Asymmetric synthesis of α-substituted aldehydes by Pd-catalyzed asymmetric allylic alkylation-alkene isomerization-Claisen rearrangement

Article abstract of DOI:10.1021/ol0624878

(Chemical Equation Presented) Enantiospecific aliphatic Claisen rearrangement was realized with generally high chirality transfer. The requisite substrates were synthesized via Pd-catalyzed asymmetric allylic alkylation (AAA) from easily obtained starting

Full text of DOI:10.1021/ol0624878

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6007-6010
Asymmetric Synthesis of
Aldehydes by Pd-Catalyzed Asymmetric
Allylic Alkylation Alkene
Isomerization Claisen Rearrangement
r-Substituted
−
−
Barry M. Trost* and Ting Zhang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received October 9, 2006
ABSTRACT
Enantiospecific aliphatic Claisen rearrangement was realized with generally high chirality transfer. The requisite substrates were synthesized
via Pd-catalyzed asymmetric allylic alkylation (AAA) from easily obtained starting materials. After protection, the resultant bisallyl ethers
underwent olefin isomerization and in situ Claisen rearrangement (ICR) to generate
r-chiral aldehydes. Remarkable chemoselectivity in the
olefin isomerization step was observed. An asymmetric synthesis of communiol A was accomplished applying this methodology.
The aliphatic Claisen rearrangement constitutes an important
synthetic method with much more potential than has yet been
realized.1 On the other hand, the Ireland ester enolate Claisen
rearrangement has had much more use which may be
attributed to (1) the ease of access of the requisite substrates
and (2) the development of asymmetric versions.2 Our
development of an asymmetric synthesis of bisallyl ethers
via Pd asymmetric allylic alkylation (AAA) led us to question
whether such intermediates could undergo chemoselective
isomerization to allyl vinyl ethers which would undergo the
Claisen rearrangement in situ, a process termed isomeriza-
tion-Claisen rearrangement (ICR) by Nelson.3-5 Herein, we
report our studies in this transformation sequence. We wish
Figure 1. Planned vinyl epoxide opening and isomerization-
Claisen rearrangement sequence.
(1) (a) Ziegler, F. Chem. ReV. 1988, 88, 1423. (b) Hiersemann, M.;
Abraham, L. Eur. J. Org. Chem. 2002, 1461. (c) Nubbemeyer, U. Synthesis
2003, 961. (d) Castro, A. M. M. Chem. ReV. 2004, 104, 2939.
(2) (a) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28, 43. (b) Chai, Y.;
Hong, S.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905.
to report the realization of this sequence with a most
surprising chemoselectivity.
As shown in Figure 1, the less-substituted olefin in the
resulting bisallyl ether was expected to isomerize given the
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thermostability and steric hindrance of the multisubstituted
olefin. However, in our substrate system, the remarkable
reverse phenomenon was observed: the isomerization took
place on the 1,2-disubstituted olefin instead of on the
monosubstituted olefin. Furthermore, the issue of chirality
transfer in the Claisen rearrangement arises. When there is
only one stereogenic center existing both before and after
the Claisen rearrangement, complete chirality transfer should
be more difficult because of lower conformational rigidity
in the Claisen transition state.
Scheme 2. Olefin Isomerization
The initial trial for the AAA of butadiene monoepoxide
with 1 mol % of (C2H5)3B resulted in 29% yield and 82%
enantiomeric excess with the reaction finishing within 1 h
(Scheme 1).5 We postulated that the low yield resulted from
ylsilane, and formic acid were also examined yet without
encouraging results. The highest conversion (10%) was
Scheme 1. Pd-AAA
Scheme 3. Chemoselectivity of the Double-Bond
Isomerization
the competition of the product alcohol for the palladium
reaction to produce oligomeric species. Slow addition of
vinyl epoxide only slightly improved the yield to 41%.
Increasing the temperature did not improve the yield or the
ee, whereas lowering the temperature to 0 °C decreased the
ee to 37%. With an excess amount of allylic alcohol, the
yield increased to 74%, as the excess alcohol both increased
the conversion of vinyl epoxide and suppressed the oligomer
formation. Fortunately, the excess amount of allylic alcohol
was recovered almost quantitatively after the reaction. The
borane cocatalyst was observed to have the greatest impact
on the enantioselectivity. A higher borane loading to 5%
decreased the ee to 68%, whereas lowering the loading to
0.5% or 0.2% gave 87-89% or 90% ee, respectively. The
sterically more hindered borane, tri-sec-butylborane, gave a
2% increase in ee but resulted in 32% lower yield and
required a much longer reaction time than with (C2H5)3B.
achieved by using 5 mol % of [Ir(COD)(PPh3)2]PF6 in
combination with H2 gas in methylene chloride at room
temperature.6a Utilizing conditions reported by Nelson and
co-workers gave only trace conversion after 5 h.4 Therefore,
we postulated that the hydroxyl group on the bisallyl ether
Table 1. Optimization for Chirality Transfer of the Claisen
Rearrangementa
Screening conditions for isomerizing the bisallyl ether 3a
showed that, although the conversions were extremely low
in most cases, iridium catalysts gave the best E selectivity.6
Different hydride sources including H2 gas, NaBH4, trieth-
entry
condition of rearrangement
heat, 80 °C, 59 h
microwave, 150 °C, 10 min
microwave, 140 °C, 15 min
microwave, 130 °C, 20 min
product % ee
1
2
3
4
5
6
7
72
83
85
83
(3) For early development of ICR, see: (a) Reuter, J. M.; Salomon, R.
G. J. Org. Chem. 1977, 42, 3360. (b) Swenton, J. S.; Bradin, D.; Gates, B.
D. J. Org. Chem. 1991, 56, 6156.
(4) Recent development of ICR: (a) Nelson, S. G.; Bugard, C. J.; Wang,
K. J. Am. Chem. Soc. 2003, 125, 13000. (b) During the final stage of our
study, an asymmetric version generating vicinal stereogenic centers was
reported. See: Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232.
(5) Pd-AAA of vinyl epoxide with alcohol nucleophiles: Trost, B. M.;
McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702.
1 equiv of BSA, microwave, 140 °C, 15 min 88
add 2 equiv of MADb, DCM, -78 °C, 1 h
no reaction
no reaction
add 2 equiv of MADb, DCM, rt, 1 h
a The yields of the reactions were 70-80%. b MAD ) methyl aluminum
bis(2,6-di-tert-butyl-4-methylphenolate).
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Org. Lett., Vol. 8, No. 26, 2006

Table 2. Optimized Conditions and Reaction Scope
a Yields were reported for the AAA step where R ) H and for the protection step where R ) PG (protecting group). b Determined by chiral HPLC for
the alcohols or the corresponding silyl ether derivatives of the AAA products. c TBS ) tert-butyldimethylsilyl; Ac ) acyl; TBDPS ) tert-butyldiphenylsilyl.
d Yields were reported for the in situ reduction products 5a′-5m′ of the resulting aldehydes to prevent racemization during chromatography isolation (E/Z
1
> 30:1, separable). e Determined by chiral HPLC for the alcohols or the corresponding benzoates of the in situ reduction products or by H NMR for the
corresponding O-methylmandelates. In the case of entry 6, the ee was determined by chiral HPLC for the O-methylmandelate derivative. f % ct (chirality
transfer) ) product’s ee/substrate’s ee. g 98% ee for 2k. h Diastereomeric excesses rather than enantiomeric excesses were reported. i (R,R)-L1 was used in
the AAA step. j Isoprene monoepoxide was used instead of butadiene monoepoxide in the AAA step. k Two separable Z,E isomers were obtained after the
Claisen rearrangement.
might have interfered with the catalytic cycle by saturating
the open coordination site on the Ir catalyst. Indeed, after
protecting the free OH with a tert-butyldimethylsilyl group,
25% conversion was achieved with 5 mol % of [Ir(COD)-
(PPh3)2]PF6/H2 under the above conditions. More satisfyingly,
by revisiting Nelson’s conditions, full conversion of the
protected diallyl ether was obtained by using 2.5 mol % of
[(C8H14)2IrCl]2, 15 mol % of PCy3, and 5 mol % of NaBPh4
Org. Lett., Vol. 8, No. 26, 2006
6009

Realizing the protecting group’s influence on the conver-
sion and chirality transfer was close to none (Table 2, entries
1 and 2), we envisioned that the protecting group could
actually be turned into a leaving group, leading to the
synthesis of useful building blocks. A short synthesis of the
revised structure of communiol A was completed as an
example (Scheme 4). Starting from the known allylic achohol
2e, the Pd-AAA-acylation-ICR sequence gave aldehyde
5f (Table 2, entry 6), which was in situ reduced to the
corresponding primary alcohol 5f′.8 A Pd-catalyzed ring-
closure reaction developed by our group afforded the 2,4-
disubstituted tetrahydrofuran in a 4.5:1 trans/cis ratio.9
Following the oxidative cleavage of the terminal olefin,
Grignard addition using an excess amount of 2:1 HMPA/
EtMgBr resulted in product 8 with an 8:1 erythro/threo ratio
of separable diastereomers.10 Hydrolysis of ethyl ester
furnished the revised communiol A structure 9.11
Scheme 4. Synthesis of the Revised Structure of Communiol
A
In summary, we have reported a Pd-AAA-ICR sequence
with generally high chirality transfers and an unusual
chemoselectivity in the isomerization step. The reaction scope
is relatively broad, and the products can form useful building
blocks through simple transformations as exemplified by the
synthesis of communiol A.
in 50:1 DCE/acetone at room temperature after 5 h (Scheme
2). Notably, the isomerization took place exclusively at the
1,2-disubstituted double bond with high E selectivity (the Z
isomer was undetectable by 1H NMR). A possible rationale
depicted in Scheme 3 takes into consideration the allylic
strain in a 1,1-disubstituted allyl complex compared to a 1,3-
disubstituted one.
The Claisen rearrangement would result in an R-chiral
aldehyde, which tends to racemize. Thus, striking a balance
between time and temperature for the rearrangement was
crucial for the chirality transfer. Simple heating of the
reaction proved to be inefficient for our substrate both in
conversion and in selectivity (Table 1, entry 1). Therefore,
a chemical microwave was applied and afforded full conver-
sion at 150 °C within 10 min (Table 1, entry 2). Further
optimization showed that using a microwave at 140 °C for
15 min gave the least chirality loss (Table 1, entry 3). Adding
1 equiv of O,N-bistrimethylsilylacetamide (BSA) could
further inhibit the racemization (Table 1, entry 5). Lewis acid
catalyzed Claisen rearrangement was also attempted but did
not bring down the required temperature with acceptable
conversion or chirality transfer (Table 1, entries 6 and 7).
The optimized conditions and substrate scope for Pd-AAA-
ICR are summarized in Table 2.7
Acknowledgment. We thank the National Science Foun-
dation and National Institute of Health (NIH-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.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0624878
(7) Absolute configuration: 3a-l were established by analogy to our
previous work (ref 5); 5a-m (5a′-m′) were proposed by the chair transition
states of Claisen rearrangement, among which 5a′, 5l′, and 5m′ were
degraded to known γ-phenylpropylsuccinic acid, and the absoluted con-
figurations were confirmed by comparing the optical rotation signs with
(D)-(+)-γ-phenylpropylsuccinic acid. Trost, B. M.; Zhang, T. unpublished
results.
(8) Casara, P. Tetrahedron Lett. 1994, 35, 3049.
(9) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006,
128, 6745.
(10) (a) Amouroux, R.; Ejjiyar, S.; Chastrette, M. Tetrahedron Lett. 1986,
27, 1035. (b) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett.
1986, 27, 4011.
(11) Isolation and synthetic studies of communiols: (a) Che, Y.; Gloer,
J. B.; Scott, J. A.; Malloch, D. Tetrahedron Lett. 2004, 45, 6891. (b)
Kuvahara, S.; Enomoto, M. Tetrahedron Lett. 2005, 46, 6297. (c) Murga,
J.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2005, 46, 8199.
(6) Selected olefin isomerization references: (a) Matsuda, I.; Kato, T.;
Sato, S.; Izumi, Y. Tetrahedron Lett. 1986, 27, 5747. (b) Frauenrath, H.;
Runsink, J. J. Org. Chem. 1987, 52, 2707. (c) Frauenrath, H.; Sawicki, M.
Tetrahedron Lett. 1990, 31, 649. (d) Hu, Y.-J.; Dominique, R.; Das, S. K.;
Roy, R. Can. J. Chem. 2000, 78, 838.
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