A new chiral Rh(II) catalyst for enantioselective [2 + 1]-cycloaddition. Mechanistic implications and applications

Article abstract of DOI:10.1021/ja047064k

A novel chiral Rh(II) catalyst (1) is introduced for the [2 + 1]-cycloaddition of ethyl diazoacetate to terminal acetylenes and olefins with high enantioselectivity. The catalyst 1 consists of one acetate bridging group and three mono-N-triflyldiphenylimidazoline-2-one bidentate ligands (DPTI) spanning the Rh(II)-Rh(II) metallic center in a structure that was determined by single-crystal X-ray diffraction analysis. A rational mechanism is advanced that provides a straightforward explanation for the enantioselectivity and absolute stereochemical course of the [2 + 1]-cycloaddition reactions. A key element in this explanation is the cleavage of one of the Rh-O bonds of the bridging acetate group in the intermediate Rh-carbene complex to form a new pentacoordinate Rh carbene complex (formally 1.5 valent Rh) that can undergo [2 + 2]-cycloaddition with the C-C π-bond of the acetylenic or olefinic substrate. Reductive elimination of the resulting adduct affords the cyclopropene or cyclopropane product. The C₂-symmetry of the two DPTI ligands orthogonal to the bridging acetate also contributes to the high observed enantioselectivity and mechanistic clarity. The catalyst 1, which functions effectively at 0.5 mol %, can be recovered efficiently for reuse. Its ready availability, robustness, and effectiveness suggest it as a useful addition to the list of practical chiral Rh(II) catalysts for synthesis. Copyright

Full text of DOI:10.1021/ja047064k

Published on Web 06/30/2004
A New Chiral Rh(II) Catalyst for Enantioselective [2 + 1]-Cycloaddition.
Mechanistic Implications and Applications
Yan Lou, Manabu Horikawa, Robin A. Kloster, Natalie A. Hawryluk, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts, 02138
Received May 19, 2004; E-mail: corey@chemistry.harvard.edu
The use of rhodium(II) compounds (e.g., Rh2(OAc)4) as catalysts
for the reactions of diazo compounds has developed into a major
tool for chemical synthesis, especially for the cyclopropanation of
olefins and the formation of rings by intramolecular C-H insertion.1
Additionally, the ability of Rh(II) compounds to catalyze C-H
insertion of sulfonyl, phosphoryl, and N-acyl iodosoimines has
allowed oxidative cyclization with C-N bond formation to be
effected in an analogous way.2 Of great current interest are
enantioselective versions of the Rh(II)-catalyzed diazocarbonyl
cyclopropanation and C-H insertion reactions. The most effective
of these chiral catalysts thus far have been Rh2-bridged dimers
having four identical chiral bridging ligands, especially the ligands
of McKervey/Davies (N-arylsulfonylproline),1i,3 Doyle (chiral
2-oxopyrrolidines),1a,b,4 and Hashimoto/Ikegami (N-phthaloyl-tert-
butylglycine).1e,5 Despite extensive studies of the mechanism of
these important Rh(II)-catalyzed processes and the achievement of
very good enantioselectivities in numerous reactions, there is still
no satisfactory understanding of the product-forming step of the
cyclopropanation and C-H insertion processes or of the basis for
enantioselection. It is clear that the rate-limiting step in the catalytic
cycle is the nucleophilic attack of the R-diazocarbonyl substrate
on the catalyst Rh2X4 to form a rhodium carbenoid complex after
loss of nitrogen.6,7 Although the structures of the intermediate
reactive rhodium carbenoids have not been determined experimen-
tally, they have generally been considered to retain the tetrabridged
framework characteristic of Rh2(OAc)4.8 The subsequent product-
forming step has recently been studied computationally by two
groups, each of which has assumed the involvement of the generally
accepted tetrabridged rhodium carbenoid.9,10
In this paper we describe new developments concerning enan-
tioselective [2 + 1]-cycloaddition reactions of ethyl diazoacetate,
including the following: (1) invention of a novel chiral catalyst
(1) that leads to the highly enantioselective and efficient conversion
of acetylenes and olefins to cyclopropenes and cyclopropanes,
respectively; (2) mechanistic insight that stimulated the design and
discovery of the catalyst and that provides a clear and simple
explanation of the product-determining events and the absolute
stereochemical course of the reactions; and (3) a number of useful
applications.
Catalyst 1 was synthesized from (R,R)-1,2-diphenylethylenedi-
amine11 by the following sequence: (1) carbonylation to the
corresponding cyclic urea by reaction with (tert-BuCO)2O and
4-(dimethylamino)pyridine in CH3CN at 23 °C for 16 h (87% yield);
(2) conversion to the mono-N-triflyl derivative (diphenyltriflylimi-
dazolidinone, DPTI) by reaction with triflic anhydride and triethy-
lamine in CH2Cl2 at -78 °C for ca. 1 h (92%); and (3) heating of
DPTI thus obtained with Rh2(OAc)4 at reflux in chlorobenzene as
a solvent using a Dean-Stark apparatus for removal of HOAc for
ca. 20 h (71%).12 The structure of the catalyst was determined by
single-crystal X-ray diffraction analysis.13 The remaining bridging
acetate of Rh2(OAc)(DPTI)3 (1) is displaced much more slowly
than the other acetate ligands of Rh2(OAc)4, which accounts for
the successful and efficient formation of 1. Nonetheless, prolonged
heating of 1 with >1 equiv of DPTI ligand in concentrated
chlorobenzene solution at reflux with CaH2-Celite 545 in a Soxhlet
extractor for removal of HOAc produces Rh2(DPTI)4, the structure
of which was determined to be 2 by single-crystal X-ray diffraction
analysis.13 Comparative experiments with 1 and 2 as catalysts (0.5
mol %) for the reaction of ethyl diazoacetate with olefins
demonstrated that catalyst 1 is superior to 2 with regard to catalytic
efficiency and enantioselectivity. Catalyst 1 is not only easier to
prepare than 2 but also more robust and more readily recovered
from catalytic reactions, an important ancillary factor because of
the expense of rhodium. The focus on catalyst 1 was also
mechanistically guided, as will be clear from the discussion below.
The addition of ethyl diazoacetate to a series of terminal
acetylenes using 0.5 mol % 1 as a catalyst was selected for study
for a number of reasons, including the following: (1) the only
stereochemical issue is enantioselectivity, in contrast to olefinic
substrates, which can give cis and trans [2 + 1]-cycloadducts; (2)
ethyl diazoacetate, one of the most readily available, inexpensive,
and useful diazo compounds, generally leads to poor enantiose-
lectivity with the McKervey and Hashimoto catalysts; and (3) the
cyclopropene products are more reactive and versatile synthetic
intermediates than the cyclopropanes that result from terminal
olefins (see below). The results of a study of the reaction of ethyl
diazoacetate with a series of eight terminal acetylenes in the
presence of 0.5 mol % 1 as a catalyst are summarized in Table 1.
In each case, a 2-substituted-2-cyclopropene carboxylic acid ethyl
ester was obtained with better average enantiomeric purity than
previously reported.14a All products were dextrorotatory, indicating
the same absolute configuration that was assigned from literature
data.14 In terms of enantioselectivity, yield, scope of reaction, and
efficiency of catalyst recovery, catalyst 1 is outstanding.14 Catalyst
1 also leads to considerably higher enantioselectivity than does
catalyst 2 under the conditions of Table 1. For instance, the
enantiomeric purity of the product of entry 2 of Table 1 is only
80% with catalyst 2 as compared with 93% for catalyst 1. Entry 8
of Table 1 is of special interest because it shows that [2 +
9
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10.1021/ja047064k CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalyzed Enantioselective Addition of Ethyl
Diazoacetate to Terminal Acetylenes
We advance a simple explanation for the enantioselectivity of
the reactions catalyzed by 1. We propose that the reactive form of
the intermediate carbenoid derived from ethyl diazoacetate and 1
is the tribridged species 8 in which the more labile acetate bridge
to the carbene-bearing rhodium has been broken. That cleavage
allows the forward rhodium (now formally 1.5 valent) to form a
much stronger dπ-bond to the carbene ligand that compensates for
the acetate debridging. In 8 the carbene fragment, HCCOOEt, which
in principle could attach to the Rh with COOEt either cis or trans
to the Rh-O bond, is in the more favorable steric arrangement
(COOEt s-cis to the Rh-O bond). We argue further that the
product-forming step involves a [2 + 2]-cycloaddition of the
1-alkyne to 8, as shown in 9, followed by reductive elimination to
form the (1S)-cyclopropene carboxylate, the observed major enan-
tiomer, as shown in Table 1. It is important to note that the same
enantiomeric cyclopropene would result if the roles of the two
rhodiums in structures 8 and 9 are reversed, because of the
C2-symmetry of the two chelate rings orthogonal to the acetate
bridge of 1. An analogous mode of addition of styrene and 1,1-
diphenylethylene to 8 leads to the observed products 3-5. We
believe that this type of pathway may be general for other Rh(II)-
catalyzed cyclopropanations.3-5,17
a Enantiomeric purity for entries 1-7 was determined by GC analysis
using either a Cyclosil B or γ-TA column; for entry 8, ee was determined
by HPLC analysis using a Chiracel OJ column. Absolute configurations
were assigned from comparison of rotation with literature values except
for entries 2, 5, 7, and 8 for which the assignment followed from the
observed dextrorotation. b Pentane was used as a solvent.
1]-cycloaddition of ethyl diazoacetate to the ene yne substrate occurs
selectively at the acetylenic linkage.15
The reaction of ethyl diazoacetate and styrene with 0.5 mol %
1 as a catalyst (CH2Cl2, 23 °C) affords a 2:1 mixture of ethyl
(1S,2R)-2-phenylcyclopropane carboxylate (3, 99% ee) and ethyl
(1S,2S)-2-phenylcyclopropane carboxylate (4, 94% ee) in 84% yield.
The formation of 3 and 4 implies high face-selectivity for the
[2 + 1]-cycloaddition at the carbenoid center but only 2:1 π-facial
selectivity at the olefinic linkage. Internal competition experi-
ments with a mixture of 4-methoxystyrene and 4-nitrostyrene
(N2CHCOOEt, 0.5 mol % 1 in CH2Cl2 at 23 °C) demonstrated that
the former olefin underwent reaction 1.7 times faster than the latter
(97% ee for each of the two cis-cyclopropyl esters), a surprisingly
small rate factor for a reaction thought to proceed by asynchronous
attack of an electrophilic carbenoid on the terminal carbon of the
double bond.10 As expected, 1,1-diphenylethylene and ethyl diaz-
oacetate (0.5 mol % 1, CH2Cl2, 23 °C) gave the (S)-cyclopropyl
ester 5 with high enantioselectivity (92% ee, 74% yield).
Powerful independent support for the mechanistic pathway
described above has been obtained by the synthesis of complex 10
(structure proved by X-ray analysis), prepared from Rh2(t-BuCO2)4
(chosen for its solubility) and (R,R)-DPTI, and the study of
enantioselective [2 + 1]-cycloaddition of N2CHCOOEt with a
sampling of the terminal acetylenes of Table 1. For the cases
corresponding to entries 2, 4, and 5, the same products were formed
using 10 (0.05 mol %) instead of 1 with ee values of 91, 80, and
88%, respectively, under the conditions indicated in Table 1. The
reaction of N2CHCOOEt with styrene under catalysis by 10 (0.05
mol %) provided 3 (97% ee) and 4 (91% ee), nearly identical to
the results with catalyst 1. The similarity of results with catalysts
1 and 10 is readily explained in terms of transition states 9 and 11.
In contrast, there seems to be no way in which the good ee values
obtained with 10 can be rationalized in terms of a tetrabridged
carbenoid intermediate since the upper right quadrant of 10, which
is sterically most open for [2 + 1]-cycloaddition of acetylene to
the carbenoid,10 is also effectively achiral.
Catalyst 1 has also been found to be effective in promoting C-H
bond insertion reactions, for example the conversion of 6 to 7 in
96% ee and 51% yield.16
The chiral 2-substituted 2-cyclopropene-carboxylic esters that
are available through the use of catalyst 1 in high enantiomeric
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C O M M U N I C A T I O N S
Scheme 1. Some Useful Transformations of Chiral Cyclopropenes
for the synthesis of the structurally related fatty acid (11R,12S)-
lactobacillic acid.20
Note Added after ASAP Posting. After this paper was posted
ASAP on 06/30/2004, structures 8-11 were corrected and the
reaction conditions were added to Scheme 1. The corrected version
was posted 07/06/2004.
Supporting Information Available: Experimental procedures for
reactions and X-ray structural data for 1, 2, and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
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then EtOAC, then I2 (71%). (e) DIBAL (2 equiv) in PhCH3 for 1 h at
-78 °C, then 1 h at 23 °C (83%). (f) 5% Pd on CaCO3 (1 mol %) in EtOAc
with H2 (1 atm) 2 h (92%). (g) Pd(PPh3)4 (1 mol %) and n-Bu3SnH
(1.1 equiv) in THF at -78 °C for 1 h (82%).
Scheme 2. Synthesis of (9R,10S)-Dihydrosterculic Acid
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purity are valuable and versatile synthetic intermediates. Scheme
1 details a number of interconversions that have been carried out
with ethyl (1S)-2-n-pentyl-2-cyclopropene-carboxylate.18 It is note-
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access to the cis or trans cyclopropyl derivatives that would result
from cyclopropanation of terminal olefins, but without problems
of cis/trans stereoselectivity.
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mixture (10:1 C6H6-CH3CN) periodically. A mixture of anhydrous Na2-
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diazoacetate and 0.5 mol % 1 in CH2Cl2 at 23 °C with 1-nonyne is 2.4
times as fast as with 1-nonene.
(16) Trans isomer of 7 was also formed as a minor product (ratio 5:1).
(17) These analyses will be detailed in a subsequent publication. Even if the
intermediate Rh-carbene complex is an equilibrating mixture of tetra-
bridged and tribridged species (the latter analogous to 8) and even if the
tribridged species is only a minor component of that equilibrium, the
metallacyclobutane pathway (e.g., as in 9) proposed herein could still
dominate kinetically.
We have also applied the methodology described above to the
first enantioselective synthesis of the naturally occurring fatty acid
(9R,10S)-dihydrosterculic acid (12), a common cyclopropyl fatty
acid of microorganisms and subtropical plants.19 The chiral cyclo-
propene 13 (87% ee), which is readily available from ethyl
diazoacetate and 1-decyne using the enantiomer of catalyst 1
(synthesized starting from (S,S)-diphenylethylenediamine), was
converted to the cis aldehyde 14 by the sequence: (1) catalytic
reduction using 5% Pd-CaCO3 and 1 atm of H2 in EtOAc at 23
°C for 2 h (90%); (2) reduction of COOEt to CH2OH using LiAlH4
in ether at 23 °C for 1 h (78%); and (3) Swern oxidation of CH2OH
to CHO with Me2SO and oxalyl chloride in CH2Cl2 at -78 °C
followed by Et3N and warming to 23 °C (95%). Wittig coupling
of aldehyde 14 with the ylide from 7-triphenylphosphonioheptanoic
acid bromide and 2 equiv of LDA in THF at -78 to 23 °C produced
the unsaturated acid 15 (72%, Z/E ) 4:1), which was reduced by
stirring with H2NNH2 and air in ethanol containing a catalytic
amount of CuSO4 (via diimide, N2H2) to afford (9R,10S)-dihy-
drosterculic acid as a colorless solid, mp 29-30 °C, in 85% yield.
This synthesis is much shorter than a recently published process
(18) For recent reviews of transformations on cyclopropenes, see: (a) Baird,
M. S. Cyclopropanes: Synthesis: From Cyclopropenes. In Houben-Weyl;
Thieme: Stuttgart, 1997; pp 114-255. (b) Nakamura, M.; Isobe, H.;
Nakamura, E. Chem. ReV. 2003, 103, 1295-1326.
(19) (a) Grogan, D. W.; Cronan, J. E., Jr. Microbiol. Mol. Biol. 1997, 61, 429-
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(20) Coxon, G. D.; Al-Dulayymi, J. R.; Baird, M. S.; Knobl, S.; Roberts, E.;
Minnikin, D. E. Tetrahedron: Asymmetry 2003, 14, 1211-1222.
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