Regioselective rhodium-catalyzed hydroformylation of 1,3-dienes to highly enantioenriched β,γ-unsaturated aldehyes with diazaphospholane ligands

Article abstract of DOI:10.1021/ol102797t

Regioselective and enantioselective rhodium-catalyzed hydroformylation of 1,3-dienes with chiral bisdiazaphospholane ligands yields β,γ- unsaturated aldehydes that retain a C=C functionality for further conversion. The reaction conditions are mild, featuring low catalyst loadings (0.5 mol %), pressures readily obtained in glass bottles, and convenient reaction times (1.5-12 h). Optimized reaction conditions produce high enantioselectivity (>90% ee), regioselectivity (88-99%), and conversion to β,γ- unsaturated aldehydes (99%) for ten 1,3-dienes encompassing a variety of substitution patterns.

Full text of DOI:10.1021/ol102797t

ORGANIC
LETTERS
2011
Vol. 13, No. 1
164-167
Regioselective Rhodium-Catalyzed
Hydroformylation of 1,3-Dienes to Highly
Enantioenriched ꢀ,γ-Unsaturated
Aldehyes with Diazaphospholane
Ligands
Avery L. Watkins and Clark R. Landis*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706, United States
landis@chem.wisc.edu
Received November 17, 2010
ABSTRACT
Regioselective and enantioselective rhodium-catalyzed hydroformylation of 1,3-dienes with chiral bisdiazaphospholane ligands yields ꢀ,γ-
unsaturated aldehydes that retain a CdC functionality for further conversion. The reaction conditions are mild, featuring low catalyst loadings
(0.5 mol %), pressures readily obtained in glass bottles, and convenient reaction times (1.5-12 h). Optimized reaction conditions produce
high enantioselectivity (>90% ee), regioselectivity (88-99%), and conversion to ꢀ,γ-unsaturated aldehydes (99%) for ten 1,3-dienes encompassing
a variety of substitution patterns.
Asymmetric hydroformylation (AHF) of alkenes is a cata-
lytic, atom economical route to enantioenriched aldehydes
under mild reaction conditions.1,2 Chiral diazaphospholane
ligands yield particularly fast and selective rhodium catalysts
for the AHF of simple alkenes.3 The AHF of 1,3-dienes
provides convenient access to ꢀ,γ-unsaturated aldehyde
intermediates in natural product syntheses,4 as demonstrated
by Jacobsen and Liu’s synthesis of (+)-ambruticin.5a Al-
though considered to be “especially challenging”,5a Takaya,
Nozaki, et al.4b,c demonstrated effective hydroformylation
(78-94% regioselectivity and 80-97% ee) for three diene
substrates with rhodium catalysts modified by the (R,S)-
BINAPHOS ligand. However, the procedure requires 1-3
day reaction times, high-pressure autoclaves, and excess
ligand. In this contribution, we report the synthesis of
R-chiral ꢀ,γ-unsaturated aldehydes by regio- (88-99%) and
enantioselective (90-97% ee) rhodium-catalyzed AHF of
ten 1,3-diene substrates in the presence of chiral diazaphos-
(1) For a recent review on enantioselective hydroformylation see: Breit,
B.; Seiche, W. Synthesis 2001, 1
.
(2) See for example: Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am.
Chem. Soc. 1993, 115, 7033. Dieguez, M.; Pamies, O.; Ruiz, A.; Claver,
C. New J. Chem. 2002, 26, 827. Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker,
G. T. Org. Lett. 2004, 6, 3277. Cobley, C. J.; Gardner, K.; Klosin, J.;
Praquin, C.; Hill, C.; Whiteker, G. T.; Zanotti-Gerosa, A.; Petersen, J. L.;
Abboud, K. A. J. Org. Chem. 2004, 69, 4031. Yan, Y. J.; Zhang, X. M.
J. Am. Chem. Soc. 2006, 128, 7198
.
(3) (a) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud,
K. A. J. Am. Chem. Soc. 2005, 127, 5040. (b) Klosin, J.; Landis, C. R.
Acc. Chem. Res. 2007, 40, 1251. (c) Thomas, P. J.; Axtell, A. T.; Klosin,
J.; Peng, W.; Rand, C. L.; Clark, T. P.; Landis, C. R.; Abboud, K. A. Org.
Lett. 2007, 9, 2665. (d) Watkins, A. L.; Hashiguchi, B. G.; Landis, C. R.
Org. Lett. 2008, 10, 4553.
(4) See for example (+)-Ambruticin: (a) Liu, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2001, 123, 1072. (b) Amphidinolixe, X.; Furstner, A.; Kattnig,
E.; Lepage, O. J. Am. Chem. Soc. 2006, 128, 9194. (c) Discodermolide,
L. E.; Poree, F.; Bourin, A.; Barbion, J.; Agouridas, E.; Lannou, M.;
Commercon, A.; Betzer, J.; Pancrazi, A.; Ardisson, J. Chem.sEur. J. 2008,
14, 11092.
10.1021/ol102797t  2011 American Chemical Society
Published on Web 12/06/2010

pholane ligands (Figure 1) using glass bottle reactors, 1-12
h reaction times, and 1.1 equiv of ligand.
During the course of our studies, we were unable to
achieve high enantioselectivities for 1,3-dienes that comprise
(E) and (Z) stereoisomer mixtures. This suggests that the
enantioselectivity of the reaction depends on the 1,3-diene
stereochemistry. For example, subjecting (E)-1-trisisopro-
pylsilyoxy-1,3-diene to AHF yielded the 2-formyl aldehyde
2.5:1 ratio of the (E)- and (Z)-stereoisomers (Scheme 2) and
Scheme 2. Substrate Stereochemistry Effect
Figure 1. Diazaphospholane ligand structures.
with 90% enantiomeric excess for the (Z)-product (we were
unable to determine the ee of the (E)-product). On the other
hand, AHF of the (Z)-stereoisomer gives the 2-formyl
aldehyde with identical 2:1 E:Z ratio and, for the (Z)-product,
the opposite sense of chirality in only 70% enantiomeric
excess. Thus, we focused our attention primarily on 1,3-
dienes that could be obtained as pure samples of the (E)-
stereoisomer.
AHF of monosubstituted 1,3-dienes bearing aromatic and
heteroaromatic substituents (entries 1 and 2) gives excellent
enantioselectivities (91% ee and 97% ee, respectively) and
exclusive formation of the (E)-stereoisomer. AHF of dienyl
ethers produces 2-formyl aldehydes with high levels of
enatioselectivity (90-94% ee). However, these aldehydes
exist as a 1:1 mixture of (E)- and (Z)-stereoisomers, with
somewhat reduced enantioselectivity observed for the (Z)-
isomer. Attempts to increase the stereoselectivity by incor-
porating a sterically demanding TIPS group (entry 5)
provided only a small increase in stereoselectivity (2.5:1 E:Z)
while maintaining excellent enantioselectivity. Dienyl ethers
are interesting substrates for AHF because reduction of both
the aldehyde and alkene provides a straightforward route to
monoprotected chiral 1,4-butanediols. Highly selective AHF
extends to carboethoxy-1,3-pentadiene (Table 1, entry 6).
AHF of this 1,1-disubstituted diene completes in only 1.5 h
yielding exclusively the (E)-stereoisomer of the ꢀ,γ-unsatur-
ated, 2-formyl aldehyde in 91% enantiomeric excess.
One approach to non-AHF, direct synthesis of chiral ꢀ,γ-
unsaturated aldehydes involves the asymmetric organocata-
lytic addition of vinyl triflourborate salts to “SOMO”
activated nascent enamines as reported by MacMillan and
Kim.6 Hydroformylation of dienes presents many opportuni-
ties for the synthesis of both fine and commodity chemicals.7
AHF of dienes to yield chiral ꢀ,γ-unsaturated aldehydes
intrinsically are advantaged due to the mild temperatures and
essentially neutral pH, so long as the stereoselectivity of the
double bond, along with regioselectivity and enantioselec-
tivity of formylation, are controlled. For the dienes examined
herein, 2-formyl products are preferred (see eq 1 for the
numbering scheme used for all products and reactants).
We initiated our studies by evaluating the hydroformyla-
tion of (E)-1-phenyl-1,3-butadiene (4) under conditions of
150 psi synthesis gas (1:1 CO:H2) using 0.5 mol % of
Rh(acac)(CO)2 and 0.55 mol % of ligands 1-38 at 40 °C
(Scheme 1). The reactions were complete within 4 h,
Scheme 1. Ligand Influence on Enantioselectivity
(5) (a) Smejkal, T.; Han, H.; Breit, B.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 10036. (b) Horiuchi, T.; Ohta, T.; Nozaki, K.; Takaya, H.
Chem. Commun. 1996, 155. (c) Horiuchi, T.; Ohta, T.; Shirakawa, E.;
Nozaki, K.; Takaya, H. Tetrahedron 1997, 53, 7795.
producing the ꢀ,γ-unsaturated 2-formyl regioisomer as the
sole product in each case. Although excellent enantioselec-
tivity (90% ee) was observed with use of ligand 1, only
modest enantioselectivities of 60% ee and 26% ee were
obtained with ligands 2 and 3, respectively. All three ligands
yielded (E) alkene stereochemistry, exclusively.
(6) Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398.
(7) (a) Clement, W. H.; Orchin, M. Ind. Eng. Chem. Prod. Res. DeV.
1965, 4, 283. (b) Fell, B.; Bahrmann, H. J. Mol. Catal. 1977, 2, 211. (c)
Bahrmann, H.; Fell, B. J. Mol. Catal. 1980, 8, 329. (d) Botteghi, C.; Branca,
M.; Saba, A. J. Organomet. Chem. 1980, 184, C17. (e) van Leeuwen,
P. W. N. M.; Roobeek, C. F. J. Mol. Catal. 1985, 31, 345. (f) Chalchat,
J. C.; Garry, R. P.; Lecomte, E.; Michet, A. FlaVour Fragrance J. 1991, 6,
178. (g) Bertozzi, S.; Campigli, N.; Vitulli, G.; Lazzaroni, R.; Salvadori,
P. J. Organomet. Chem. 1995, 487, 41. (h) Barros, H. J. V.; Hanson, B. E.;
dos Santos, E. N.; Gusevskaya, E. V. Appl. Catal., A 2004, 278, 57. (i)
Barros, H. J. V.; da Silva, J. G.; Guimaraes, C. C.; dos Santos, E. N.;
Gusevskaya, E. V. Organometallics 2008, 27, 4523.
(8) Ligands 1 and 2 are commercially available from Sigma Aldrich.
Org. Lett., Vol. 13, No. 1, 2011
165

Table 1. Substrate Scope for the Asymmetric Hydroformylation 1,3-Dienes with Ligands 1-3a
a Reaction conditions unless otherwise noted: [alkene] ) 1.2 M, [Rh] ) 0.006 M, [ligand] ) 0.0066 M, 150 psi 1:1 CO/H2, 40 °C in toluene. b Determined
via H NMR spectroscopy. c Determined by chiral GC or chiral SFC chromatography (see the Supporting Information). d Reaction performed with 120 psi
1
CO, 40 psi H2, 50 °C. e Values for % ee are listed as (E-isomer, Z-isomer); E- and Z-isomers have opposite absolute configurations.
The successful hydroformylation of carboethoxy-1,3-
pentadiene is noteworthy, as evidenced by Fu¨rstner et al.’s
recent use of the same aldehyde in the total synthesis of
Iejimalide B.9 Their route to the chiral aldehyde involved 6
steps starting from enantiopure Roche ester (methyl 3-hy-
droxy-2-methylpropionate). In contrast, catalytic AHF of the
achiral 1,3-diene substrate provides this aldehyde in one step.
the 2-formyl aldehyde was observed with exclusive (E)
stereochemistry and 93% enantiomeric excess. Greater
selectivity is observed when the phenyl group is replaced
with the less bulky and more electron rich furyl group (entry
8). AHF of 1-(2-furyl)-2-methyl-1,3-butadiene gives 2-formyl
aldehydes regioselectively (98%) as a single (E)-stereoisomer
with 93% enantiomeric excess. The more rigid vinyl cyclo-
hexene (entry 9) substrate proceeds with reduced regiose-
lectivity (88% 2-formyl and 12% achiral 1-formyl) but with
92% ee.
AHF of 1,2-disubstituted dienes (Table 1, entries 7-9) is
more challenging. The combination of the less sterically
hindered ligand 3 and a slightly elevated partial pressure of
CO (120 psi CO, 40 psi H2) were necessary to achieve good
selectivity. From ligand screening results (see the Supporting
Information), it appears that the steric parameter of the ligand
affects the regioselectivity. Increasing the carbon monoxide
partial pressure suppresses formation of 1-formyl aldehydes
and increases enantioselectivity for the formation of 2-formyl
aldehydes. AHF of 1-phenyl-2-methyl-1,3-butadiene with
ligand 3 at 50 °C with 120 psi CO, 40 psi H2 (entry 7) is
complete within 4 h, yielding 2-formyl (88%) and 4-formyl
aldehydes (12%). Interestingly, both regiosomers are ꢀ,γ-
unsaturated aldehydes. Despite the reduced regioselectivity,
AHF of internal alkenes is especially challenging, never-
theless 1-phenyl-1(E),3(Z)-diene yields high selectivity with
ligand 2 (Table 1, entry 10). Complete consumption of the
1,3-diene is observed in 12 h, yielding the (E)-2-formyl
aldehyde as the sole reaction product with excellent enan-
tioselectivity (90% ee).
It is interesting that diazaphospholane-based AHF of (E)-
1,3-dienes yields mixed (E)- and (Z)-stereoisomers with
opposite absolute senses of stereochemistry (i. e., 2(R),3(E)
and 2(S),3(Z)-2-formyl aldehydes) for entries 3-5 (Table
1). Analysis of the reaction mixtures at partial substrate
conversion revealed no evidence for E-Z interconversion
of the parent diene. This suggests that E-Z interconversion
occurs “on” the cycle without dissociation of isomerized
(9) Fu¨rstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.;
Teply, F.; Aissa, C.; Moulin, E.; Mu¨ller, O. J. Am. Chem. Soc. 2007, 129,
9150.
166
Org. Lett., Vol. 13, No. 1, 2011

Scheme 3. Proposed Mechanism for the AHF of 1,3-Dienes
diene. The left side of Scheme 3 provides a plausible
rationalization: the initial insertion of the vinyl group into
the Rh-H bond is highly selective for the re enantioface
but E-Z isomerization necessarily inverts the stereochemistry
at the 2-position. Similar π-allyl complexes have been
previously suggested as intermediates in the hydroformyla-
tion of 1,3-dienes7a,i,4b and the sequence of σ-π allyl
interchanges and C-C bond rotations have well-documented
precedent in π-allylpalladium complexes.10 Ultimately the
E:Z ratio is controlled by the flux through points A and B of
Scheme 3.
Further insight into stereocontrol is provided by the
stereochemical outcome of the hydroformylation of (Z)-TIPS
dienyl ether (Scheme 2). As illustrated on the right side of
Scheme 3, addition of Rh-H to the diene is re selective but
less so than for the (E) diene. Rapid σ-π exchanges and
C-C rotations establish Curtin-Hammet conditions with the
E:Z ratio controlled by the relative fluxes through points D
and C. Because the ultimate product regioselectivity is
independent of the initial diene stereochemistry, this model
requires that fluxA/fluxB ) fluxD/fluxC ≈ 2.5. For the R )
OAc, OMe substituents, fluxA/fluxB ≈ 1. For substrates that
give 2-formyl aldehydes with exclusively (E)-alkene stere-
ochemistry, it is likely that rotation about the C4-C3 bond
is prevented for steric reasons.
scaffold, introduction of a chiral branching point, and
installation of a versatile aldehyde group while retaining
an alkene functionality for further transformation in an
atom efficient catalytic process. The resulting ꢀ,γ-unsatur-
ated aldehydes may be subjected to alkene metathesis,
reduced and subjected to Sharpless epoxidation, hydro-
genated to the corresponding alkanes and/or alcohols, etc.
Although one must take caution in comparing catalysts’
performance because conditions may not be optimized,
the diazaphospholane ligands appear to give significantly
(at least 10-fold) higher rates and somewhat higher
selectivities under milder conditions than prior re-
ports.4b,c
Acknowledgment. This research was supported by a grant
from the National Science Foundation (NSF-CHE-0715491).
We are grateful to Dow Chemical for their generous donation
of Rh(acac)(CO)2 and assistance with large-scale ligand
preparation. We also would like to thank Prof. Tehshik Yoon
and co-workers of the University of Wisconsin-Madison
for access to SFC instrumentation.
Supporting Information Available: Experimental details,
characterization data, and conditions for the determination
of enantiomeric excess. This material is available free of
charge via the Internet at http://pubs.acs.org.
The significance of successful diene AHF to organic
synthesis lies in the simultaneous extension of the carbon
(10) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,
39, 747.
OL102797T
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