Development of a rhodium carbenoid-initiated claisen rearrangement for the enantioselective synthesis of α-hydroxy carbonyl compounds [1]

Full text of DOI:10.1021/ja983294l

1748
J. Am. Chem. Soc. 1999, 121, 1748-1749
Communications to the Editor
Development of a Rhodium Carbenoid-Initiated
Claisen Rearrangement for the Enantioselective
Synthesis of r-Hydroxy Carbonyl Compounds
Scheme 1
John L. Wood,* George A. Moniz, Derek A. Pflum,
Brian M. Stoltz, Alexandra A. Holubec, and
Hans-J u¨ rgen Dietrich
Sterling Chemistry Laboratory, Department of Chemistry
Yale UniVersity, New HaVen, Connecticut 06520-8107
ReceiVed September 16, 1998
In the course of a recent total synthesis, we required a method
for the stereocontrolled preparation of â-hydroxy ester 5. Eventu-
ally we envisioned an asymmetric approach that called for the
initial preparation of R-allyloxy-â-ketoester 3 (Scheme 1), a
substrate we believed to be accessible from 1 via rhodium-
mediated O-H insertion chemistry.1 Based on reports by
Scheme 2
,2
Koreeda we anticipated advancing 3 to 5 via a Claisen rearrange-
3
ment. In the event, we unexpectedly discovered that the Rh
2
-
(
3
4
OAc) -catalyzed dediazotization of 1 in the presence of (S)-(+)-
-buten-2-ol (2) directly produces (R)-(+)-5 in what appeared to
be an extraordinarily stereoselective tandem O-H insertion/[3,3]
rearrangement process (i.e., 1 f 3 f 5). In this paper we describe
4
investigations that establish this rhodium carbenoid-initiated
Claisen rearrangement as a general stereoselective method for
preparing tertiary alcohols. Additionally we report that this process
occurs via a mechanism wherein the O-H insertion event delivers
a reactive enol intermediate (i.e., 4a) and not the anticipated
ketone 3, a finding which clearly suggests that rhodium-mediated
O-H insertion reactions of R-diazo ketones proceed via initial
proton transfer to oxygen.
column chromatography, when individually advanced through the
subsequent deprotection and purification steps, each isomer
furnishes the same mixture of diastereomeric ethers (3). Interest-
ingly, when exposed to reaction conditions that had previously
furnished the Claisen product R-(+)-5 (benzene at reflux for 20
min, Scheme 1), 3 produces only a trace of 5. When the reaction
time is increased to 18 h, the Claisen product can be isolated in
Intrigued by the facility with which 1 and 2 combine to produce
7
5% yield. However, under these conditions chirality transfer is
diminished and the opposite enantiomer [(S)-(-)-5] predominates
47% ee). Additionally, 3 is recovered unchanged when incor-
5
, we initiated investigations into the course of this transformation.
5
Favoring an anion-accelerated mechanism that would bypass the
classical O-H insertion step by proceeding via a transient (Z)-
rhodium enolate (i.e., 4b), we set out to establish positive proof
against the initially envisioned intermediate, 3 (Scheme 2). To
this end, 1 was converted to TBS-enol ether 6 which, when
(
9
porated as a substrate in the reaction of 1 with deuterated 2.
Although these results clearly indicate that the rhodium-initiated
reaction does not proceed via 3, the novel pathway illustrated in
Scheme 1 (i.e., 1 f 4a f 5) was not identified until we expanded
our investigation to include a variety of substituted allylic alcohols,
diazo substrates, and catalysts (vide infra).
2 4
combined with (S)-(+)-2 in the presence of Rh (OAc) , was found
to produce a mixture of diastereomeric O-H insertion products
6
-8
(7).
Although this mixture is separable by standard flash
As can be surmised from the data in Tables 1 and 2, our
investigations into generality revealed that rhodium carbenoid-
initiated Claisen rearrangements similar to that illustrated in
Scheme 1 occur readily when either acyclic (Table 1) or cyclic
(Table 2) diazo substrates are combined with a range of allylic
alcohols. In some cases (e.g., Table 1, entry 1a) the classical O-H
insertion product is coproduced in varying amounts. Transfer of
stereochemistry from enantio-enriched allylic alcohols to the
derived R-hydroxy ketones is in all cases consistent with the
intermediacy of a chairlike transition state possessing a (Z)-enol
(
1) For a recent review, see: Miller, D. J.; Moody, C. J. Tetrahedron 1995,
5
1, 10811.
(
2) For a recent and elegant stereoselective preparation of R-hydroxy
carbonyls, see: Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan,
D. W. C. J. Am. Chem. Soc. 1997, 119, 7893.
(
3) (a) Koreeda, M.; Luengo, J. I. J. Am. Chem. Soc. 1985, 107, 5572. (b)
Examples of both [2,3] and [3,3] rearrangement of R-allyloxy ketones have
been reported, see: Ziegler, F. E. Chem. ReV. 1988, 88, 1423 and references
therein.
(
4) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. J. Am. Chem. Soc. 1995,
1
2
Rh
17, 10413. In a typical experiment, a mixture of 1 (3.17 g, 22.3 mmol) and
(1.93 g, 26.8 mmol, 98% ee) is diluted in benzene (75 mL), treated with
2
(OAc)
4
(30 mg, 0.068 mmol), and heated to reflux. After 20 min at reflux
the reaction is cooled, and the solvent removed in vacuo. Chromatographic
(9) This experiment eliminates the possibility that a transient species,
purification (20% EtOAc/Hex) furnishes 3.20 g of 5 (77% yield, 95% ee).
2 4
generated in the presence of 1, 2, 3, and Rh (OAc) , is responsible for
(
5) Evans, D. A.; Golub, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
promoting the formation of 5. Deuterium incorporation into the Claisen product
obtained from this experiment (i.e., i) was quantitative as determined by 500
(
6) The structure assigned to each new compound is in accord with its
1
13
1
infrared and high-field H (500 MHz) and C (125 MHz) spectra, as well as
with appropriate parent ion identification by high-resolution mass spectrometry.
Details regarding the assignment of relative and absolute stereochemistry are
included as Supporting Information.
MHz H NMR.
(
7) For the preparation of 6, see: Davies, H. M. L.; Houser, J. H.; Thornley,
C. J. Org. Chem. 1995, 60, 7529.
8) The reported yield for 7 includes three silylated products, see Supporting
Information for details.
(
1
0.1021/ja983294l CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/10/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 8, 1999 1749
Table 1. Examples with Acyclic R-Diazoketones6
Scheme 3
2
2 2 2 4
in CD Cl with Rh (TFA) (0.01 equiv) the substrates undergo
rapid conversion to an intermediate which, in accord with our
studies of 3 (vide supra), did not compare to an authentic sample
of the classical O-H insertion product 12. If left undisturbed this
intermediate underwent slow conversion to the Claisen product
(
11). However, upon TLC or attempted isolation the intermediate
Table 2. Examples with Cyclic R-Diazoketones6,10
rapidly furnished 12. On the basis of these data we speculated
that the initially formed carbenoid engages the allylic alcohol to
form an intermediate rhodium stabilized ylide (9) which selec-
tively furnishes the reactive (Z)-enol 10 via intramolecular proton
transfer.1
1,12
This suspicion was confirmed by a trapping study
wherein 8 was converted to the enoltrifluoroacetate 13 in the
presence of 14.13
In summary, a novel rhodium carbenoid-initiated C-C bond
forming reaction has been discovered and developed into an
exceptionally useful method for the asymmetric construction of
R-hydroxy carbonyl compounds. Particularly striking is the extent
to which olefin geometry is controlled in the intermediate enols
and the facility with which the latter undergo Claisen rearrange-
ment. Further investigations into the intrinsic reactivity of these
enols and the scope of this reaction are in progress.
Acknowledgment. We are pleased to acknowledge the support of
this investigation by the NIH (1RO1GM54131). Eli Lilly, Glaxo-
Wellcome, and Bristol-Myers Squibb provided additional support through
their Junior Faculty Awards Programs. J.L.W. is a fellow of the Alfred
P. Sloan Foundation.
Supporting Information Available: Spectral and experimental data
pertaining to all products illustrated in Schemes 2 and 3 and Tables 1
and 2 (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA983294L
(10) Experiments in this series were performed with racemic alcohol as
substrate. Thus, where defined, the structures illustrate only relative stereo-
chemistry.
and an equatorially disposed methyl substituent (e.g., 4a, Scheme
(11) Although the transient species 9 can be envisioned with or without
rhodium, the known influence of asymmetric rhodium catalysts on other
sigmatropic rearrangements suggests its inclusion, see: Pierson, N.; Fern a´ dez-
Garci a´ ; C.; McKervey, M. A. Tetrahedron Lett. 1997, 38, 4705.
(12) Acid-promoted tautomerization of 10 would account for observations
of 12 by TLC.
1). The efficiency of stereochemical transfer is, with the exception
of entry 5, excellent.
In furthering the investigation we began exploring various
Rh(II) catalysts (Scheme 3). Although in general the reaction
outcome was unaffected by changes in ligand, we did observe
(
13) The inclusion and recovery of 14 in this experiment provides positive
proof against its intermediacy en route to 13. The structure of 13 was confirmed
(by NMR) that within seconds after treating a solution of 8 and
via chemical correlation, see Supporting Information.