enantioselective Claisen
rearrangement, see: (i) Abraham, L.; Czerwonka, R.; Hiersemann, M.
Angew. Chem., Int. Ed. 2001, 40, 4700.
(2) (a) Mascarenhas, C. M.; Duffey, M. O.; Liu, S. Y.; Morken, J. P.
Org. Lett. 1999, 1, 1427. (b) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc.
1999, 121, 12202. (c) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am.
Chem. Soc. 2000, 122, 4528. (d) Mascarenhas, C. M.; Miller, S. P.; White,
P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601. (e) Zhao, C. X.;
Taylor, S. J.; Bass, J.; Morken, J. P. Org. Lett. 2001, 3, 2839. (f) Zhao, C.
X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829.
similar enolate generation techniques might be used to access
silylketene acetals that might then participate in an Ireland-
(3) Me-DuPhos: 1,2-bis(dimethylphospholano)benzene. See: Burk, M.
J.; Feaster, J. E.; Harlow, R. L. Organometallics 1990, 9, 2653.
(4) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897.
(b) Ireland, R. E.; Willard, A. K. Tetrahedron Lett. 1975, 46, 3975. (c)
Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98,
2868. (d) Ireland, R. E.; Varney, M. D. J. Am. Chem. Soc. 1984, 106, 3668.
(e) Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650.
(f) Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem. 1991, 56, 3572.
10.1021/ol026273b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/13/2002

Claisen ester enolate rearrangement.4,5 In order for successful
reaction outcome, there are two issues of critical concern.
First, the rate of hydrosilation of the acrylate must be faster
than that of the pendant alkene. Second, control of silylketene
acetal geometry is crucial for control of reaction stereo-
selectivity.
reactivity results from silanes with more than one inductively
withdrawing group attached.
Experiments aimed at surveying the reaction substrate
scope were examined and employed dichloromethylsilane
since it provided the optimal combination of yield and
diastereoselection in our initial studies. As described above,
trans-2-hexenylacrylate (entry 1, Table 2) undergoes reduc-
On the basis of the precedent in the reductive aldol reaction
described in eq 1, we attempted the reductive Ireland-
Claisen rearrangement in eq 2. Our first experiments, using
ether as the reaction solvent, were suboptimal, providing 8%
yield and 7.3:1 stereoisomer ratio. A survey of reaction
solvents found benzene to be superior to ether, CH2Cl2 (36%,
5.3:1 dr), THF (45%, 4.4:1 dr), toluene (54%, 9.8:1 dr), and
hexanes (no reaction), providing reaction product in 74%
isolated yield and 11:1 diastereomer ratio. Standard condi-
tions employ 2.5 mol % [(cod)RhCl]2, 5 mol % MeDuPhos,
and 1.25 equiv of silane in each experiment. Notably, while
reactions were carried out under nitrogen with rigorously
purified reagents and solvents, we have subsequently found
that reagents and solvents used as received from commercial
vendors provide similar yields and stereoselection. In accord
with our observations on reductive aldol reactions, the
product configuration is consistent with generation of an
E-silylketene acetal followed by rearrangement through a
chairlike six-membered transition state.6
Table 2. Reductive Claisen Rearrangement with 5 mol %
Rh-DuPhos and Cl2MeSiH
To examine the impact of reaction variables on product
outcome, a series of experiments with different silanes were
carried out (Table 1). As can be seen from the results of
Table 1. Reductive Claisen Rearrangement with 5 mol %
Rh-DuPhos and Various Silanes
entry
silane
time (h)
yield
dr
1
2
3
4
5
6
7
8
Cl2MeSiH
Ph(Me)ClSiH
ClPh2SiH
1
15
6
2
2
2
1
1
74
8
nr
47
47
9
11:1
4.3:1
na
21:1
>25:1
10:1
na
(EtO)3SiH
(EtO)2MeSiH
(EtO)Me2SiH
Me2PhSiH
Et2MeSiH
tive Claisen rearrangement to provide the anti diastereomer
of product in high yield and diastereoselection. The opposite
product diastereomer was obtained from cis-2-hexenyl-
acrylate (entry 2), in accord with the stereochemical model
proposed by Ireland for the ester enolate Ireland-Claisen
rearrangement. Substitution at the carbinol position (entry
3) is tolerated and leads to the trans alkene in the reaction
product in 91% yield and with an exceptional level of
stereocontrol. Reaction of the cyclic allylic ester depicted
in entry 4 proceeds with low levels of stereoselection and in
low yield. This is presumably a consequence of incipient
steric interactions in the required cyclic transition structure
for rearrangement.7 Trisubstituted olefins (entries 5 and 6)
nr
nr
na
this survey, dichloromethylsilane provides highest product
yield (entry 1), although the highest levels of diastereo-
selection were obtained when diethoxy(methyl)silane (entry
5) was used as reductant. While there are no readily
interpretable correlations between reductant structure and
reactivity, from inspection of the data it appears that highest
(5) For one example of a reductive Claisen rearrangement, see: Cambie,
R. C.; Milbank, J. B. J.; Rutledge, P. S. Org. Prep. Proced. Int. 1997, 29,
367.
(6) While we have not been able to observe the presumed intermediate
silylketene acetal in any of our experiments, the reactions products are
racemic.
(7) For a similar Ireland-Claisen rearrangement with a cyclic allylic
ester that proceeds in low stereoselection, see: Bartlett, P. A.; Pizzo, C. F.
J. Org. Chem. 1981, 46, 3896.
2744
Org. Lett., Vol. 4, No. 16, 2002

participate in the reductive Claisen rearrangement. The
example in entry 5 also demonstrates the ability to form all-
carbon quaternary centers in good yields with this methodol-
ogy. Allylic carbonate functionality (entry 7) survives the
rearrangement, suggesting that silyl ketene acetal formation
is faster than formation of the rhodium-π-allyl species
documented by Matsuda.8
untouched (eq 3). The success of this transformation is a
direct consequence of the reducing nature of enolate genera-
tion10 as opposed to base-promoted enolization under stan-
dard conditions. We expect that this difference in reactivity
may allow for effective rearrangement with other base-
sensitive substrates that are currently difficult under standard
ester enolate Claisen conditions.
The experiment depicted in eq 4 (Scheme 2) indicates that
the reductive Ireland-Claisen rearrangement may be ac-
complished on large scale and requires only 0.5 mol % Rh
metal. While higher temperature and extended reaction times
were required with lower catalyst loading, the reaction still
proceeded in a 70% yield and with 8:1 diastereomer ratio.
In conclusion, we have used a readily available catalyst,
prepared from [(cod)RhCl]2 and Me-DuPhos, for the chemo-
and stereoselective reduction of allyl acrylates to E-
silylketene acetals. The intermediate may then participate
in an Ireland-Claisen rearrangement providing γ,δ-unsatur-
ated carboxylic acids with a high level of stereocontrol. The
chemoselective nature of the transformation may offer a
practical complement to base-promoted ester enolate Claisen
rearrangements.
To demonstrate the complementary aspects of the reductive
Ireland-Claisen rearrangement relative to base-promoted
ester enolate rearrangements, we undertook the experiments
described in Scheme 2. The base-mediated ester enolate
Scheme 2
Acknowledgment. We thank NIGMS (GM064451),
Bristol-Myers Squibb, Dow, DuPont, GlaxoSmithKline, and
the David and Lucile Packard Foundation for financial
support. We thank Emily Houston for experimental as-
sistance.
Supporting Information Available: Characterization
data for all new compounds and experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Claisen rearrangement involving the propionate ester deriva-
tive of 1, instead of the acrylate ester, would yield product
mixtures as a result of competitive enolization of both
carbonyls.9 However, the chemoselectivity of the reductive
Ireland-Claisen rearrangement allows the acrylate to par-
ticipate in the rearrangement while the saturated ester remains
OL026273B
Bellamy, C. L.; Corkill, D. J.; Cossins, J.; Courtney, P. F.; Davies, S. J.;
Davidson, A. H.; Drummond, A. H.; Helfrich, K.; Lewis, C. N.; Mangan,
M.; Martin, F. M.; Miller, K.; Nayee, P.; Ricketts, M. L.; Thomas, W.;
Todd, R. S.; Whittaker, M. Bioorg. Med. Chem. Lett. 1998, 8, 1359.
(10) For reports of presumed catalytic reductive enolate generation
followed by C-C bond formation, see: (a) Revis, A.; Hilty, T. K.
Tetrahedron Lett. 1987, 28, 4809. (b) Isayama, S.; Mukaiyama, T. Chem.
Lett. 1989, 2005. (c) Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett.
1990, 31, 5331. (d) Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett.
1998, 39, 5237.
(8) Muraoka, T.; Matsuda, I.; Itoh, K. J. Am. Chem. Soc. 2000, 122,
9552.
(9) For elegant examples of chemoselective Ireland-Claisen rearrange-
ments involving selective deprotonation, see: (a) Burke, S. D.; Fobare, W.
F.; Pacofsky, G. J. J. Org. Chem. 1983, 48, 5221. (b) Paterson, I.; Hulme,
A. N. J. Org. Chem. 1995, 60, 3288. (c) Pratt, L. M.; Beckett, R. P.;
Org. Lett., Vol. 4, No. 16, 2002
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