Development of ProPhenol ligands for the diastereo- and enantioselective synthesis of β-hydroxy-α-amino esters

Article abstract of DOI:10.1021/ja4129394

A zinc-ProPhenol-catalyzed direct asymmetric aldol reaction between glycine Schiff bases and aldehydes is reported. The design and synthesis of new ProPhenol ligands bearing 2,5-trans-disubstituted pyrrolidines was essential for the success of this process. The transformation operates at room temperature and affords syn β-hydroxy-α-amino esters in high yields with good to excellent levels of diastereo- and enantioselectivity.

Full text of DOI:10.1021/ja4129394

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Communication
Development of ProPhenol Ligands for the Diastereo- and
Enanti-oselective Synthesis of #-Hydroxy-#-Amino Esters
Barry M. Trost, and Frédéric Miege
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4129394 • Publication Date (Web): 06 Feb 2014
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Development of ProPhenol Ligands for the Diastereo- and Enanti-
oselective Synthesis of β-Hydroxy-α-Amino Esters
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Barry M. Trost* and Frédéric Miege
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
Supporting Information Placeholder
mentioned reactions had to be conducted under cryogenic
conditions. Thus, access to the syn aldol adducts with control
of both diastereo- and enantioselectivity constitutes an im-
portant unsolved problem.
ABSTRACT: A zinc−ProPhenol-catalyzed direct asymmetric
aldol reaction between glycine Schiff bases and aldehydes is
reported. The design and synthesis of new ProPhenol ligands
bearing 2,5-trans-disubstituted pyrrolidines was essential for
the success of this process. The transformation operates at
room temperature and affords syn β-hydroxy-α-amino esters
in high yields with good to excellent levels of diastereo- and
enantioselectivity.
Our research group has a longstanding interest in the de-
velopment of dinuclear zinc−ProPhenol catalysts for the
asymmetric direct aldol reaction.12,13 14
, Therefore, we initiated
our studies by evaluating our standard ProPhenol catalyst L1
in the direct aldol reaction between N-(diphenylmethylene)-
glycine methyl ester 1 and 2-ethyl-butyraldehyde 2 in dioxane
at rt. After one-pot reductive work-up to provide a conven-
ient benzhydryl protected amino group, the reaction af-
forded the desired diastereomeric β-hydroxy-α-amino esters
in a 2.7:1 ratio, favoring syn adduct 3 which was isolated in
45% yield and with an encouraging enantiomeric excess of
77% (Table 1, entry 1).15 Examination of solvent effects in the
reaction revealed that toluene was most suitable in terms of
conversion, diastereo- and enantioselectivity (Table 1, entry
1-5). Other Prophenol ligands L2-L4 possessing different
steric (Table 1, entries 6 and 7) or electronic (Table 1, entry 8)
properties were also screened; however these ligands did not
perform better than the standard ProPhenol L1. Addition of
Optically active β-hydroxy-α-amino acids represent an im-
portant class of α-amino acids that can be found in numer-
ous complex natural and/or biologically active molecules
such as vancomycin and teicoplanin antibiotics.1 They are
also synthetically useful as precursors to valuable chiral
building blocks, as demonstrated by their conversion to
β-lactams or aziridine carboxylic acid derivatives.2 As a re-
sult, various catalytic asymmetric methods have been re-
ported for the construction of enantioenriched β-hydroxy-α-
amino acid derivatives.3
The direct catalytic asymmetric aldol reaction between
glycinate Schiff bases and aldehydes represents a particularly
elegant and straightforward method to access β-hydroxy-α-
amino esters in which the 1,2-aminoalcohol functionality is
assembled simultaneously with the formation of a new C-C
bond.4,5 Miller and Gasparski reported the first catalytic
asymmetric synthesis of β-hydroxy-α-amino esters by the
direct aldol reaction between N-(diphenylmethylene)glycine
tert-butyl ester and various aldehydes using the O’Donnell
cinchoninium chloride phase-transfer catalyst but low di-
astereroselectivities and negligible enantiomeric excesses
were obtained.6 Further evaluation of other monomeric and
dimeric cinchoninium catalysts by Castle et al. revealed vari-
able enantioselectivities despite modest diastereoselectiv-
ities.7 Maruoka et al. achieved a significant breakthrough
when they demonstrated that their N-spiro, binaphthyl-
based ammonium catalysts could provide a variety of anti
β-hydroxy-α-amino esters in high yields, diastereo- and
enantioselectivities,8 but obtention of syn diastereomers
proved problematic.9 Additionally, Shibasaki described the
use of the heterobimetallic Li3[La(S-BINOL)3] but moderate
steroselectivities were obtained.10,11 It is worth noting that, in
each one of these processes, only the tert-butyl glycinate
derivative is a competent partner. Additionally, the afore-
Table 1. Selected Solvent and Ligand Optimization.a
a All reactions were performed at rt for 24 h using 1 equiv of 1 and 2
equiv of 2 in the designated solvent at c = 0.5 M, followed by a reduc-
tive treatment with NaBH3CN (2.5 equiv) and AcOH (2 equiv) in
1
MeOH at rt for 16 h. b Determined by analysis of the H NMR spec-
trum of the crude material. c Yield of isolated pure syn diastereomer.
d
Determined by HPLC with
a
chiral stationary phase.
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Lewis basic additives, which proved effective in enhancing
zinc−ProPhenol complexes integrating trans 2,5-pyrrolidines
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3
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8
stereoselectivities in other zinc−ProPhenol-catalyzed proc-
wherein the C5 substituent exerts its constraining effect by
interaction with the central phenoxy ring. The synthesis of
these ligands L6-L9 started with highly diastereoselective
(dr > 12:1) copper-mediated arylations of the iminium derived
from known hemiaminal ether 8.18 trans Pyrrolidines 9-12
were isolated in yields ranging from 20% to 99%. These
products were treated with an excess of phenylmagnesium
bromide (THF, rt), followed by cleavage of the Boc groups
under basic conditions (NaOH, EtOH, reflux) to generate the
unprotected aminoalcohols 13-16 (41-87%, 2 steps). Coupling
these intermediates with dibromide 7 (K2CO3, DMF, 0 °c to
rt) provided the desired ProPhenol [(S,S),(S,S)]-L6-L9 in 80-
99% yield (Table 2).
esses, had little or no effect here.16
Based on our previous model for the zinc−ProPhenol-
catalyzed direct aldol reaction of α-hydroxyketones, we pro-
pose that the stereochemical outcome of the transformation
can be rationalized by intermediate A in which the (Z)-
enolate, arising from 1, serves as a bidentate ligand of the
dinuclear zinc complex. Coordination of the aldehyde to the
more Lewis acidic zinc atom directs its approach, allowing
the enolate to attack the Si face and deliver (2S,3R)-β-
hydroxy-α-amino ester 3 as the major product. Following this
model, we speculated that catalysts bearing additional sub-
stitution on the C5/C5’ carbon of the pyrrolidine rings would
provide a more sterically constrained catalytic pocket that in
turn may yield the desired aldol adduct with enhanced stere-
oselectivities (Scheme 1).
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With the new set of ligands in hand, we re-examined the
direct asymmetric aldol reaction between methyl glycinate 1
and aldehyde 2. The use of [(S,R),(S,R)]-L5, bearing the cis
pyrrolidines, led to a dramatic decrease in reactivity and the
desired adduct 3 was isolated in 20% yield with negligible
enantiopurity (Table 3, entry 2). In contrast, when ligands
L6-L9 incorporating trans 5-arylpyrrolidine 2-diarylcarbinol
moieties were screened, marked increases in conversion,
diastereo- and enantioselectivity were observed, compared to
the standard ProPhenol ligand L1. Overall, L6 performed best
and afforded syn β-hydroxy-α-amino ester 3 in 84% yield and
an excellent 89% ee (Table 3, entry 3-6). Interestingly, de-
creasing the reaction temperature had a detrimental effect
on the conversion and stereoselectivity (Table 3, entry 7).19
Thus, in contrast to the previous catalytic systems which
require cryogenic conditions, this system is ideal at ambient
temperature.
Scheme 1. Stereochemical Rationalization.
We were first interested in assessing a ProPhenol ligand
bearing cis-2,5-disubstituted pyrrolidines since this feature
introduces more steric interactions between the C5 substitu-
ent and the reactants. The synthesis of [(S,R),(S,R)]-L5 as
shown in Scheme 2 set the stereochemistry by the reduction
of the iminium derived from δ-ketocarbamate 4.17
With an optimized set of conditions in hand (Table 3, en-
try 3), the scope of the reaction was examined next (Table 4),
initially focusing on the methyl glycinate derivative since it
has not previously been shown to provide adequate stereo-
control. In all cases examined, complete consumption of the
starting material was observed and the reactions proceeded
with high to excellent levels of diastereoselectivity (dr > 10:1).
Aldol reaction of methyl glycinate 1 with α-tertiary alde-
hydes, such as iso-butyraldehyde or cyclohexanecarboxalde-
hyde, afforded the corresponding syn aminoalcohols 17 and
18 in excellent yields and good to very good enantiomeric
excesses. Even sterically hindered pivaldehyde provided
adduct 19 in 76% yield and 83% ee. Interestingly, when alde-
hydes bearing a protected α-tertiary alcohol were used, we
observed that the nature of the protecting group had a sig-
nificant effect in the enantioselectivity of the reaction; while
a TBS protected α-hydroxy-aldehyde generated the desired
adduct 20 in 96% yield and 83% ee, the presence of a MOM
Scheme 2. Synthesis of ProPhenol Ligand Containing
cis 2,5-disubstituted Pyrrolidine Moieties.
We also sought to evaluate the catalytic activity of
Table 2. Synthesis of ProPhenol Ligands Bearing trans 2,5-Disubstituted Pyrrolidines.
a Determined by analysis of the 1H NMR spectrum of the crude material. b Isolated yield.
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-tioselectivity (71% and 73% ee, respectively). The potential
Table 3. Evaluation of the New Ligands L5-L9a
1
2
3
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5
6
7
8
of the N-(diphenylmethylene)glycine tert-butyl ester was
also evaluated as a donor partner. Its reaction with iso-
butyraldehyde worked well and the product 25 was isolated
in 87% yield and 91% ee. The fact that the stereocontrol for
both the methyl and tert-butyl ester is virtually the same
exemplifies the high catalyst control of the reaction. Alde-
hydes bearing a coordinating oxygenated group at the
α-position again performed well and adducts 27 and 28
were isolated in 81% and 90% yield (ee = 89% and 94%,
respectively).
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We were also interested in utilizing α-chiral aldehydes
with the new zinc−ProPhenol system to determine their
performance in a diastereoselective aldol reaction. To this
end, N-(diphenylmethylene)glycine methyl ester 1 was
coupled with enantiopure TBS-protected (S)- and
(R)-lactaldehyde using [(S,S),(S,S)]-L6 as ligand. When the
(S) aldehyde was utilized, the desired reaction proceeded
with a high diastereoselectivity (dr = 9:1, ratio of desired
syn,syn adduct 29 vs. other diastereoisomers) and the sin-
gle diastereomeric product 29 was isolated in 77% yield.
Reaction with the (R) aldehyde afforded the syn,anti prod-
uct 30 also with an excellent diastereoselectivity (19:1, 91%
yield) and possessing the same absolute stereochemistry at
C2 and C3. Comparable results were obtained when analo-
gous glycinate tert-butyl ester was used as the donor part-
ner to afford the syn,syn α-amino-β,γ-dihydroxyester 31
(dr = 9:1, 89% yield) and the syn,anti α-amino-β,γ-
dihydroxyester 32 (dr > 19:1, 92% yield), respectively.
Hence, for this class of aldehydes bearing an
α-stereocenter, a very minimal match/mismatch effect was
observed, the matched case being between the [(S,S),(S,S)]
ligand L6 and the (R) aldehyde while the mismatched case
involves [(S,S),(S,S)]-L6 and the (S) aldehyde. Garner alde-
hyde was also a competent partner in our zinc−ProPhenol-
catalyzed transformation. Its aldol reaction with glycinate
a All reactions were performed at rt for 24 h using 1 equiv of 1 and 2
equiv of 2 in toluene at c = 0.5 M, followed by a reductive treat-
ment with NaBH3CN (2.5 equiv) and AcOH (2 equiv) in MeOH at
rt for 16 h. b Determined by analysis of the 1H NMR spectrum of the
crude material. c Yield of isolated pure syn diastereomer. d Deter-
mined by HPLC with a chiral stationary phase.e For 48 h at 0 °C.
group provided the corresponding α-amino-β,γ-dihydroxy
ester 21 (84%) in an excellent 95% ee. This significant effect
was also observed when employing an aldehyde possessing
a diethyl ketal at the α-carbon and the corresponding ami-
noalcohol 22 was obtained in excellent yield (86%) and ee
(95%) presumably due to an additional coordination point
to the zinc atom. On the other hand, aromatic or linear
alkyl aldehydes, such as benzaldehyde or hydrocinnamal-
dehyde, gave less satisfactory results and the β-hydroxy-α-
amino esters 23 and 24 were obtained with moderate enan-
Table 4. Enantioselective Zinc−ProPhenol-Catalyzed
Aldol Reaction of Glycine Schiff Bases with Ligand L6a
Table 5. Zinc−ProPhenol-Catalyzed Aldol Reaction of
Glycine Schiff Bases with α-Chiral Aldehydes a
a All reactions were performed at rt for 24 h using 1 equiv of glyci-
nate Schiff base and 2 equiv of aldehyde in toluene at c = 0.5 M,
followed by a reductive treatment with NaBH3CN (2.5 equiv) and
AcOH (2 equiv) in MeOH at rt for 16 h. dr was determined by
a All reactions were performed at rt for 24 h using 1 equiv of glyci-
nate Schiff base and 2 equiv of aldehyde in toluene at c = 0.5 M,
followed by a reductive treatment with NaBH3CN (2.5 equiv) and
AcOH (2 equiv) in MeOH at rt for 16 h. dr was determined by
analysis of the 1H NMR spectrum of the crude material. b Yields are
of the isolated pure syn diastereomer. Enantiomeric excesses were
determined by HPLC with a chiral stationary phase.
1
b
analysis of the HNMR spectrum of the crude material. Yields are
of the isolated pure syn diastereomer. c Conversion stopped at 60%
(analysis of the 1H NMR spectrum of the crude material).
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methyl and tert-butyl ester derivatives proceeded with
We thank the National Science Foundation (CHE-1145236)
and the National Institute of Health (GM033049) for their
generous support of our programs.
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excellent levels of diastereoselectivity and afforded the
corresponding α,γ-diamino-β,δ-dihydroxy esters 33 and 34
in 73% and 53% yield, respectively. Finally, the aldol reac-
tion between methyl glycinate 1 and the monoaldehyde
derived from dimethyl 2,3-O-isopropylidene-L-tartrate pro-
ceeded in high diastereoselectivity (dr = 9:1) and provided
the highly functionalized diester 35 in 88% yield (Table 5).
REFERENCES
(1) For a review on vancomycin and other related glycopeptides,
see: Boger, D. L. Med. Res. Rev. 2001, 21, 356-381.
(2) Selected references: for conversion to β-lactams, see: (a) Miller,
M. J. Acc. Chem. Res. 1986, 19, 49-56. For a review on aziridines,
see: (b) Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619.
(3) For a review on β-hydroxy-α-amino acids, see: Makino, K.;
Hamada, Y. J. Synth. Org. Chem. Jpn. 2005, 63, 1198-1208.
(4) Aldolases, such as serine hydroxymethyltransferase (SHMT)
and threonine aldolase (ThrA), can catalyze direct aldol reactions
using glycine as donor, see: Fesko, K.; Gruber-Khadjawi, M. Chem-
CatChem 2013, 5, 1248-1272 and references therein.
Additionally, cleavage of the benzhydryl protecting
group can be easily achieved under mild conditions. For
instance, hydrogenolysis of 21 (Pd/C, H2, THF/MeOH, rt)
afforded the free aminoalcohol 36 in 96% yield (Scheme 3).
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Scheme 3. Hydrogenolysis of the Benzhydryl Group
(5) Catalytic asymmetric direct aldol of other glycinate derivatives
affording protected β-hydroxy-α-amino esters have also been
reported: for
a recent review on α-isocyano esters, see: (a)
Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G.
Chem. Rev. 2010, 110, 5235-5331. For α-isothiocyanato esters, see: (b)
Xue, M.-X.; Guo, C.; Gong, L.-Z. Synlett 2009, 13, 2191-2197. (c)
Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2009, 131, 17082-17083. For α-nitroesters, see: (d)
Shirakawa, S.; Ota, K.; Terao, S. J.; Maruoka, K. Org. Biomol. Chem.
2012, 10, 5753-5755. (e) Ji, C.-B.; Liu, Y.-L.; Cao, Z.-Y.; Zhang, Y.-Y.;
Zhou, J. Tetrahedron Lett. 2011, 52, 6118-6121.
(6) Gasparski, C. M.; Miller, M. J. Tetrahedron 1991, 47, 5367-5378.
(7) (a) Mettah, S.; Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L.
J. Org. Chem. 2004, 69, 6489-6492. (b) Ma, B.; Parkinson, J. L.;
Castle, S. L. Tetrahedron Lett. 2007, 48, 2083-2086.
(8) (a) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew.
Chem. Int. Ed. 2002, 41, 4542-4544. (b) Ooi, T.; Kameda, M.; Tani-
guchi, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685-9694.
(9) (a) Kano, T.; Lan, Q., Wang, X.; Maruoka, K. Adv. Synth. Catal.
2007, 349, 556-560. (b) Kitamura, M.; Shirakawa, S.; Arimura, Y.;
Wang, X.; Maruoka, K. Chem. Asian J. 2008, 3, 1702-1714.
(10) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58, 8289-8298.
(11) Asymmetric Mukaiyama-type aldol reaction of ketene silyl
acetals derived from glycinate Schiff bases which must be synthe-
sized in a distinct step have also been described. However, this
process may not be considered a direct aldol. See: (a) Horikawa,
M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843-
3846. (b) Kobayashi, J.; Nakamura, M.; Mori, Y.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 9192-9193.
In summary, we have developed a direct zinc−ProPhenol-
catalyzed asymmetric aldol reaction between glycinate
Schiff base derivatives and aldehydes. Functionalized syn
β-hydroxy-α-amino esters were obtained with very good to
excellent diastereo- and enantioselectivity enabling isola-
tion of the adducts in high yields as pure diastereomers.
Further, the stereochemical outcome, in additions to sub-
strates containing α-stereocenters, was demonstrated to be
catalyst controlled. Thus, single diastereomers could be
obtained in excellent yields after chromatography in these
cases. The high level of stereocontrol was achieved by the
development of novel ProPhenol ligands incorporating
trans 2,5-disubstituted pyrrolidines. This success of the
trans ligands suggests that conformational constraints due
to the interaction of the C5/C5’ substituent with the phenol
ring rigidifying the asymmetry of the chiral space without
impeding reactivity is best accomplished with such trans
isomers. On the other hand, in the case of the ProPhenol
bearing cis 2,5-disubstituted pyrrolidines, the steric crowd-
ing due to the cis-1,3-relationship between the substituents
at C2 and C5 disrupts the chiral space as well as make the
“active site” too sterically encumbered to provide access to
the substrate. A complete evaluation of the potential of this
class of ligands in other direct aldol reactions, as well as the
development of other ProPhenol ligands, is currently un-
derway in our laboratory. 20
(12) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-
12004. (b) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497-
2500. (c) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc.
2004, 126, 2660-2661. (d) Trost, B. M.; Shin, S.; Sclafani, J. A. J. Am.
Chem. Soc. 2005, 127, 8602-8603.
(13) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123,
3367-3368.
(14) (a) Trost, B. M.; Michaelis, D. J.; Truica, M. I. Org. Lett. 2013,
15, 4516-4519. (b) Trost, B. M.; Amans, D.; Seganish, W. M.; Chung,
C. K. J. Am. Chem. Soc. 2009, 131, 17087-17089.
ASSOCIATED CONTENT
Supporting Information
Detail experimental details, compound characterization
data, and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Configurational assignment of the aldol adducts were deter-
mined by chemical correlation of 17 and analogy (see SI)
(16) Addition of PPh3S or PPh3O (20 mol %), 1,3-propanediol,
AUTHOR INFORMATION
cis 1,2-cyclopentanediol
or
methyl
2,2-dimethyl-3-hydroxy-
propionate (10 mol %) had no significant effect on the reaction.
(17) 4 is accessible in two steps from (S)-pyroglutamic acid, see:
Rudolph, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett. 2004,
45, 4895-4898.
(18) 8 is accessible in four steps from (S)-pyroglutamic acid, see:
Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1998, 39, 4789-4792.
(19) Decreasing the catalyst loading to 5 mol % of [(S,S)-(S,S]-L6
resulted in a sluggish reaction which was incomplete after 24h.
(20) For a 2,5-disubstituted ProP type ligand see Kim, Y.B.; Kim,
M.K.; Kang, S.H.; Kim, Y.H. Synlett, 2005, 1995-1998.
Corresponding Author
bmtrost@stanford.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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