Base-catalyzed direct aldolization of α-alkyl-α-hydroxy trialkyl phosphonoacetates

Article abstract of DOI:10.1002/anie.201200559

Pass the P: Catalytic direct aldol addition of α-hydroxy trialkyl phosphonacetates to aldehydes affords α-hydroxy-β-phosphonyloxy ester products (see scheme). The fully substituted glycolate enolate intermediate is generated in situ under mild conditions by a [1,2] phosphonate-phosphate rearrangement. High enantioselectivity and dramatic enhancement of reaction diastereocontrol is realized by the application of chiral iminophosphorane catalysts. Copyright

Full text of DOI:10.1002/anie.201200559

Angewandte
Chemie
DOI: 10.1002/anie.201200559
Direct Aldol Reaction
Base-Catalyzed Direct Aldolization of a-Alkyl-a-Hydroxy Trialkyl
Phosphonoacetates**
Michael T. Corbett, Daisuke Uraguchi, Takashi Ooi,* and Jeffrey S. Johnson*
Catalytic direct aldol reactions offer a convenient method for
the rapid construction of b-hydroxy carbonyl compounds
through the coupling of carbonyl donors and aldehyde
acceptors.[1] The generation of the reactive enolate by
a basic or nucleophilic catalyst obviates the need to preform
an enolate equivalent. Reaction subtypes can be broadly
categorized by the oxidation state of the pronucleophile.
Ketones and aldehydes can be used in direct aldolization
because of their relatively high acidity (by Brønsted base
catalysis) or their ability to form an enamine (by Lewis base
catalysis).[2] Catalytic direct aldol and Mannich reactions
involving donors in the carboxylic acid oxidation state are
considerably more elusive.[3] Mechanistic nuances of these
Scheme 1. Base-catalyzed direct-aldolization employing phosphonate–
reactions are more diverse and reactions that give products
that are fully substituted at the a carbon atom are difficult to
achieve. We report herein a new base-catalyzed direct
glycolate aldol addition that relies upon the strategic use of
a [1,2] phosphonate–phosphate rearrangement (Scheme 1).
This strategy was deployed in the development of highly
enantio- and diastereoselective variants through the applica-
tion of chiral iminophosphorane catalysts. A consequence of
the reaction design is that products containing a leaving group
are directly produced by the aldolization, a circumstance that
is favorable for subsequent nucleophilic displacement reac-
tions.
Although analogous to the well-studied isoelectronic [1,2]
Brook rearrangement,[4] the [1,2] phosphonate–phosphate
rearrangement of a-hydroxy phosphonates is comparatively
underutilized.[5,6] Incorporation of an adjacent electron-with-
drawing group facilitates C!O dialkoxyphosphinyl migra-
phosphate rearrangement.
tion (2!2’!2’’; Scheme 1) through stabilization of the
incipient negative charge. The [1,2] phosphonate–phosphate
rearrangement of a-hydroxy phosphonates has been
employed in the formal racemic and enantioselective reduc-
tion of a-keto esters;[7] however, it has seldom been used for
[6,8]
ꢀ
C C bond construction through umpolung reactivity.
The
fully substituted glycolic acid derivatives that would result
from productive trapping of 2’’ feature a b-phosphonyloxy
moiety that can serve as an electrophile in secondary trans-
formations,[9] and can be used as intermediates in the syn-
thesis of biologically active compounds such as tagetitoxin,
leustroducsin B, and phoslactomycin A.[10] The generation
and electrophilic trapping of glycolate enolates through
a base-catalyzed C!O dialkoxyphosphinyl migration was
accordingly undertaken.
Initially, we examined the reaction of a-hydroxy phos-
phonate 1a[11] with an aryl aldehyde in the presence of
a variety of bases (Table 1). The temperature of the reaction
determined the product identity. When the reaction was
conducted at room temperature, epoxide 5 was isolated in
23% yield with 2:1 d.r. (Table 1, entry 1); however, at ꢀ788C,
under otherwise identical reaction conditions, a-hydroxy-b-
phosphonyloxy ester 3a was isolated in 97% yield and 2:1 d.r.
(Table 1, entry 2). We propose that both products arise from
the same reaction pathway (see below): at elevated temper-
ature, the aldolate of 3a can react to give epoxide 5 through
an intramolecular Darzens-type SN2 displacement of the
vicinal phosphate.[12] At cryogenic temperatures, epoxide
formation is completely suppressed. The identity of the
counterion of the base affected diastereoselectivity, with
LiOtBu (Table 1, entry 5) giving a slightly lower diastereose-
lectivity than KOtBu (Table 1, entry 2) and NaOtBu giving
the lowest diastereoselectivity (Table 1, entry 3). A higher
reaction temperature was required for Cs2CO3 to initiate the
[*] M. T. Corbett, Prof. Dr. J. S. Johnson
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
E-mail: jsj@unc.edu
Dr. D. Uraguchi, Prof. Dr. T. Ooi
Department of Applied Chemistry
Graduate School of Engineering, Nagoya University
Furo-cho B2-3(611), Chikusa, Nagoya 464-8603 (Japan)
E-mail: tooi@apchem.nagoya-u.ac.jp
[**] The project described was supported by the National Institute of
General Medical Sciences (Award R01 GM084927), the NEXT
program, and a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocatalysts”
from MEXT. M.T.C. acknowledges a JSPS/NSF EAPSI Fellowship and
the Global COE program in Chemistry of Nagoya University.
Additional support from Novartis is gratefully acknowledged. X-ray
crystallographic analysis was performed by Yusuke Ueki of Nagoya
University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200559.
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Table 1: Direct aldol addition: reaction optimization.[a]
Table 2: Aldehyde substrate scope.[a]
Entry
R
Product
Yield [%][b]
anti/syn[c]
Entry
Base [mol%]
Yield [%][b]
d.r.[b]
(anti/syn)
1
2
3
4
5
6
7
8
4-ClC6H4
2-FC6H4
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
95
91
87
92
95
91
93
97
98
97
89
81[e]
89
78
2.0:1.0
2.3:1.0
1.5:1.0
2.4:1.0
2.8:1.0
2.1:1.0
2.4:1.0
2.1:1.0
2.1:1.0
2.0:1.0
4.9:1.0
6.7:1.0
4.4:1.0
5.8:1.0
3a
4
5
1[c]
2
KOtBu (120)
KOtBu (120)
NaOtBu (120)
Cs2CO3 (120)
LiOtBu (120)
KHMDS (20)
tBu-P4[e] (20)
KOtBu (20)
–
–
–
–
58
–
19
–
–
23
–
–
–
–
–
–
–
2.0:1.0
2.0:1.0
1.2:1.0
1.9:1.0
1.8:1.0
2.2:1.0
1.0:3.3
1.9:1.0
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CF3C6H4
4-CNC6H4
C6H5
97
88
41
81
74
97
98
3
4[d]
5
6
7
9
4-FC6H4
8[f]
10
11[d]
12
13[d]
14[d]
4-MeC6H4
4-MeOC6H4
2-thienyl
(E)-CH CHPh
CH2CH2Ph
[a] Reactions were performed on 0.10 mmol scale, using 1.5 equiv of
aldehyde in THF (1.0 mL) at ꢀ788C for 1 h. [b] Yields and diastereose-
lectivities were determined by 1H NMR spectroscopy using mesitylene as
an internal standard. [c] Ar=Ph, T=258C; [d] The reaction was warmed
=
=
=
to room temperature. [e] tBu-P4ꢁ((Me2N)3P N)3P NtBu.
[f] [1]0 =0.20m, 2.0 equiv aldehyde. Bn=benzyl, KHMDS=potassium
hexamethyldisilazide.
[a] Unless noted, reactions were performed on 0.20 mmol scale, using
2.0 equiv of aldehyde in THF (1.0 mL) at ꢀ788C for 2 h. [b] Yield of
isolated product. [c] Determined by 1H NMR analysis of the crude
reaction mixture. [d] With 5.0 equiv of aldehyde. [e] Product isolated as
the anti diol following column chromatography.
[1,2] phosphonate–phosphate rearrangement and competitive
enolate quenching was observed, thus resulting in the
formation of 4 (Table 1, entry 4). Attempts to render the
reaction catalytic were successful because the use of 20 mol%
of either KHMDS or KOtBu promoted the reaction in good
yield (Table 1, entries 6 and 8, respectively). The phospha-
zene base tBu-P4 was also an effective catalyst for this
reaction and gave preferentially the opposite (syn) diastereo-
isomer (Table 1, entry 7). The effect of independently
increasing either the number of equivalents of aldehyde or
the reaction concentration was marginal in minimizing the
formation of 4, but simultaneously increasing both provided
the best ratio of desired product 3a to quenched enolate 4;
(Table 1, entry 8). The identity of the carboxy and phospho-
nate ester had little impact on the diastereoselectivity of the
reaction (not shown).[13]
Table 3: a Substituent scope.[a]
Entry
R
Product
Yield [%][b]
anti/syn[c]
1
2
3
4
5
H (1 f)
Me (1b)
CH2CH CH2 (1c)
3o
3p
3q
3r
trace
81
89
93
97
–
1.9:1.0
1.2:1.0
2.9:1.0
2.1:1.0
=
ꢁ
CH2C CH (1d)
CH2Ph (1a)
3h
[a] Reactions were performed on 0.20 mmol scale, using 2.0 equiv of
aldehyde in THF (1.0 mL) at ꢀ788C for 2 h. [b] Yield of isolated product.
1
[c] Determined by H NMR analysis of the crude reaction mixture.
With high-yielding reaction conditions established
(Table 1, entry 8), we examined the scope of the reaction by
varying the aldehydes used (Table 2). The use of electron-
poor and electron-neutral aromatic aldehydes afforded prod-
ucts in excellent yield, albeit with marginal diastereoselectiv-
ity (Table 2, entries 1–10). The use of electron-rich aromatic,
alkenyl, and alkyl aldehydes afforded product with a notable
enhancement in anti diastereoselectivity and the use of an
excess amount of aldehyde (5.0 equivalents) was optimal in
these cases (Table 2, entries 11, 13, and 14). The isolation of
products typically only consisted of their separation from
excess aldehyde. The major byproduct formed during the
reaction was the quenched glycolate enolate 4. Bulkier
aldehydes such as isobutyraldehyde and pivaldehyde were
not suitable electrophiles under these reaction conditions.
The scope of the a-hydroxy phosphonate coupling partner
was investigated, with benzaldehyde as the other partner, by
varying the a substituent (Table 3). The presence of an
a substituent was found to be critical: reactions of phospho-
nates in which R = H suffered from poor reactivity (< 5%
conversion; Table 3, entry 1). In addition to the benzyl group,
other alkyl substituents were well-tolerated under the re-
action conditions, thus allowing for the incorporation of
functional handles such as terminal alkenes and alkynes
(Table 3, entries 3 and 4).
Having established a baseline protocol for achieving
a new direct ester aldol addition reaction, we directed our
efforts toward improving the modest reaction diastereoselec-
tivity and developing an enantioselective variant of this
reaction. Catalytic aldolization using tBu-P4 provided the
opposite major diastereomer to that obtained using alkali
bases (Table 1), thus hinting at the possibility that both
relative and absolute stereocontrol issues could conceivably
be addressed through the use of a chiral iminophosphorane
base possessing appropriate structural features and sufficient
basicity.[14] Exploratory experiments to test this hypothesis are
summarized in Table 4. The aldolization of 1e did indeed take
place in the presence of catalytic amounts of chiral imino-
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Table 4: Development of an asymmetric aldolization.[16]
Table 5: Diastereo- and enantioselective direct aldol additions.[a]
Entry[a]
6
Ar
Solvent
Conv. [%][b] 7[c]/4b
e.r.[d]
Entry
R
Product Yield [%][b] syn/anti[c]
e.r.[d]
1
2
3
4
5
6
6a 4-CF3C6H4
6b 4-FC6H4
6c C6H5
6d 4-MeC6H4
6e 4-MeOC6H4 THF
6c C6H5
6c C6H5
6c C6H5
THF
THF
THF
THF
<5
53
–
–
95:5
92:8
88:12
89.5:10.5
91:9
92.5:7.5
95:5
1
2
3
4
5
6
7
8
9
C6H5
7a
7b
7c
7d
7e
7 f
71
68
56
64
89
87
82
91
89
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
95:5
94.5:5.5
94:6
95:5
94:6
95:5
95:5
95.5:4.5
97:3
1:0.6
1:0.8
1:0.7
1:1.1
1:0.6
1:0.8
1:0.4
2-naphthyl
2-FC6H4
2-ClC6H4
3-NCC6H4
3-BrC6H4
4-ClC6H4
4-BrC6H4
76
80
>95
>95
Et2O
7
2-MeTHF >95
8[e]
2-MeTHF >90[f]
7g
7h
[a] Reactions were performed on 0.10 mmol scale, using 5.0 equiv of
PhCHO in solvent (0.5 mL) for 20 h. [b] Conversions and diastereomeric
ratios were determined by 1H NMR analysis of the crude reaction
mixture. [c] The syn/anti ratio was >30:1 in all cases. [d] Determined by
HPLC using a CHIRALPAK AD3 column. [e] The reaction was conducted
at ꢀ508C. [f] The product was isolated in 71% yield. Conv=conversion.
4-MeO2CC6H4 7i
[a] Reactions were performed on 0.10 mmol scale, using 5.0 equiv of
aldehyde in 2-MeTHF (0.5 mL) at ꢀ508C for 20 h. [b] Yield of isolated
product. [c] Determined by 1H NMR analysis of the crude reaction
mixture. [d] Determined by HPLC using a CHIRALPAK AD3 column.
phosphoranes such as l-valine-derived 6 and product 7 was
isolated with good enantioselectivity. Enantiocontrol could be
tuned through changes of the electronics at the 4-position of
the four aryl groups, but the use of electron-poor variants led
to reduced reaction efficiency, presumably as a result of the
reduced basicity (Table 4, entries 1–5). The identity of the
solvent appeared important in terms of product distribution
(ratio of aldol 7 to the quenched enolate 4b) and stereose-
lectivity (Table 4, entries 6 and 7). Optimal results were
obtained when using 10 mol% of 6c in 2-MeTHF, as the
reaction solvent, at ꢀ508C: the hydroxy phosphate adduct 7a
was isolated in 71% yield and 95:5 enantioselectivity
(Table 4, entry 8). Perhaps most remarkably, the chiral
iminophosphorane-catalyzed aldolization proceeded with
essentially complete diastereocontrol (> 30:1 syn/anti),[15]
thus revealing this strategy as a powerful method for
stereoselective glycolate aldolization that give products with
a fully substituted a center.
Preliminary experiments suggest that application of the
optimized reaction conditions to other aldehyde electrophiles
provides access to enantiomerically enriched aldol adducts.
As illustrated in Table 5,[17] the use of 2-substituted aldehydes
gives products in slightly reduced yields in comparison to the
reaction with benzaldehyde, although complete diastereose-
lectivity is observed and good enantiocontrol is maintained.
The structure and absolute stereochemistry of aldol adduct 7e
was determined by X-ray crystallography,[18] and other
products were assigned by analogy. For electron-donating
aromatic and aliphatic aldehydes, the relative rate of ir-
Scheme 2. Mechanistic proposal.
A catalytic cycle that accounts for the observed reactivity
of the a-hydroxy phosphonate 1e in the aldol addition is
proposed in Scheme 2. After deprotonation of the alcohol 1e
by the basic catalyst, a subsequent [1,2] phosphonate–
phosphate rearrangement generates the reactive glycolate
enolate 8. Consideration of frontier molecular orbital (FMO)
theory[20] led us to favor the illustrated Z enolate as the
kinetically preferred product of C!O phosphinyl migration.
Enolate addition to the aldehyde would lead to the aldolate 9.
The precise structures of the enolate 8 and the aldol transition
state remain open for discussion. Approximately thermoneu-
tral O!O phosphinyl migration occurs from the tertiary
alcohol to the vicinal secondary alkoxide, presumably to
reduce steric strain at the fully substituted center, thus
affording aldolate 10. The reaction is rendered catalytic
through proton transfer between the aldolate 10 and the a-
hydroxy phosphonate starting material 1e, either directly or
via the free base 6.
ꢀ
reversible stereoselective C C bond formation to afford 7 was
slower than the irreversible protonation of the chiral enolate 8
to 4b (see Scheme 2), thus resulting in diminished yields (R =
4-MeC6H4: 48% yield, syn/anti > 30:1, e.r. 89:11). Under
proton transfer conditions, minimization of undesired proto-
nation of the chiral enolate 8[7d] remains a challenge despite
the enhanced basicity of the chiral catalyst 6c.[19]
The reaction is especially attractive because the aldoliza-
tion directly installs a leaving group that can be immediately
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Na2SO4, filtered, and concentrated in vacuo. The diastereomeric ratio
was determined by 1H NMR analysis of the crude residue. The
residue was purified by column chromatography on silica gel eluting
with 30% acetone/hexane to afford the aldol adduct 7a (29.0 mg,
0.07 mmol, 71% yield, > 30:1 syn/anti) as a white solid (mp 119–
1278C).
deployed in nucleophilic displacement chemistry. The
OPO3R2 groups in benzylic phosphates are viable leaving
groups in acid-promoted Friedel–Crafts alkylations.[21] Upon
treatment of (ꢂ)-3a (d.r. 2:1) and anisole with TfOH, the a-
hydroxy ester 11 was isolated in 91% yield as a single
diastereomer. Heteroatom and heteroaromatic nucleophiles
were also employed in this Friedel–Crafts alkylation in good
to excellent yields (Scheme 3),[22] thus providing stereogenic
b-diaryl glycolates in a single step with pronounced stereo-
convergency. Formation of a discrete carbenium ion explains
the stereoconvergence and finds precedent in the diastereo-
selective Friedel–Crafts alkylations pioneered by Bach and
co-workers.[23]
Received: January 19, 2012
Published online: April 3, 2012
Keywords: aldol reaction · asymmetric catalysis ·
.
enantioselectivity · phosphates · rearrangement
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Scheme 3. Stereoconvergent Friedel–Crafts alkylations. Tf=trifluorome-
thanesulfonyl.
In conclusion, a catalytic direct aldol addition of a-
hydroxy trialkyl phosphonoacetates to aldehydes to afford a-
hydroxy b-phosphonyloxy esters has been developed. A [1,2]
phosphonate–phosphate rearrangement was utilized to gen-
erate the reactive glycolate enolate in situ. The reaction
works well for a variety of alkyl, alkenyl, aryl, and heteroaryl
aldehydes to afford the desired products in good to excellent
yields in low to moderate diastereoselectivities. Iminophos-
phorane catalysts enabled positive outcomes in asymmetric
versions of this reaction, providing excellent levels of
stereocontrol. Stereoconvergent second stage transforma-
tions have also been developed to enhance the synthetic
utility of the method. The applicability of this mechanistic
framework in the context of other new reactions is the topic of
ongoing investigations.
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Experimental Section
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˙
˘
A dried test tube was charged with the a-hydroxy phosphonoacetate
1e (30.2 mg, 0.10 mmol, 1.0 equiv) and benzaldehyde (51 mL,
0.50 mmol, 5.0 equiv), and the mixture was dissolved in 2-MeTHF
(500 mL, 0.2m) under an atmosphere of argon. The solution was
cooled to ꢀ508C. Iminophosphorane 6c (5.8 mg, 0.01 mmol,
0.1 equiv) was added and the reaction mixture stirred at ꢀ508C for
20 h. The reaction was quenched at ꢀ508C with 0.5m TFA in toluene
(40 mL, 0.2 equiv). The resulting solution was diluted with 1n HCl at
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Angewandte
Chemie
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and catalyst optimization both 1c (34% yield, > 30:1 syn/anti,
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[18] CCDC 854995 (7e) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[19] Competitive enolate quenching was also observed in the KOtBu-
catalyzed aldolization (Table 2). Entries 11, 13, and 14 neces-
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