Phosphine-Catalyzed Doubly Stereoconvergent γ-Additions of Racemic Heterocycles to Racemic Allenoates: The Catalytic Enantioselective Synthesis of Protected α,α-Disubstituted α-Amino Acid Derivatives

Article abstract of DOI:10.1021/jacs.5b05528

Methods have recently been developed for the phosphine-catalyzed asymmetric γ-addition of nucleophiles to readily available allenoates and alkynoates to generate useful α,β-unsaturated carbonyl compounds that bear a stereogenic center in either the γ or t

Full text of DOI:10.1021/jacs.5b05528

Article
pubs.acs.org/JACS
Phosphine-Catalyzed Doubly Stereoconvergent γ‑Additions of
Racemic Heterocycles to Racemic Allenoates: The Catalytic
Enantioselective Synthesis of Protected α,α-Disubstituted α‑Amino
Acid Derivatives
Marcin Kalek and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Methods have recently been developed for the phosphine-
catalyzed asymmetric γ-addition of nucleophiles to readily available
allenoates and alkynoates to generate useful α,β-unsaturated carbonyl
compounds that bear a stereogenic center in either the γ or the δ position
(but not both) with high stereoselectivity. The utility of this approach
would be enhanced considerably if the stereochemistry at both termini of
the new bond could be controlled effectively. In this report, we describe
the achievement of this objective, specifically, that a chiral phosphepine
can catalyze the stereoconvergent γ-addition of a racemic nucleophile to
a racemic electrophile; through the choice of an appropriate heterocycle
as the nucleophilic partner, this new method enables the synthesis of
protected α,α-disubstituted α-amino acid derivatives in good yield,
diastereoselectivity, and enantioselectivity.
substantially enhance the utility of this strategy by developing a
method that would control the stereochemistry at both termini
of the newly created bond (eq 3). To the best of our
INTRODUCTION
■
In recent years, nucleophilic catalysis by chiral tertiary
phosphines has emerged as a powerful strategy for the
enantioselective synthesis of a wide array of useful compounds.1
Exemplary of this approach is the phosphine-catalyzed addition
of nucleophiles to the γ-position of electron-deficient alkynes
and allenes,2 which furnishes α,β-unsaturated carbonyl
compounds that are well-suited for further stereoselective
functionalizations (eqs 13 and 24).5
knowledge, there has been only a single isolated example of a
phosphine-catalyzed γ-addition between such partners, a
coupling that proceeded with modest diastereoselectivity
(2.5:1) and good enantiomeric excess (91−92%).3c
Although we were concerned that this effort might be
stymied by the propensity of the electrophilic allene/alkyne to
isomerize to a 1,3-diene6 rather than form a carbon−carbon
bond with a hindered tertiary nucleophile, we were particularly
attracted by the potential to generate products that are more
stereochemically rich than in previous studies and to achieve a
doubly stereoconvergent reaction of two racemic coupling
partners, one with a stereogenic center and the other with a
stereogenic axis. In this report, we describe the achievement of
our objective, specifically, a phosphine-catalyzed γ-addition that
furnishes α,α-disubstituted α-amino acid derivatives,7,8 an
important family of target molecules, with very good
diastereoselectivity and enantioselectivity (eq 4).
To date, systematic studies of phosphine-catalyzed enantio-
selective γ-additions have been limited to processes that control
a single stereocenter, either in the γ or in the δ position (eqs 1
and 2, respectively).3,4 We recently decided to attempt to
Received: May 28, 2015
© XXXX American Chemical Society
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DOI: 10.1021/jacs.5b05528
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Table 2. Phosphine-Catalyzed Doubly Stereoconvergent γ-
a
Additions: Scope with Respect to the Allenoate
RESULTS AND DISCUSSION
■
Upon exploring a variety of reaction parameters for a model
coupling between a 1,3-oxazol-5(4H)-one and an allenoate, we
have been able to develop conditions that furnish the desired γ-
addition product in good yield, diastereoselectivity, and
enantioselectivity in the presence of phosphepine 19 (Table
1, entry 1). No γ-addition is observed in the absence of the
Table 1. Phosphine-Catalyzed Doubly Stereoconvergent γ-
a
Additions: Effect of Reaction Parameters
a
b
All data are the average of two experiments. Yield of purified
c
product, isolated as a mixture of diastereomers. Determined through
1
analysis by H NMR spectroscopy of the unpurified reaction mixture.
d
e
ee of the major diastereomer. Catalyst loading: 10%.
position of the allenoate (R1) are tolerated, and functional
groups such as a silyl ether, a cis alkene, an alkyne, a thiophene,
and a primary alkyl chloride are compatible with the reaction
conditions (entries 5−13). On a gram scale (1.17 g of product),
the catalytic enantioselective γ-addition illustrated in entry 10
proceeds in 90% yield, 15:1 dr, and 94% ee.
a
b
All data are the average of two experiments. Combined yield of the
c
two diastereomers. Determined through analysis by 1H NMR
spectroscopy. ee of the major diastereomer. A negative ee value
d
We have also examined the scope with respect to the
nucleophilic partner (the 1,3-oxazol-5(4H)-one) in the doubly
stereoconvergent γ-addition (Table 3).13 As the substituent R
in the 4 position increases in size from Me to i-Bu, a small loss
in ee is observed, although the yield and the diastereoselectivity
remain high (entries 1−3). Functional groups such as an olefin,
an ether, an imide, a protected indole, and a sulfide are
tolerated. The enantiomeric excess of the product is
independent of whether racemic or enantioenriched 1,3-
oxazol-5(4H)-one is employed as the nucleophile.
An attempt to achieve a doubly stereoconvergent γ-addition
of a 1,3-oxazol-5(4H)-one bearing an aromatic substituent in
the 4 position furnished essentially none of the desired product
(<1% yield). Building on our hypothesis that the greater
stability of the conjugate base of this coupling partner might be
attenuating its nucleophilicity, we decided to explore the
reactivity of a more electron-rich family of heterocycles,
specifically, 2-amino-3,5-dihydro-4H-imidazol-4-ones. We were
pleased to determine that, under related conditions, an array of
γ-additions of this family of aryl-substituted nucleophiles can be
signifies the predominant formation of the enantiomer of the
illustrated product.
phosphine (entry 2), and related phosphepines (2 and 3) as
well as spirophosphine 410 do not provide satisfactory results
(entries 3−5). A modestly inferior yield, diastereoselectivity,
and/or enantioselectivity are obtained at room temperature or
in the absence of the phenol (entries 6 and 7).11
Having identified effective conditions, we examined the
scope of this new method for the catalytic asymmetric synthesis
of α,α-disubstituted α-amino acid derivatives. With regard to
the allenoate coupling partner (Table 2),12 the choice of the R2
group of the ester has only a modest impact on the course of
the reaction (entries 1−4). A variety of substituents in the γ-
B
DOI: 10.1021/jacs.5b05528
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Table 3. Phosphine-Catalyzed Doubly Stereoconvergent γ-
Additions: Scope with Respect to the 1,3-Oxazol-5(4H)-
one
Table 4. Phosphine-Catalyzed Doubly Stereoconvergent γ-
Additions: 2-Amino-3,5-dihydro-4H-imidazol-4-ones as
Nucleophiles
a
a
a
b
All data are the average of two experiments. Yield of purified
c
product, isolated as a mixture of diastereomers. Determined through
1
analysis by H NMR spectroscopy of the unpurified reaction mixture.
d
ee of the major diastereomer.
consecutive stereocenters wherein the newly introduced
oxygens are differentiated (eq 6).
A possible mechanism for these phosphine-catalyzed γ-
additions of heterocycles to allenoates is outlined in Figure 1. In
a
b
All data are the average of two experiments. Yield of purified
c
product, isolated as a mixture of diastereomers. Determined through
1
analysis by H NMR spectroscopy of the unpurified reaction mixture.
d
e
ee of the major diastereomer. The diastereomeric products were
isolated separately.
achieved in good yield, diastereoselectivity, and enantioselec-
tivity (Table 4). In addition to serving as protected α,α-
disubstituted α-amino acid derivatives, 2-amino-3,5-dihydro-
4H-imidazol-4-ones are interesting targets in their own right.14
The products of our phosphine-catalyzed stereoconvergent γ-
additions can be transformed into other interesting compounds.
For instance, selective hydrolytic ring opening of the 1,3-
oxazol-5(4H)-one reveals an N-protected α,α-disubstituted α-
amino acid (eq 5).7 Furthermore, ruthenium-catalyzed
Figure 1. Outline of a possible mechanism for the phosphine-catalyzed
γ-addition of 1,3-oxazol-5(4H)-ones to allenoates (for the sake of
simplicity, all steps are drawn as irreversible, and alkenes are illustrated
as single isomers).
the first step of the catalytic cycle, the nucleophilic phosphine
catalyst adds to the β position of the allenoate to furnish
zwitterion A, which upon protonation by the 1,3-oxazol-5(4H)-
one affords ion pair B.15 Next, the deprotonated heterocycle
adds γ to the carbonyl group of the phosphonium salt,
generating ylide C; if the phosphonium salt (B) is instead
deprotonated in the δ position, then the undesired diene can be
formed.6a Tautomerization (C → D) followed by fragmenta-
dihydroxylation, followed by in situ lactonization, proceeds
with high diastereoselectivity to afford a product that bears four
C
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tion yields the desired γ-addition product and regenerates the
phosphine catalyst.
AUTHOR INFORMATION
■
Corresponding Author
By following the progress of a phosphine-catalyzed
enantioselective γ-addition over time, we have determined
that there is a modest kinetic resolution of the racemic
allenoate (selectivity factor ∼4).16 We have separated the
enantiomers of the allenoate, and we have confirmed that they
do indeed react at different rates and that they generate the γ-
addition product with the same enantiomeric excess, consistent
with the mechanism outlined in Figure 1 wherein the original
stereochemistry of the allenoate is lost in the formation of
intermediate A. We have determined that the unreacted 1,3-
oxazol-5(4H)-one (pKa ∼19 in DMSO)17 is essentially racemic
throughout the course of the reaction. The ee of the product
remains constant during the γ-addition process.
*gcfu@caltech.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences: R01-
GM57034) and the Swedish Research Council (fellowship for
M.K.: Dnr 350-2012-6645). We thank Dr. Nathan D. Schley,
Dr. Michael K. Takase (X-ray Crystallography Facility; a Bruker
KAPPA APEX II X-ray diffractometer was purchased via NSF
CRIF:MU Award CHE-0639094), Dr. David G. VanderVelde
(NMR Facility), Dr. Scott C. Virgil (Center for Catalysis and
Chemical Synthesis, supported by the Gordon and Betty
Moore Foundation), and Dr. Daniel T. Ziegler for assistance.
The rate law for the phosphine-catalyzed γ-addition of a 1,3-
oxazol-5(4H)-one to an allenoate is first-order in the catalyst
and in the allenoate, and it is zeroth-order in the nucleophile
and in the phenol; moreover, we have established through a 31
P
NMR spectroscopic study that the resting state of the catalyst is
the free phosphine. Taken together, these observations are
consistent with a mechanism wherein the first step of the
catalytic cycle, the addition of the phosphine catalyst to the
allenoate to form zwitterion A, is the turnover-limiting step.18
REFERENCES
■
(1) For recent reviews and leading references, see: (a) Xiao, Y.; Sun,
Z.; Guo, H.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089−2121.
(b) Fan, Y. C.; Kwon, O. In Science of Synthesis: Asymmetric
Organocatalysis; List, B., Maruoka, K., Eds.; Georg Thieme Verlag:
Stuttgart, 2012; Vol. 1, pp 723−782.
(2) For initial studies of γ-addition processes that generated achiral or
racemic products, see: (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc.
1994, 116, 3167−3168. (b) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc.
1994, 116, 10819−10820.
(3) For examples of processes that generate a γ stereocenter with
good enantiomeric excess, see: (a) Chung, Y. K.; Fu, G. C. Angew.
Chem., Int. Ed. 2009, 48, 2225−2227. (b) Smith, S. W.; Fu, G. C. J.
Am. Chem. Soc. 2009, 131, 14231−14233. (c) Sinisi, R.; Sun, J.; Fu, G.
C. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20652−20654. (d) Sun, J.;
Fu, G. C. J. Am. Chem. Soc. 2010, 132, 4568−4569. (e) Fujiwara, Y.;
Sun, J.; Fu, G. C. Chem. Sci. 2011, 2, 2196−2198. (f) Lundgren, R. J.;
Wilsily, A.; Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew. Chem.,
Int. Ed. 2013, 52, 2525−2528. (g) Fang, Y.-Q.; Tadross, P. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2014, 136, 17966−17968.
(4) For examples of processes that generate a δ stereocenter with
good enantiomeric excess, see: (a) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao,
D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631−5635. (b) Wang,
T.; Yao, W.; Zhong, F.; Pang, G. H.; Lu, Y. Angew. Chem., Int. Ed.
2014, 53, 2964−2968. (c) Chen, J.; Cai, Y.; Zhao, G. Adv. Synth. Catal.
2014, 356, 359−363.
(5) For leading references, see: Catalytic Asymmetric Conjugate
Reactions; Cordova, A., Ed.; Wiley−VCH: Weinheim, 2010.
(6) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933−7935. (b) For a review, see: Kwong, C. K.-W.; Fu, M. Y.; Lam,
C. S.-L.; Toy, P. H. Synthesis 2008, 2008, 2307−2317.
(7) For a brief review with leading references on the synthesis and
the significance of α,α-disubstituted α-amino acids, see: Metz, A. E.;
Kozlowski, M. C. J. Org. Chem. 2015, 80, 1−7.
(8) For an example of a bioactive 1,3-oxazol-5(4H)-one, see: Pinto, I.
L.; West, A.; Debouck, C. M.; DiLella, A. G.; Gorniak, J. G.;
O'Donnell, K. C.; O'Shannessy, D. J.; Patel, A.; Jarvest, R. L. Bioorg.
Med. Chem. Lett. 1996, 6, 2467−2472.
CONCLUSIONS
■
We have developed the first phosphine-catalyzed γ-addition
reactions in which two adjacent stereogenic centers are
controlled with very good diastereoselectivity and enantiose-
lectivity; this doubly stereoconvergent process employs two
racemic coupling partners, one with a stereogenic center and
the other with a stereogenic axis. The method provides ready
access to an array of protected, unsaturated α,α-disubstituted α-
amino acid derivatives, which can undergo selective trans-
formations that further enlarge the diversity of products that
can be generated through this method. A mechanistic
investigation establishes that, during the course of the γ-
addition, there is modest kinetic resolution of the racemic
allenoate, whereas the nucleophile remains racemic. The
available data are consistent with the addition of the phosphine
catalyst to the allenoate being the turnover-limiting step of the
catalytic cycle. Further studies of phosphine-catalyzed stereo-
selective reactions are underway.
EXPERIMENTAL SECTION
■
General Procedure. An oven-dried 20 mL vial was charged with
catalyst 1 (6.8 mg, 0.018 mmol, 5%), 2-chloro-6-methylphenol (4.2
μL, 5.0 mg, 0.035 mmol, 10%), and the 1,3-oxazol-5(4H)-one (0.35
mmol). The vial was capped with a PTFE-lined septum cap and
evacuated/backfilled with nitrogen (3 cycles). Diisopropyl ether
(anhydrous; 3.5 mL) was added via syringe, and then the vial was
cooled to 0 °C. Next, the allenoate (0.42 mmol, 1.2 equiv) was added
via syringe, and then the reaction mixture was stirred at 0 °C for 24 h.
To deactivate the catalyst, a solution of tert-butyl hydroperoxide (5.0−
6.0 M in decane; 50 μL) was added. The resulting mixture was stirred
at 0 °C for 10 min, and then it was allowed to warm to rt. The mixture
was concentrated under reduced pressure, and the residue was purified
by column chromatography.
(9) (a) This family of phosphepines was originally developed to
serve as chiral ligands for metal-catalyzed enantioselective processes.
For an overview, see: Gladiali, S.; Alberico, E.; Junge, K.; Beller, M.
Chem. Soc. Rev. 2011, 40, 3744−3763. (b) For the first application of
such a phosphepine as a chiral nucleophilic catalyst, see: Wurz, R. P.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234−12235.
(10) (a) This spirophosphine was originally developed to serve as a
chiral ligand for metal-catalyzed enantioselective processes. See: Zhu,
S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b05528.
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2333−2335. (b) For the first application of this spirophosphine as a
chiral nucleophilic catalyst, see: Reference 3a.
(11) In a preliminary study, the use of TBME as the solvent led to a
somewhat lower yield (∼82%) and enantioselectivity (∼88% ee).
(12) In preliminary studies, when the γ-substituent of the allenoate
(R1) was Ph, Bn, or cyclopentylmethyl, unsatisfactory results were
obtained.
(13) Under our standard conditions, an attempt to employ a 1,3-
oxazol-5(4H)-one with R = i-Pr led to a low yield of the γ-addition
product.
(14) For examples of natural products/bioactive compounds that
include a 2-amino-3,5-dihydro-4H-imidazol-4-one subunit, see:
(a) Gadwood, R. C.; Kamdar, B. V.; Dubray, L. A. C.; Wolfe, M. L.;
Smith, M. P.; Watt, W.; Mizsak, S. A.; Groppi, V. E. J. Med. Chem.
1993, 36, 1480−1487. (b) Tsukamoto, S.; Kato, H.; Hirota, H.;
Fusetani, N. J. Nat. Prod. 1996, 59, 501−503. (c) Edrada, R. A.;
Stessman, C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939−942.
(15) We hypothesize that the phenol may serve as a proton shuttle in
this process.
(16) For other phosphine-catalyzed enantioselective γ-additions in
which kinetic resolution of the allene has been examined, see: (a) No
kinetic resolution: References 3b, d. (b) Kinetic resolution:
References 3c, e.
(17) Estimated through computations: B3LYP/6-311+G(2d,2p);
DFT-D3; CPCM; gas-phase G correction.
(18) Under the same conditions but in the absence of the 1,3-oxazol-
5(4H)-one, the allenoate isomerizes to the 1,3-diene (Reference 6) at
a rate and with a selectivity factor (kinetic resolution of the allenoate)
that are essentially identical to those for the γ-addition reaction,
consistent with the two processes sharing the same turnover-limiting
step (formation of A).
E
DOI: 10.1021/jacs.5b05528
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX