Development of the enantioselective addition of ethyl diazoacetate to aldehydes: Asymmetric synthesis of 1,2-diols

Article abstract of DOI:10.1021/ja206995s

A novel synthetic strategy toward the asymmetric synthesis of vicinal diols bearing a tertiary center is presented. The method encompasses the dinuclear Mg-catalyzed asymmetric addition of ethyl diazoacetate into several aldehydes, oxidation of the diazo functionality, and diastereoselective alkyl transfer of various organometallics into the resulting chiral β-hydroxy-α- ketoesters to afford a diverse range of 1,2-diols in high yield, diastereoselectivity, and chirality transfer.

Full text of DOI:10.1021/ja206995s

ARTICLE
pubs.acs.org/JACS
Development of the Enantioselective Addition of Ethyl Diazoacetate
to Aldehydes: Asymmetric Synthesis of 1,2-Diols
Barry M. Trost,* Sushant Malhotra, Philipp Koschker, and Pascal Ellerbrock
Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
ABSTRACT: A novel synthetic strategy toward the asymmetric
synthesis of vicinal diols bearing a tertiary center is presented. The
method encompasses the dinuclear Mg-catalyzed asymmetric addi-
tion of ethyl diazoacetate into several aldehydes, oxidation of the
diazo functionality, and diastereoselective alkyl transfer of various
organometallics into the resulting chiral β-hydroxy-α-ketoesters to
afford a diverse range of 1,2-diols in high yield, diastereoselectivity,
and chirality transfer.
Scheme 1. Strategy for the Asymmetric Synthesis of α,β-
Dihydroxy-α-alkyl Esters
1. INTRODUCTION
Vicinal diols bearing a tertiary carbinol have played a vital role
in the synthesis of natural products.1 Several strategies toward
the enantioselective synthesis of these structural motifs exist.2
Asymmetric dihydroxylation and epoxidation/ring-opening re-
actions have found broad utility.3 In these processes, product
diastereoselectivity is highly dependent on the preparation of
stereochemically defined trisubstituted olefins. Chemoselective
control in these reactions may be attenuated by pendant olefins
often present in complex molecules.4a Our work on the total syn-
thesis of alternaric acid reveals the challenges of such a motif,
wherein a seven-step sequence was required to assemble the
vicinal diol fragment onthebasisof anasymmetric dihydroxylation
strategy.4b To address these limitations, Misaki, Sugimura, and Lu
have recently reported an aldol-based approach toward vicinal
diols via CꢀC bond formation by the development of direct
asymmetric catalytic aldol reactions using α-oxycarbonyls.5
As a complementary strategy, we envisioned accessing a broad
range of 1,2-diols bearing a tertiary carbinol employing the direct
catalytic asymmetric addition of ethyl diazoacetate to aldehydes
and manipulation of the diazo group to access a diverse range of
vicinal diols via sequential oxidation and stereoselective alkyl
transfer, as illustrated in Scheme 1.6 At the outset, we recognized
the conversion of β-hydroxy-α-diazo esters 4 to β-hydroxy-α-
keto ester electrophiles A and the subsequent addition of carbon
nucleophiles to such reactive intermediates with high chirality
transfer could prove to be challenging due to the high propensity
of these electrophiles to undergo competitive enolization or an
α-ketol rearrangement.7 Furthermore, the accessibility of the result-
ing 1,2-diols without recourse to protecting group manipulation
would rely upon the identification of carbon nucleophiles that are
compatible with a free alcohol. Despite these challenges, the flexibility
of this approach to afford 1,2-diol motifs contained in numerous
natural products led us to investigate the viability of such a pro-
tocol. Herein we provide a full account of our studies that led
to the development of a highly enantioselective magnesium-
catalyzed addition of ethyl diazoacetate to aldehydes. In this paper,
we also report the ability of the resulting β-hydroxy-α-diazo esters
to undergo the chemo- and diastereoselective synthesis of diverse
1,2-diols bearing a tertiary alcohol with high chirality transfer (see
Scheme 1).5a,8
2. RESULTS AND DISCUSSION
2.1. Asymmetric Addition of Diazo Esters to Aldehydes.
The catalytic asymmetric direct aldol reaction constitutes a
powerful strategy toward the atom-economical synthesis of β-
hydroxy carbonyl compounds.5a Although much progress has been
made in the development of a direct ketone aldol, significantly
fewer methods exist for the equivalent ester aldol reaction. The
chemical reactivity of esters precludes their use in enamine
Received: August 1, 2011
Published: November 16, 2011
r
2011 American Chemical Society
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|

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Scheme 2. Asymmetric Addition of Diazo Esters to
Aldehydes
aldehydes gave higher levels of enantioinduction than did aliphat-
ic aldehydes. Arai and co-workers employed a chiral phase trans-
fer cinchonidium-derived catalyst that afforded the desired pro-
ducts in 0ꢀ81% ee and demonstrated the utility of the resulting
products in accessing α-amino acids.10 We became interested in
obtaining a related product in high enantiocontrol to access a
natural product fragment. This necessitated the development of a
new method aimed at affording products with higher enantiocon-
trol. Herein we describe our efforts toward developing such a
process, a portion of which has appeared in a preliminary com-
munication, and the elaboration of such adducts for the asym-
metric synthesis of vicinal diol motifs.6
In our work, initial evaluation of the catalyst derived from the
treatment of 5 mol % ProPhenol (1) with 10 mol % diethylzinc
using ethyl diazoacetate (2) as the nucleophile and benzaldehyde
(3a) as the electrophile afforded the desired product 4a in high
yields but with low enantioinduction. Further optimization
(Table 1) revealed that the replacement of diethylzinc with di-n-
butylmagnesium afforded the desired product in up to 27% ee
(entries 1ꢀ5). Previous work on the use of the catalyst derived
from ProPhenol (1) and diethylzinc, wherein the remaining
coordinative unsaturation had revealed that addition of com-
plexing agents (additives) presumably to bind to the catalyst,
provided a considerably more selective reaction pathway.11
Exploration of this concept with a dinuclear magnesium
complex derived from the treatment of 10 mol % di-n-butyl-
magnesium, 5 mol % ProPhenol (1), and 5 mol % of the
β-hydroxy ester 9, the preferred additive in a previous Zn-
catalyzed process, enhanced the enantioselectivity to 37% ee
(entry 6).
Coordinating groups possessing a mono alcohol such as 9 and
10 enhanced the enantiomeric excess to 37% ee (entries 6 and 7).
The addition of methanesulfonamide (11) had no influence on
the enantioinduction (entry 8). Replacement of mono alcohols
with bis alcohols such as 2-substituted 1,3-propanediols 12ꢀ15
further enhanced the enantioselectivity up to 51% ee (entries
9ꢀ12). Although the use of dithiol 16 increased the enantios-
electivity, markedly low conversion was observed (entry 13).
Finally, the use of meso-cis-1,2-cyclopentanediol (17) resulted in
the greatest increase in the enantiocontrol, affording 4a in 65% ee
(entry 14).
Having identified that the addition of complexing groups can
markedly influence the enantioselectivity in the formation of
diazo ester 4a, we reinvestigated the effect of various solvents em-
ploying additive 17 (Table 2). These studies revealed the super-
iority of THF over other coordinating and noncoordinating
solvents such as dimethoxyethane (DME), 2-methyltetrahydro-
furan, toluene, and heptane. Comparison of the results presented
in Tables 1 and 2 also reinforces the role of the additive 17 in
achieving higher optical purity of product 4a (compare experi-
ments employing toluene, DME, and THF in Tables 1 and 2).
Additionally, as a direct consequence of conducting the reaction
on a larger scale, we observed that higher selectivity was achieved
when ethyl diazoacetate (2) was added over a period of 2 min.
Next, we investigated the influence of varying the stoichio-
metric ratio between (R,R)-ProPhenol (1), di-n-butylmagnesium,
and meso-cis-1,2-cyclopentanediol (17) (Table 3). Equalizing the
molar ratio of magnesium and ligand 1 afforded only trace amounts
of the desired product 4a (entry 2). Increasing the molar ratio of
magnesium and (R,R)-ProPhenol (1) to 4:1 resulted in the for-
mation of unidentified byproducts and lowered the optical purity
of diazo ester 4a (compare entries 1 and 3). Presumably, the ad-
Table 1. Selected Optimization Studies
entrya
solvent
additive
ee (%)b
1
PhCH3
Et2O
dioxane
DME
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
ꢀ
9
8
2
ꢀ
3
ꢀ
ꢀ11
ꢀ16
27
4
ꢀ
5
ꢀ
6
9
37
7
10
11
12
13
14
15
16
17
35
8
27
9
44
10
11
12
13
14
38
47
51
48
65
a All reactions run on a 0.47 mmol scale at 1 M concentration in both
donor 2 and acceptor 3a. b Determined by chiral HPLC.
catalysis; the higher pKa values of α-protons of esters relative to
aldehydes or ketones also makes them less reactive substrates in
direct aldol reactions. Furthermore, the thermal instability of
simple ester enolates has limited the development of asymmetric
aldol addition reaction of simple esters.
A tactic that has been employed in accessing β-hydroxy ester
containing scaffolds involves the asymmetric addition of diazo
esters to aldehydes. A summary of methods utilizing asymmetric
catalysis are presented in Scheme 2. Wang and co-workers first
demonstrated the utility of diazo esters as nucleophiles in an
asymmetric aldol reaction.9 A BINOL-derived zirconium catalyst
afforded the desired products in 53ꢀ83% ee, where aromatic
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Table 2. Influence of Solvent with the Incorporation of
Additive 17
Table 4. Influence of Temperature on the Enantioinduction
Employing Diols 15 and 17
entrya
amt of EDA (mmol)
Solvent
THF
yield (%)
ee (%)b
entrya
additive
temp (°C)
ee (%)b
1
0.47
1.76
1.76
1.76
1.76
1.76
NDc
72
65
ꢀ77e
ꢀ47e
ꢀ65e
ꢀ19e
ꢀ51e
1
2
3
4
5
6
7
8
15
15
15
15
17
17
17
17
ꢀ40
ꢀ20
4
74
78
68
51
72
82
78
65
2d
3d
4d
5d
6d
THF
DME
25
2-MeTHF
PhCH3
heptane
67
25
47
ꢀ40
ꢀ20
4
52
a All reactions run on a 0.47 mmol scale at 1 M concentration in both
donor 2 and acceptor 3a. b Determined by chiral HPLC. c ND = not de-
termined. d Addition over 2 min. e (R,R)-ProPhenol (1) employed.
25
a All reactions conducted on a 0.47 mmol scale at 1 M concentration
in both donor 2 and benzaldehyde acceptor 3a. b Determined by
chiral HPLC.
Table 3. Investigating the Ratio of (R,R)-1, Magnesium, and
Additive 17
Table 5. Influence of Ring Size of Additive on
Enantioinduction
entrya
solvent
X
Y
Z
time (h)
yield (%)b
ee (%)c
entrya
n
temp (°C)
additive
ee (%)b
1
2
3
4
5
THF
THF
THF
THF
THF
5
5
5
5
5
10
5
5
20
20
20
20
20
72
77
NDd
5
5
trace
52
1
2
3
4
5
1
1
1
2
4
room temp
ꢀ20
17
17
17
18
19
65
82
95c
20
10
10
47
10
30
69
31
ꢀ20
66
72
ꢀ20
79
a All reactions were conducted using 1.76 mmol of both ethyl diazoa-
cetate (2) and benzaldehyde (3a) at a concentration of 1.0 M in THF
unless otherwise noted. b Isolated yields. c Determined by chiral HPLC.
d ND = not determined.
ꢀ20
80
a All reactions run on a 0.47 mmol scale at 1 M concentration in both
donor and acceptor. b Determined by chiral HPLC. c Diazo ester 2 added
via slow addition using a syringe pump.
dition of adventitious base promotes the formation of product
4a via the direct deprotonation of ethyl diazoacetate (2) with
excess di-n-butylmagnesium. Furthermore, studies revealed that
increasing the stoichometric ratio between cis-1,2-cyclopentanediol
(17) and (R,R)-ProPhenol (1) also had a negative influence on the
enantiocontrol (entries 4 and 5). Interestingly, a significant drop
in optical purity was observed when the quantity of additive was
increased from 5 to 10 mol %. Greater enantiocontrol could be
regained using 30 mol % meso-cis-1,2-cyclopentanediol (17).
The influence of temperature on the enantioinduction was
investigated by employing the 1,3- and 1,2-diol additives 15 and
17, respectively (Table 4). These studies reinforced the super-
iority of 1,2-diols over 1,3-diols. Presumably, the conformational
bias present in diol 17 enhances its coordination ability to the
dinuclear magnesium catalyst. Additionally, it was observed that
the highest level of enantioinduction was achieved at a reaction
temperature of ꢀ20 °C employing either additive 15 or 17.
The small decrease in selectivity by lowering the temperature
to ꢀ40 °C could potentially be due to lowered reactivity leading
to an increase in overall concentration of the diazo ester during
the slow addition that may result in the formation of a catalyst
involving the coordination of multiple diazo esters. Another ex-
planation invokes a shift of the relative energies of the diastero-
meric transition states due to their differential temperature
dependence. Experimental results support that the decrease in
enantioselectivity is likely not due to a background reaction. The
influence in the ratio of ligand to Bu2Mg (Table 3, entries 1ꢀ3)
suggests the presence of a background reaction only when a
ProPhenol to magnesium ratio of 1:4 is employed. Subsequent
control experiments (vide infra) further support that the tem-
perature effect is not due to a background reaction. Regardless of
the exact explanation, the effect is small.
Additionally, the evaluation of various ring sizes of commer-
cially available 1,2-diols 17ꢀ19 revealed little influence of the
ring size on enantioinduction (Table 5, entries 2, 4, and 5). The
use of diol 17 offered a practical advantage, as it can be added to
the catalyst via syringe without further dilution and was selected
as the additive of choice for further evaluation of this reaction.
Further, we wondered whether the diazo ester coordinated
so strongly to the catalyst that multiple such units would be
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Table 6. Expanded Reaction Scope for Asymmetric Catalytic
Diazo Ester Aldols
50ꢀ77% and in 90ꢀ98% ee using ethyl diazoacetate (2) and
only up to 2 molar equiv of the respective aldehyde. With
cyclopropylcarboxaldehyde (3n) the yield increased from 52%
to 77% by increasing from 1 to 2 equiv of the aldehyde (Table 6,
entry 15 vs 16). For cyclohexanecarboxaldehyde higher yields
were obtained by increasing the catalyst loading to 10 mol %
(Table 6, entry 13). Finally, of the two α,β-unsaturated alde-
hydes evaluated, cinnamyl aldehyde (3p; Table 6, entry 18)
afforded the desired products with high enantioinduction.
Further experiments revealed that the yield for this substrate
was variable. Greater success was achieved with aldehyde 3o
(Table 6, entry 17).
entrya
R in RCHO
Ph (3a)
product time (h) yield (%)b ee (%)c
1
2d
4a
4a
4b
4c
4d
4e
4f
18
24
18
18
18
24
24
18
18
18
24
24
24
24
24
24
24
18
92
95
83
70
91
78
87
88
85
83
56
50
49
52
52
77
86
50
95
ꢀ95
90
Ph (3a)
2.3. Mechanistic Discussion. A catalytic cycle for the trans-
formation supported by experimental evidence is illustrated
in Figure 1a. Treatment of ProPhenol (1) with 2 equiv of di-n-
butylmagnesium presumably affords species II. Although direct
structural evidence for this complex II could not be ascertained
by electrospray mass spectral analysis or X-ray crystallography,
previous work by Ding and co-workers suggests the formation of
a dinuclear complex (Figure 1b).14 Experimental results under-
score the importance of the 1:2 ratio between (R,R)-ProPhenol
(1) and magnesium and reveal that minimal background reaction
takes place in the presence of free di-n-butylmagnesium alone or
free ProPhenol (1) alone (Table 7). In the presence of an equi-
valent ratio of ProPhenol (1) and magnesium, only trace
amounts of the desired product are formed (Table 7, entry 1).
A significant increase in yield is observed when the ratio between
ProPhenol and magnesium is adjusted to 1:2. When the ratio is
further increased to 1:4 (ProPhenol to magnesium), lowered
yields and enantioselectivity are obtained. Initially we hypothe-
sized that the lowered enantioselectivity was due to a compet-
itive background reaction catalyzed either directly by free di-n-
butylmagnesium, by a magnesium alkoxide dissociated from the
chiral ligand (such as the magnesium alkoxide of the product), or
from free ProPhenol serving as a tertiary amine base. Further
experimentation revealed that, in the absence of ProPhenol or di-
n-butylmagnesium, no reaction at room temperature was ob-
served (Table 7, entry 4). The presence of 5 mol % of ProPhenol
but no di-n-butylmagnesium afforded only trace amounts of
product. Presumably the tertiary amine present in ProPhenol is
promoting the formation of the trace product (Table 7, entry 5).
Whether di-n-butylmagnesium itself could catalyze the reaction
led us to evaluate the reaction in the absence of ProPhenol.
Interestingly, with 10 mol % Bu2Mg the desired product was
obtained in 10% yield after 24 h at room temperature (Table 7,
entry 6). Replacing benzaldehyde with valeraldehyde (3k) led to
the formation of a complex mixture of products (Table 7, entry 7).
In contrast, conducting the reaction in the presence of a catalyst
derived from Bu2Mg, ProPhenol (1), and diol 17 at ꢀ20 °C with
valeraldehyde (3k) as the electrophile and with the slow addition
of diazo ester 2 (optimized results presented in Table 6) afforded
the desired product in 50% yield (Table 7, entry 8).
3
m-CH3OC6H4 (3b)
p-CH3OC6H4 (3c)
o-CIC6H4 (3d)
m-FC6H4 (3e)
p-FC6H4 (3f)
m-CIC6H4 (3g)
p-CIC6H4 (3h)
2-furyl (3i)
4
87
5
89
6
7e
91
94
8
4g
4h
4i
98
9f
10f
11f
12
96
96
i-Pr (3j)
4j
97
n-Bu (3k)
4k
4l
97
13g cyclohexyl (3l)
14h Et (3m)
91
4m
4n
4n
4o
4p
96
15
cyclopropane (3n)
>99
>99
90
16h cyclopropane (3n)
17
18i
E-BDMSCHdCH (3o)
PhCHCH (3p)
94
a All reactions were conducted using 0.88 mmol of both ethyl diazoa-
cetate (2) and the respective aldehyde 3aꢀp at a concentration of 1.0 M
in THF, unless otherwise noted. b Isolated yields. c Determined by
chiral HPLC. d Reaction conducted on a 1.76 mmol scale of benzalde-
hyde (3a) using (R,R)-1. e Ethyl diazoacetate (2) added at ∼12.5 μL/h.
f Reactions conducted at 0.5 M. g Reaction conducted using 10 mol % of
(R,R)-1, 20 mol % of Bu2Mg, 10 mol % of 17, and 2 equiv of diazo ester 2.
h Reactions conducted using 2 equiv of aldehyde with respect to ethyl
diazoacetate (2). i See Mechanistic Discussion.
simultaneously involved which, in turn, would decrease the
enantioselectivity. Interestingly, slow addition of ethyl diazoace-
tate (2) to the reaction mixture employing diol additive 17
afforded the desired product in the highest enantiomeric excess
of 95% ee (Table 5, entry 3). Presumably when a low concentra-
tion of ethyl diazoacetate (2) is maintained during the reaction,
competition between the additive 17 and the nucleophile 2 is
minimized, thereby leading to greater enantiocontrol.
2.2. Scope. Evaluation of the reaction scope revealed that high
levels of enantioinduction could be achieved for a broad range
of aldehydes. Carbocyclic aromatic aldehydes possessing both
electron-donating and -withdrawing groups (Table 6, entries 1ꢀ9)
all afforded products 4aꢀf with high levels of enantioinduction.
The use of 2-furaldehyde (furfural) also afforded the aldol ad-
dition product 4g in 83% yield and 96% ee (entry 10).12 Aliphatic
aldehydes such as those presented in entries 11ꢀ16 can be
challenging substrates in metal-catalyzed direct aldol reactions,
due to the presence of enolizable protons. Previous studies em-
ploying ProPhenol (1) for direct aldol reactions with unbranched
aliphatic aldehydes required a 10-fold excess of the donor and re-
sulted in the isolation of products in modest yields and enantio-
selectivity.13 Employing aliphatic aldehydes in this process
affords β-hydroxy diazo ester products in yields in the range
These results suggest that free Bu2Mg promotes a detectable
background reaction but only stoichiometrically to the amount of
Bu2Mg in the case of benzaldehyde. In the case of the enolizable
aldehyde valeraldehyde (3k), a plethora of products are formed,
and only a minor amount of the desired product is detected.
Furthermore, the studies support that the dinuclear metal complex
illustrated in Figure 1 is indeed the reactive form. The influence of
the slow addition of ethyl diazoacetate in enhancing the optical
purity of the desired product is less due to non-ProPhenol-
catalyzed processes, but potentially because a higher concentration
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Figure 1. Proposed catalytic cycle for asymmetric addition of diazo ester 2 to aldehyde 3a.
of ethyl diazoacetate leads to multiple coordination of diazo
esters to the dinuclear complex, leading to ambiguity of which
one adds to the carbonyl group. Presumably, one role of the
addition of the bidentate additive (diol 17) is that it minimizes
the number of available coordination sites where nucleophile 2
can complex.
On the basis of these results, we postulate that upon initial
addition of di-n-butylmagnesium three of the alkyl groups are
consumed by the three protons on the ligand. The fourth alkyl
group serves as the base to remove a proton from the 1,2-diol 17
to afford the desired complex III. Previous results on the incuba-
tion of diazo ester 2 with D2O lead to significant H/D exchange
at ambient temperature without the incorporation of an
extraneous base, thereby suggesting that the pKa of ethyl
diazoacetate is suitably low for it to be deprotonated by the
putative magnesium alkoxide in III (Figure 1c).23 The deproto-
nation would be expected to dramatically increase the rate of
addition of ethyl diazoacetate to the aldehyde substrate. Thus,
the deprotonation of ethyl diazoacetate (EDA; 2) employing
magnesium alkoxide III affords complex IV. Coordination of
benzaldehyde 3a then affords species V, which undergoes an
intramolecular aldol reaction to afford the magnesium alkoxide
complex VI. Protonation of this alkoxide in complex VI with ethyl
diazoacetate (2) reveals the desired product and recycles to the
catalytic species IV.
2.4. Synthesis of 1,2-Diols. Treatment of readily accessible
(S)-4a (95% ee) with dimethyldioxirane15 and concentration fol-
lowed by the addition of alkyl Grignard reagents at low tem-
peratures resulted in complete conversion of the starting material:
however, with disappointingly low yields and diastereocontrol of
the tertiary alcohol products. We then turned our attention to
less basic organoindium and organozinc reagents. Allylindium
reagents readily undergo 1,2-addition with both aldehydes and
ketones.16 These reagents, generated in situ, are efficacious in
protic media. Paquette and co-workers have demonstrated the
addition of allylindium reagents to achiral α-hydroxy carbonyl
compounds.17 The transfer in chirality upon the addition of such
nucleophiles to enantiomerically enriched β-hydroxy-α-keto
esters remained unknown. Gratifyingly, the addition of In(0)
and allyl iodide in DMF to the crude reaction mixture afforded
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Table 7. Evaluation of a Background Reaction
Table 8. Diastereoselective Addition of Carbon Nucleophiles
to β-Hydroxy α-Keto Esters A
entrya
R
X
Y
yield (%)b
1
2c
Ph
5
5
5
0
5
0
0
5
5
trace
Ph
10
20
0
72
3
Ph
52
4
Ph
0
5
Ph
0
trace
6d
7d
8c,e
Ph
10
10
10
10
complex mixture
50
n-Bu
n-Bu
a All reactions were conducted using 1.76 mmol of both ethyl diazoa-
cetate (2) and benzaldehyde (3a) at a concentration of 1.0 M in
THF unless otherwise noted. b Isolated yields. c Reaction conducted in
the presence of 5 mol % diol 17. d 10 mol % Bu2Mg added to a solution of
ethyl diazoacetate prior to the addition of the respective aldehyde.
e Reaction conducted under optimized conditions at ꢀ20 °C with slow
addition of diazo ester 2.
1,2-diol 20 in 99% yield, 91% ee, and >20:1 dr over two steps
(Table 8, entry 1).
Exploration of the nucleophiles that can be employed is pre-
sented in Table 8. Using crotyl bromide, high levels of diaster-
eocontrol at the carbinol centers was accomplished; however, a
1:1.3 ratio of products 21 and 22 epimeric at the methyl-bearing
stereocenter was obtained, potentially due to the rapid E/Z iso-
merization of the crotyl indium intermediate, as has been pre-
viously observed by Paquette and co-workers (entry 2).18
Reverse prenylation of the keto ester derived from 4a led to the
exclusive formation of 23 in 95% ee (entry 3). Stereotriad 24 was
accessed from In(0) and 3-bromo-1-acetoxypropene to generate
a formal 1-hydroxyallyl anion equivalent.19 The desired product
was obtained with a 5:1 dr with respect to the acetoxy-bearing
stereocenter and 92% ee (entry 4). Using 3-bromoprop-1-yne
led to propargyl alcohol 26 in 95% ee (entry 5). Organozinc re-
agents are also effective nucleophiles for the transfer of nonallyl
groups. Commercially available Et2Zn and Me2Zn afforded 1,2-
diols 27 and 28 both in >20:1 dr and in 95% ee (entries6 and 7).20
The addition of vinylzinc chloride, an sp2-hybridized nucleophile,
afforded the desired diol 29 in 8:1 dr and 85% ee (entry 8). In
contrast to these results, ethylmagnesium bromide afforded diol
28 in 24% and 4:1 dr and vinylmagnesium bromide afforded diol
29 in 24% and 1.9:1 dr in the absence of zinc chloride.
a Conditions: (i) DMDO, concentrate; (ii) In (1.1 equiv), allyl halide
(2.0 equiv) (entries 1ꢀ5), Me2Zn/Et2Zn/vinylzinc bromide (entries
6ꢀ8). b Combined isolated yield (over two steps). c Determined by
crude NMR. d ct (chirality transfer, %) = (ee product (%))/(ee (S)-4a
(%)) (HPLC). e Assigned by NOE on acetonide. f Diastereoselectivity at
allylic position. g Isolated as a 5:1 mixture of homopropargyl alcohol and
allenyl alcohol. h See the Supporting Information for assignment.
product. Interestingly, we found that the addition of racemic
ProPhenol (1) promoted the alkyl transfer, thereby affording
the requisite 1,2-diol. The ability of ProPhenol to facilitate alkyl
transfer to such easily enolizable substrates may prove to be a use-
ful additional application of this catalytic zinc complex.
Chemoselective acylation afforded western fragment 35 in
95% ee (Scheme 3).
Next, we turned our attention to the diastereo- and enantio-
selective allyl transfer to β-hydroxy α-keto esters where R ¼ Ph.
Replacement of the phenyl group in diazo ester 4a with other
aromatic, aliphatic, and olefinic groups also affords vicinal diols
30ꢀ34 with high dr and chirality transfer (Table 9).
2.5. Determination of Relative and Absolute Configuration.
The relative and absolute stereochemistry were established by a
combination of H NMR and X-ray techniques. In order to
1
determine the absolute configuration of the stereogenic center
created in the initial addition, we initially turned to the O-
methyl-mandelate method,21 which we applied to the more
elaborated diol 31 derived from adduct (ꢀ)-4a (Scheme 4).
While this method establishes the absolute stereochemistry of
the benzylic alcohol stereocenter, it does not establish the relative
stereochemistry of the adjacent tertiary stereocenter. To address
this deficiency, we turned to X-ray crystallographic analysis of
acetonide 38, derived from initial adduct (S)-4a. As shown in
Scheme 5a, conversionofdiazoester 4a to diol 24, protection as the
To further demonstrate the synthetic utility of this method
toward the streamlined synthesis of biologically active targets, we
rapidly assembled the western fragment of several macrolide
antibiotics, including azithromycin, which is pivotal in the con-
tainment of human bacterial infections. MagnesiumꢀProPhenol-
catalyzed diazo ester aldol with propionaldehyde affords 3m in
96% ee. Oxidation followed by the addition of Me2Zn initially
afforded a complex mixture with trace quantities of the desired
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Table 9. Reaction Scope with In-Mediated Allyl Transfer
their corresponding acetonides 39 and 40 (Scheme 5b). Thus, the
relative stereochemistry for all three acetonides 38ꢀ40 is the same.
The rationale for the diastereocontrol is based upon a chelation-
controlled ZimmermanꢀTraxler transition state18 with preferen-
tial si-face attack (Scheme 5c).
entrya
R
product
yield (%)b
drc
ct (%)d
3. CONCLUSIONS
1
2
3
4
5
p-MeOC6H4
p-CIC6H4
cyclopropane
n-Bu
30
31
32
33
34
89
90
86
91
33
>20:1
>20:1
13:1
98
>99
>99
>99
94
We have developed a highly general catalyst system for the
addition of commercially available ethyl diazoacetate to several
aliphatic and aromatic aldehydes to access diverse β-hydroxy
α-diazo esters. Initial results employing a catalyst derived from the
treatment of 5 mol % ProPhenol and 10 mol % Et2Zn or Bu2Mg
furnished a catalyst capable of promoting the addition reaction in
up to 37% ee. The incorporation of 5 mol % of several additives
that putatively complex with the metal afforded the desired
products in higher enantiocontrol. Further development of the
reaction led to the identification of a catalyst system that af-
forded the desired products in up to 98% ee, employing cis-1,
2-cyclopentanediol as the additive at ꢀ20 °C with the slow
addition of ethyl diazoacetate. We hypothesize that the combina-
tion of the additive and the slow addition minimizes the coordi-
nation of ethyl diazoacetate to the catalyst, thereby enhancing the
enantioselectivity in the formation of β-hydroxy diazo esters.
Given our long-standing interest in accessing natural products
containing vicinal diols, we envisioned the use of these enantio-
merically enriched products to access 1,2-diols bearing a tertiary
alcohol in high enantio- and diastereomeric purities using atom-
economical means. We envision that these motifs could be ac-
cessed via a sequence involving the oxidation of β-hydroxy
α-diazo esters to β-hydroxy α-keto esters followed by an alkyl trans-
fer usinga carbanion equivalent. The validity of this concept hinged
upon the ability to identify carbon nucleophiles that would main-
tain the configurational stability of highly enolizable β-hydroxy
α-keto esters without promoting α-ketol rearrangement and at the
same time afford products in high diastereocontrol without reco-
urse to protecting groups. Although initial efforts employing alkyl-
magnesium reagents led to limited yields and diastereoselectivity, it
was determined that less reactive allyl and propargyl indium species
could be employed to access several diols and a triol in high optical
purity. Furthermore, the addition of alkyl and vinyl nucleophiles
was accomplished using vinyl- and alkylzinc reagents, also affording
products in high diastereoselectivity and chirality transfer. This
strategy complements traditional asymmetric oxidations when
chemoselectivity difficulties would preclude their use for the
formation of products 20ꢀ26 and 29. Further, the ability to access
numerous α-hydroxy β-diazo esters via a direct diazo ester aldol
coupled with the range of nucleophiles that can be employed in the
sequential alkyl transfer to the corresponding β-hydroxy α-keto
ester reinforces the utility of the method in the rapid generation of
molecular complexity.
>20:1
PhCHCH
6:1
a Substrates prepared from (S,S)-ProPhenol. b Isolated yield (over two
steps). c Determined by crude NMR. d ct (chirality transfer, %) =
(ee product (%))/(ee starting material (%)) (HPLC).
Scheme 3. Synthesis of Polyketide Fragment
Scheme 4. Synthesis of Mandelate Esters 36 and 37
4. EXPERIMENTAL SECTION
4.1. General Information. All magnesiumꢀProPhenol-catalyzed
asymmetric additions of ethyl diazoacetate to aldehydes were performed
in flame-dried glassware with magnetic stirring under an atmosphere of
nitrogen in a ꢀ20 °C cryostat. All indium-mediated reactions were per-
formed using “open-flask” conditions. All organozinc-mediated cou-
plings were performed under an atmosphere of nitrogen.
acetonide, and acylation of the allylic alcohol with p-bromobenzoyl
chloride afforded crystalline product 38. To determine whether the
relativeconfigurationwas influenced by the functional natureof the
allylatingagent leading to adduct 24, the relative stereochemistry of
two more diols, 20 and 26, was determined via 1H NMR analysis of
Anhydrous DMF, dichloromethane, chloroform, tetrahydrofuran,
acetone, acetonitrile, and toluene were obtained from a Seca solvent puri-
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Scheme 5. Determination of Relative and Absolute Configuration
fication system by Glass Contour. Solvents and reagents were trans-
ferred via a syringe which had been oven-dried and cooled in a desic-
cator. Microliter syringes were dried under high vacuum for 1 h prior to
use. Aldehydes for the asymmetric addition were freshly distilled prior to
use. All other reagents were purchased from Aldrich Chemical Co. and
were used without further purification.
Analytical thin-layer chromatography was preformed on precoated
250 μm layer thickness silica gel 60 F254 plates (EMD Chemicals Inc.).
Visualization was performed by ultraviolet light and staining with ceric
ammonium molybdate, potassium permanganate, or p-anisaldehyde.
Organic solutions were concentrated by rotary evaporation at ambient
temperature (essential for all diazo compounds). Flash column chroma-
tography was performed using 40ꢀ63 μm silica gel (Silicycle silica gel)
using compressed air. The eluents employed for flash chromatography
are reported as v/v percentages.
3-hydroxy-3-phenylpropanoate (4a). To a solution of (R,R)-
ProPhenol (1; 56 mg, 0.088 mmol, 0.05 equiv) in anhydrous
THF (1.65 mL) was added a solution of di-n-butylmagnesium
(176 μL of a 1 M solution in heptane, 0.10 equiv). After the mixture
was stirred for 30 min, cis-1,2-cyclopentanediol (9 μL, 0.088 mmol,
0.05 equiv) was added and the reaction mixture was stirred for an
additional 45 min. To the reaction mixture was added benzalde-
hyde (177 μL, 1.76 mmol, 1.0 equiv). After it was stirred for 5 min at
room temperature, the reaction mixture was cooled to ꢀ20 °C and
ethyl diazoacetate (201 mg, 1.76 mmol, 1.0 equiv) was added over 8 h
(25 μL/h). Upon completion, the reaction mixture was quenched
with pH 7 buffer and extracted with Et2O (5 ꢁ 5 mL). The organic
layers were combined, dried (Na2SO4), and concentrated. Silica gel
chromatography using a gradient of 15ꢀ20% EtOAc in petroleum
ether afforded 370 mg (95%, 95% ee) of the desired product as a
yellow oil. This oil can be stored for several weeks in the freezer;
however, it transforms into the corresponding β-keto ester when
stored at room temperature. TLC: Rf = 0.50 (20% EtOAc in
Proton nuclear magnetic resonance (1H NMR) spectra were acquired
using Varian Inova 400, 500, and 600 MHz and Mercury 400 MHz spec-
trometers. Chemical shifts (δ) are reported in parts per million (ppm)
and are calibrated to residual solvent peaks: proton (CDCl3 7.26 ppm).
Coupling constants (J) are reported in Hz. Multiplicities are reported
using the followingabbreviations:s, singlet; brs, broad singlet;d, doublet;
t, triplet; q, quartet; m, multiplet. 13C NMR spectra were recorded using a
Varian Unity INOVA spectrometer at 125 MHz or a Varian Mercury
instrument at 100 MHz. Chemical shifts (δ) are reported in parts
per million (ppm) and are calibrated to residual solvent peaks: carbon
(CDCl3 77.0 ppm).
Infrared spectroscopic data were recorded on NaCl plates as thin
films on a Thermo Scientific Nicolet IR100 FT-IR spectrometer. The ab-
sorbance frequencies are recorded in wavenumbers (cmꢀ1). High-
resolution mass spectra (HRMS) were acquired by the Vincent Coates
Foundation Mass Spectrometry Laboratory, Stanford University Mass
Spectrometry (http://mass-spec.stanford.edu) on a Micromass Q-Tof
API-US mass spectrometer (Waters Corp., Milford, MA). Chiral HPLC
analysis was performed on Daicel Chiralpack columns (AD, AS, OB-H,
OC, OD, or OJ) using heptane/2-propanol mixtures. The respective
ratio of the eluent mixture, flow rate, detection wavelength, and column
are indicated within the experimental details. Retention times (Tr) are
reported in minutes (min). Optical rotations were measured using a
JASCO DIP-1000 digital polarimeter in 50 mm cells and the sodium D
line (589 nm) at the temperature, solvent, and concentration indicated.
4.2. Representative Procedure for the Asymmetric Addi-
tionofEthylDiazoacetate to Aldehydes. 4.2.1. (S)-Ethyl 2-Diazo-
25
petroleum ether). [α]D = ꢀ31.8° (95% ee, c 11.5 mg/mL,
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.44ꢀ7.31 (m, 5H), 5.91
(d, J = 3.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.97 (br s, 1H), 1.29 (t, J =
7.2 Hz, 3H). HPLC: Tr = 26.5 (minor) and 27.9 min (major)
(Chiracel OJ, λ 254 nm, isocratic elution, heptane:iPrOH = 97:3,
flow rate 0.8 mL/min). The spectroscopic data were consistent with
values reported in the literature.6
4.3. Representative Procedure for the Conversion of
β-Hydroxy-α-diazo Esters to Vicinal Diols. 4.3.1. Indium Based
Method: (S)-Ethyl 2-Hydroxy-2-((S)-hydroxy(phenyl)methyl)pent-4-
enoate (20). To a solution of (S)-ethyl 2-diazo-3-hydroxy-3-phenylpro-
panoate (40 mg, 0.18 mmol, 1.0 equiv) in acetone (2 mL) was added
DMDO (∼0.1 M solution in acetone, 3.7 mL, 0.37 mmol, 1.7 equiv) at
ꢀ35 °C. Upon completion of the reaction (determined by TLC, ∼1 h),
the reaction mixture was warmed to room temperature and concentrated
under reduced pressure. Methylene chloride was added, the solution was
dried over Na2SO4 and concentrated under reduced pressure. The re-
sidue was dissolved in DMF (1.6 mL), and indium powder (23 mg,
0.2 mmol, 1.1 equiv) and allyl iodide (33 μL, 0.36 mmol, 2.0 equiv) were
added sequentially. The reaction mixture was stirred 12 h and quenched
with saturated aqueous NaHCO3. After extraction with CH2Cl2 (4 ꢁ
10 mL) the organic layers were combined, washed with H2O (50 mL),
dried (Na2SO4), and concentrated under reduced pressure. Silica gel
chromatography using a 20ꢀ33% EtOAc in petroleum ether gradient
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ARTICLE
afforded 45 mg (>99%, 91% ee) of the desired product as a white solid.
Rf = 0.25 (20% EtOAc in petroleum ether, KMnO4 stain). Mp: 49ꢀ
51 °C. [α]D25 = ꢀ34.2° (91% ee, c 9.3 mg/mL, CHCl3). 1H NMR (400
MHz, CDCl3): δ 7.32ꢀ7.28 (m, 5H), 5.78 (dddd, J = 17.0, 10.3, 8.2, 6.5
Hz, 1H), 5.13 (m, 1H), 4.77 (d, J = 8.0 Hz, 1H), 4.10 (dq, J = 10.8, 7.2
Hz, 1H), 3.99 (dq, J = 10.8, 7.2 Hz, 1H), 3.36 (s, 1H), 3.06 (d, J = 8.0 Hz,
1H), 2.86 (ddt, J = 14.0, 6.9, 1.2, 0.6 Hz, 1H), 2.63 (ddd, J = 14.0, 7.4, 0.6
Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ
173.6, 139.4, 132.5, 128.5, 128.3, 127.4, 119.4, 80.7, 77.7, 62.3, 40.7, 14.3
ppm. IR (neat): νmax 3649, 3503, 1733, 1717, 1699, 1558, 1541, 1507,
1456 1223, 1150 cmꢀ1. HPLC: Tr = 13.1 (minor) and 14.6 (major)
(Chiracel AD Chiral HPLC, λ 220 nm, heptane:iPrOH = 90:10,
1.0 mL/min). HRMS (ES+) m/z calcd for C14H18NaO4 [M + Na]+
273.1103, found 273.1100.
7.0 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 174.5, 139.1,
128.2, 128.0, 127.0, 77.9, 775, 62.0, 22.6, 13.9 ppm. IR (neat): νmax
3473, 2984, 2939, 1730, 1453, 1243, 1160, 1049, 1026, 702 cmꢀ1
.
HPLC: Tr = 16.5 (minor) and 18.0 (major) (Chiracel AD Chiral
HPLC, l = 220 nm, heptane:iPrOH = 90:10, 0.8 mL/min).
’ ASSOCIATED CONTENT
S
Supporting Information. Text and figures giving ex-
b
perimental procedures and spectral data for all new com-
pounds (1H NMR, 13C NMR, IR, HRMS) and tables and a
CIF files giving crystal data for 38. This material is available free of
charge via the Internet at http://pubs.acs.org.
4.3.2. (S)-Ethyl 2-Hydroxy-2-((S)-hydroxy(phenyl)methyl)-3,3-di-
methylpent-4-enoate (23). To a solution of (S)-ethyl 2-diazo-3-hydroxy-
3-phenylpropanoate (40 mg, 0.18 mmol, 1.0 equiv) in acetone (2 mL)
was added DMDO (∼0.1 M solution in acetone, 6 mL, 0.6 mmol, 3.3
equiv) at ꢀ35 °C. Upon completion of the reaction (checked by TLC,
approximately 1 h) the reaction mixture was warmed to room tempera-
ture and concentrated. CH2Cl2 was added, and the solution was dried
over Na2SO4 and concentrated. The residue was dissolved in DMF
(1.6 mL), and indium powder (23 mg, 0.2 mmol, 1.1 equiv) and 3,3-
dimethylallyl bromide (90% pure, 46.6 μL, 0.36 mmol, 2.0 equiv)
were added. After 16 h additional 3,3-dimethylallyl bromide (90%
pure, 53.4 μL, 0.44 mmol, 2.0 equiv) was added and the reaction
mixture stirred for 2 h at 35 °C. The reaction was quenched with
saturated aqueous NaHCO3 solution. After extraction with Et2O
(4 ꢁ 10 mL) the organic layers were combined, washed with H2O
(50 mL), dried over Na2SO4, and concentrated. The crude product
was purified by silica gel chromatography (gradient 20ꢀ33% EtOAc
in petroleum ether) and afforded the title compound (20.7 mg, 62%,
95% ee) as a white solid. Rf = 0.40 (20% EtOAc in petroleum ether).
Mp: 97ꢀ99 °C. [α]D25 = +24.0° (95% ee, c 3.3 mg/mL, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.31ꢀ7.24 (m, 5H), 6.29 (dd, J = 17.6,
10.8 Hz, 1H), 5.19ꢀ5.09 (m, 3H), 4.00 (dq, J = 10.8, 7.2 Hz, 1H),
3.81 (dq, J = 10.8, 7.2 Hz, 1H), 3.55 (s, 1H), 2.90 (d, J = 8.2 Hz, 1H),
1.31 (s, 3H), 1.27 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 173.6, 144.7, 140.2, 128.1, 127.9, 127.6, 113.1, 83.1,
74.9, 62.0, 43.7, 23.5, 23.2, 13.8 ppm. IR (neat): νmax 3465, 2979,
1715, 1261, 1105 cmꢀ1. HPLC: Tr = 7.3 (minor) and 9.1 (major)
(Chiracel IA Chiral HPLC, l = 220 nm, heptane:iPrOH = 90:10,
1.0 mL/min). ee = 95%. HRMS (ES+): m/z calcd for C16H22NaO4
[M + Na]+ 301.1416, found 301.1408.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: bmtrost@stanford.edu.
’ ACKNOWLEDGMENT
This work has been supported by the National Institutes of
Health (No. GM33049) and the National Science Foundation.
S.M. acknowledges Stanford University for a graduate fellowship.
P.K. acknowledges Landesstiftung BW for the Baden-W€urttemberg-
Stipendium undergraduate scholarship. P.E. acknowledges the
DAAD and the Bayer Fellowship Program.
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Journal of the American Chemical Society
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references therein. Chelation control was also observed with the TBS
protected (S)-1, consistent with ref 18 (Supporting Information).
(23) Swenton, J. S.; Madigan, D. M. Tetrahedron 1972, 28, 2703.
2084
dx.doi.org/10.1021/ja206995s |J. Am. Chem. Soc. 2012, 134, 2075–2084