Amine-catalyzed asymmetric epoxidation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/adsc.200600529

The direct organocatalytic enantioselective epoxidation of α,β-unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid-derived imidazolidinones catalyze the asymmetric epoxidation of α,β-unsatur

Full text of DOI:10.1002/adsc.200600529

FULL PAPERS
DOI: 10.1002/adsc.200600529
Amine-Catalyzed Asymmetric Epoxidation of a,b-Unsaturated
Aldehydes
Gui-Ling Zhao,a Ismail Ibrahem,a Henrik SundØn,a and Armando Córdovaa,*
a
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax : (+46)-8-154-908; e-mail: acordova@organ.su.se
Received: October 13, 2006
Abstract: The direct organocatalytic enantioselective tandem epoxidation-Wittig reactions are described.
epoxidation of a,b-unsaturated aldehydes with differ- The reactions were highly diastereo- and enantiose-
entperoxides is presented. Proline, chiral pyrrolidine
lective and provide a rapid access to 2,4-diepoxy al-
derivatives, and amino acid-derived imidazolidinones dehydes. Moreover, a highly stereoselective one-pot
catalyze the asymmetric epoxidation of a,b-unsatu- organocatalytic asymmetric cascade epoxidation-
rated aldehydes. In particular, protected commercial- Mannich reaction, which proceeds via the combina-
ly available a,a-diphenyl- and a,a-di(b-naphthyl)-2- tion of iminium and enamine activation, is presented.
prolinols catalyze the asymmetric epoxidation reac- The mechanism and stereochemistry of the amino
tions of a,b-unsaturated aldehydes with high diaster- acid- and chiral pyrrolidine-catalyzed direct asym-
eo- and enantioselectivities to furnish the corre- metric epoxidation of a,b-unsaturated aldehydes are
sponding 2-epoxy aldehydes in high yield with up to also discussed.
97:3 dr and 98% ee. The use of non-toxic catalysts,
water and hydrogen peroxide, urea hydroperoxide or
sodium percarbonate as the oxygen sources could Keywords: asymmetric catalysis; diphenylprolinol;
make this reaction environmentally benign. In addi- enantioselective epoxidation; hydrogen peroxide;
tion, one-pot direct organocatalytic asymmetric one-pot reactions; unsaturated aldehydes
Introduction
asymmetric a-oxidation of aldehydes and ketones
with electrophilic oxidants such as nitrosobenzene,[11]
The catalytic asymmetric epoxidation is one of the iodosobenzene,[12] oxaziridines,[12] and singletmolecu-
most important reactions in organic synthesis.[1] The lar oxygen.[13] More nucleophilic oxygen sources such
seminal work of Katsuki and Sharpless resulted in the as tert-butyl hydroperoxide, m-CPBA and hydrogen
discovery of titanium-tartrate complexes as asymmet- peroxide failed as oxidants for this transformation.[12]
ric epoxidation catalysts of allylic alcohols.[2] Jacobsen MacMillan and co-workers have demonstrated that
and Katsuki have independently developed chiral chiral amines can catalytically activate a,b-unsaturat-
manganese-salen complexes that are excellent cata- ed aldehydes and ketones towards nucleophilic attack
lysts for the asymmetric epoxidation of unfunctional- by forming iminium ions.[14] Based on our research in-
ized olefins.[3] In addition, Shibasaki and co-workers terest in organocatalysis[15] and the development of
designed several chiral Lewis acids for the catalytic environmentally benign enantioselective oxidation
asymmetric epoxidation of a,b-unsaturated carbonyl processes,[12,13] we became intrigued in whether simple
compounds.[4] Catalytic asymmetric epoxidation reac- chiral amines would be able to catalyze asymmetric
tions are also catalyzed by metal-free organocata- epoxidations of a,b-unsaturated aldehydes with nucle-
lysts.[5] For instance, asymmetric epoxidations of a,b- ophilic oxidants by combination of an iminium and
enones are mediated by polypeptides[6] and Cinchona enamine activation mechanism (Scheme 1).
alkaloids.[7] Moreover, Shi and Aggarwal have discov-
In this context, Jørgensen[16] firstreporet d ht atpro-
ered elegant methods for the epoxidation of unfunc- tected a,a-bis[di(3,5-trifluoromethyl)phenyl]-2-pyrro-
tionalized olefins catalyzed by chiral ketones[8] and lidinemethanol catalyzes the direct enantioselective
pyrrolidines,[9] respectively. Recently, Lattanzi report- epoxidations of a,b-unsaturated aldehydes. We[17]
ed that chiral diarylprolinols catalyze the direct cata- found that chiral amines and amino acid derivatives
lytic asymmetric epoxidation of a,b-unsaturated ke- catalyze the direct asymmetric epoxidation of a,b-un-
tones.[10] Organocatalysis has also been applied in the saturated aldehydes. We[17] and Jørgensen[16b] also
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dinemethanol (9, diphenylprolinol), which has been
developed by Corey and co-workers,[18] as a catalyst.
Diphenylprolinol 9 (30 mol%) catalyzed the stereose-
lective epoxidation of 1a with excellent diastereose-
lectivity (5:95) and low enantioselectivity (22%). It
has been shown that protection of the hydroxy group
of diarylprolinols and hydroxyproline, respectively, is
an excellent strategy to improve the efficiency and
enantioelectivity of organocatalytic reactions cata-
lyzed by these chiral amines.[19–21] Hence, we decided
to convert the hydroxy group of the commercially
available 9 to a siloxy group and synthesized the cor-
responding chiral pyrrolidine 10 in one-step in excel-
lentyield. To our delight, the chiral pyrrolidine 10 (10
mol%) catalyzed the asymmetric epoxidation of 1a
within 2 h (91% conversion) and furnished epoxide
2a in 81% yield in a 93:7 dr and 97% ee. Thus, TMS
protection of the hydroxy group of 9 had a remark-
able effect on the reactivity and enantioselectivity of
the asymmetric epoxidation. In addition, TMS protec-
tion of diphenylprolinol 9 switched the diastereoselec-
Scheme 1. Plausible amine-catalyzed epoxidation of a,b-un-
saturated aldehydes by catalytic iminum and enamine acti-
vation.
found that the TMS-protected diarylprolinol-cata- tivity of the reaction. Decreasing the catalyst loading
lyzed reactions are highly enantioselective in aqueous of 10 to 5 mol% reduced the reaction rate (entry 15).
media. Herein we describe: (i) structure/activity rela- Moreover, employmentof 1 mol% of 10 only gave
tionships of the chiral amine catalysts, (ii) the sub- trace amounts of product 2a after 24 h. We also found
strate scope of the organocatalytic asymmetric epoxi- that TMS-protected di(b-naphthyl)prolinol 12 was an
dation of a,b-unsaturated aldehydes, (iii) one-pot excellent catalyst. Chiral pyrrolidine 12 (10 mol%)
direct organocatalytic tandem asymmetric epoxida- catalyzed the asymmetric formation of 2a in 86%
tion-Wittig reaction sequences, (iv) one-pot organoca- conversion with 93:7 dr and 98% ee. Thus, TMS-pro-
talytic asymmetric cascade epoxidation-Mannich reac- tected diarylprolinols are excellent catalysts for the
tions, (v) and studies concerning the reaction mecha- direct asymmetric epoxidation of a,b-unsaturated al-
nism.
dehydes. The protection of prolinol 13 with a bulky
silyl group gave chiral pyrrrolidine 14 that also cata-
lyzed the formation of 2a with 81:8 dr and 68% ee.
Moreover, we found that MacMillanꢁs imidazolidi-
nones such as 11 catalyzed the direct asymmetric ep-
Results and Discussion
We initially investigated several simple organocata- oxidation of a,b-unsaturated aldehydes with high dia-
lysts (10–30 mol%) for their ability to catalyze the stereoselectivity and modest enantioselectivity under
direct asymmetric epoxidation of cinnamic aldehyde our reaction conditons.[22] Encouraged by our initial
1a (0.25 mmol) with hydrogen peroxide (50% wt, results, we decided to investigate the synthetic scope
aqueous solution, 1.2–7 equivs.) in CHCl3 (2 mL) of the readily available, inexpensive and highly enan-
(Table 1).
tioselective catalyst 10.
The direct asymmetric epoxidation of 1a was medi-
ated by several of the catalysts (3–6 and 8–14) tested
and formed the 2-epoxy aldehyde 2a with poor to ex- Oxidant Screen
cellent diastereo- and enantioselectivity. Notably, ad-
dition of TEA (0.8 equivs.) enabled the use of proline We began to screen several different oxidants for the
and tetrazole 4 as catalysts (entries 2 and 3). For in- chiral pyrrolidine 10-catalyzed asymmetric epoxida-
stance, proline catalyzed the formation of ent-2a with tion of 1a (Table 2).
79% conversion and 36% ee. In addition, chiral pro-
The chiral amine 10 catalyzed the asymmetric epox-
line-derived diamines such as 5 and 6 catalyzed the idation of a,b-unsaturated aldehyde 1a with high dia-
asymmetric epoxidation of 1a with poor to good stereoselectivities (82:18–93:7) and excellent enantio-
enantioselectivity. For example, catalyst 5 exhibited selectivities (>95% ee) when hydrogen peroxide,
the highest asymmetric induction and catalyzed the solid SPC (sodium percarbonate), cumene hydroper-
enantioselective epoxidation of 1a with good conver- oxide, urea hydrogen peroxide (UHP) and tert-butyl
sion (60%) to furnish 2a in a 53:47 dr (trans/cis) and hydrogen peroxide were used as the oxidants. Thus,
with 66% ee. We also investigated diphenyl-2-pyrroli- several environmentally benign oxidants gave excel-
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Table 1. Catalyst screen for the direct catalytic asymmetric epoxidation of 1a
with hydrogen peroxide.[a]
[a]
To a stirred solution of catalyst (10-30 mol%) in CHCl3 (2 mL) was added
aldehyde 1a (0.25 mmol) and H2O2 (0.3–1.75 mmol, 50% aqueous solu-
tion). The reaction mixture was vigorously stirred at room temperature
and monitored by chiral-phase GC analyses.
Amountof formed productas determined by chiral-phase GC analyses.
The dr (trans/cis) and ee were determined by chiral-phase GC analyses.
30 mol% catalyst.
0.8 equivs. TEA added.
10 mol% catalyst and 1.2 equivs. H2O2.
Isolated yield of pure 2a after silica gel column chromatography.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Reaction run in H2O:EtOH (1:1).
Reaction run in dioxane.
5 mol% catalyst and 1.2 equivs. H2O2.
[i]
[j]
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[a]
Table 2. Oxidantscreen for hte chiral amine
direct asymmetric epoxidation of 1a.[a]
10-catalyzed
Table 3. Solventscreen.
[a]
To a stirred solution of catalyst (10 mol%) in CHCl3
(2 mL) was added aldehyde 1a (0.25 mmol) and oxidant
(0.3 mmol). The reaction mixture was vigorously stirred
at room temperature and monitored by chiral-phase GC
analyses.
Amountof formed productas deetrmined by chiral-
phase GC analyses.
The dr (trans/cis) and ee were determined by chiral-
phase GC analyses.
0.38 mmol SPC+50 mL H2O were added.
0.6 mmol UHP+50 mL H2O were added.
[a]
[b]
To a stirred solution of catalyst (10 mol%) in solvent
(2 mL) was added aldehyde 1a (0.25 mmol) and H2O2
(0.3 mmol, 50% aqueous solution). The reaction mixture
was vigorously stirred at room temperature and moni-
tored by chiral-phase GC analyses.
Amountof formed productas deetrmined by chiral-
phase GC analyses.
The dr (trans/cis) and ee were determined by chiral-
phase GC analyses.
[c]
[d]
[b]
[c]
[e]
lent enantioselectivity. For instance, sodium percar-
bonate (SPC) represents one of the most powerful ox-
idants available.[23] Itis pairctularly advanatgeous
owing to its ease of handling and storage. Moreover,
[d]
[e]
Isolated yield.
0.3 mL H2O was used.
the asymmetric induction was slightly higher when temperature increased the diastereo- and enantiose-
chiral amine 10 catalyzed the asymmetric epoxida- lectivity of the chiral pyrrolidine 10-catalyzed reaction
tions with solid SPC or UHP as the oxygen source as (entry 4). The organocatalyst 10-catalyzed asymmetric
compared to hydrogen peroxide. However, the reac- epoxidation reaction with 1.2 equivalents of hydrogen
tions were slower and the order of reactivity of the peroxide exhibited a high stereoselectivity in water/al-
oxidants was H2O2 >UHP>SPC.
cohol solutions and EtOH. Notably, the organocatalyt-
The asymmetric epoxidation of aldehyde 1a with ic asymmetric epoxidation reaction was highly enantio-
m-CPBA was slow and furnished 2a in low conversion selective in water. For instance, 2-epoxy aldehyde 2a
with high diastereoselectivity (96:4 dr) and moderate was formed in high conversion (89%) with 93% ee in
enantioselectivity (51% ee).
water (entry 9).
SPC and UHP are solids. Hence, a small amountof
water was added in order to increase the rate of H2O2
formation and the rate of the reaction. We found that
when the ratio between CHCl3:H2O was between
Solvent Screen
We next investigated the important aspect of perform- 95:5–90:10 the highest asymmetric induction was ach-
ing the organocatalytic asymmetric epoxidation of 1a ieved for the organocatalytic asymmetric epoxidations
in differentsolvents (Table 3).
with SPC (Table 4).
The asymmetric epoxidations with hydrogen perox-
The chiral amine 10-catalyzed asymmetric epoxida-
ide proceed smoothly in all solvents tested. The high- tion of aldehyde 1c with SPC in aqueous solvent did
est enantioselectivity was reached in CHCl3, toluene not have a beneficial effect on the enantioselectivity
and CH2Cl2. In these solvents, 2-epoxy aldehyde 2a of the reaction, which is in stark contrast to when hy-
was formed with 96–97% ee. Decreasing the reaction drogen peroxide was used as the oxygen source.
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Table 4. Influence of water on the organocatalytic asymmet-
ric epoxidations of 1c with hydrogen peroxide.[a]
Table 5. Organocatalytic asymmetric epoxidation of alde-
hydes 1 with hydrogen peroxide.[a]
[a]
To a stirred solution of catalyst (10 mol%) in CHCl3
(1 mL) was added aldehyde 1c (0.25 mmol), SPC
(0.38 mmol) and H2O. The reaction mixture was vigo-
rously stirred at room temperature and monitored by
chiral-phase GC analyses.
[b]
Amountof formed productas deetrmined by chiral-
phase GC analyses.
The dr (trans/cis) and ee were determined by chiral-
[c]
phase GC analyses.
[a]
To a stirred solution of catalyst (10 mol%) in solvent
Substrates
(2 mL) was added aldehyde 1 (0.25 mmol) and H2O2
(0.3 mmol, 50% aqueous solution). The reaction mixture
was vigorously stirred at room temperature and moni-
tored by chiral-phase GC analyses.
Isolated yield after silica-gel column chromatography.
The dr (trans/cis) was determined by chiral-phase GC
analyses or NMR analyses of the crude product.
The ee was determined by chiral-phase GC or HPLC
analyses.
Amountof formed productas deetrmined by chiral-
phase GC analyses.
Reaction performed in t-BuOH:H2O, 1:1 (2 mL).
The ee was determined on the corresponding 2-epoxy-
alcohols 13 after in situ reduction with NaBH4 by chiral-
phase HPLC analyses.
The chiral amine 10-catalyzed asymmetric epoxida-
tion of different a,b-unsaturated aldehydes 1 with
H2O2 was also investigated (Table 5).
[b]
[c]
The a,b-unsaturated aldehydes 1a–1j were excellent
substrates for the chiral amine 10-catalyzed stereose-
lective epoxidation reaction and the corresponding 2-
epoxy aldehydes 2a–2j were furnished in good to high
yields with 91–98% ee. For instance, aldehyde 1h was
catalytically converted to the corresponding 2-epoxy
aldeyde 2h in 86% yield with 83:17 dr (trans:cis) with
98% ee. The 2-epoxy aldehydes 2e–2j were also
efficiently reduced in situ with excess NaBH4 to the
corresponding 2-epoxy alcohols 13e–13j. We found
that when the R group of the aldehydes 1 was aro-
[d]
[e]
[f]
[g]
matic a slightly higher enantiomeric excess was ob- hols 13 were isolated in high yields with high dr and
tained as compared to when R was an aliphatic 94–98% ees. We also attempted the catalytic asym-
moiety. However, the enantioselectivity of the chiral metric epoxidation of a,b-unsaturated ketones with
amine 10-catalyzed epoxidations of aliphatic a,b-unsa- differentoxidants and 10 or 12 as the organocatalysts.
turated aldehydes was increased by performing the re- However, the TMS-protected diarylprolinols failed to
action in aqueous media (entry 2). In the case of 3- furnish the desired epoxides. Instead, diarylprolinols
methyl-2-butenal 2k, the reaction proceed with good such as 9 have been shown by Lattanzi to mediate the
enantioselectivity. We also investigated the direct cat- asymmetric epoxidation of a,b-unsaturated ketones.[10]
alytic asymmetric epoxidation of different aldehydes In addition, we investigated the chiral diamines 5 and
1 with solid SPC or UHP (Table 6).
6 for the direct catalytic asymmetric epoxidation of
The organocatalytic asymmetric epoxidation reac- a,b-unsaturated aldehydes 1 (Table 7).
tions with SPC or UHP proceeded smoothly and the
The diamines catalyzed the reaction with high dia-
corresponding 2-epoxy aldehydes 2 or 2-epoxy alco- stereoselectivity and poor to good enantioselectivity.
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Table 6. Organocatalytic asymmetric epoxidation of aldehydes 1 with SPC and
UHP.[a]
[a]
To a stirred solution of catalyst (10 mol%) in CHCl3 (2 mL) was added aldehyde
1 (0.25 mmol) and oxidant(0.38 mmol + 50 mL H2O). The reaction mixture was
vigorously stirred at room temperature and monitored by chiral-phase GC analy-
ses. The corresponding 2-epoxy alcohols, which were furnished by in situ reduction
with NaBH4, were isolated by silica-gel column chromatography.
Isolated yield after silica-gel column chromatography.
The dr (trans/cis) was determined by chiral-phase GC analyses or NMR analyses
of the crude product.
The ee was determined by chiral-phase GC or HPLC analyses.
The ee was determined on the corresponding 2-epoxy alcohols 13 after in situ re-
duction with NaBH4 by chiral-phase HPLC analyses.
[b]
[c]
[d]
[e]
[f]
0.6 mmol UHP+50 mL H2O were added.
Table 7. Organocatalytic asymmetric epoxidation of aldehydes 1 with catalysts 5 and
6.
[a]
To a stirred solution of catalyst (30 mol%) in CHCl3 (2 mL) was added aldehyde 1
(0.25 mmol) and oxidant(0.38 mmol + 50 mL H2O). The reaction mixture was vigo-
rously stirred at room temperature and monitored by chiral-phase GC analyses. The
corresponding 2-epoxy aldehydes were isolated by silica-gel column chromatography.
Isolated yield after silica-gel column chromatography.
The dr (trans/cis) was determined by chiral-phase GC analyses or NMR analyses
[b]
[c]
of the crude product.
The ee was determined by chiral-phase GC analyses.
60 mol% catalyst was used.
[d]
[e]
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The results show that the catalysts 5 and 6 did not dehydes as the substrates.[25,26] Based on our previous
have enough bulk for efficientshielding of the Si-face investigations of one-pot asymmetric assembly of ami-
of the chiral iminium intermediate in the first Michael nosugar derivatives,[27] we envisioned that one-pot
addition of the peroxide in the catalytic cycle direct asymmetric tandem epoxidation-Wittig reaction
(Scheme 1).
sequences would be excellent catalytic routes for the
synthesis of a,b-unsaturated 4-epoxides 14 or 2,4-
diepoxides 15 that are valuable chiral synthons
(Scheme 2).
One-Pot Organocatalytic Asymmetric Tandem and
Cascade Reactions
Thus, we reacted aldehyde 1e with H2O2 (1.2
equivs.) in the presence of a catalytic amount of cata-
Intrigued by the biosynthesis of cells, which assemble lyst 10 (10 mol%). After 4 h the (formylmethylene)-
complex molecules from simple precursors in an triphenylphosphorane was added and the reaction
asymmetric fashion,[24] we decided to embark on the was stirred for 1 h. Next, an additional amount of cat-
development of novel one-pot organocatalytic reac- alyst 10 (10 mol%) and H2O2 (1.2 equivs.) were
tions based on asymmetric tandem and cascade catal- added. More catalyst was added, since the initial cata-
ysis with hydrogen peroxides and a,b-unsaturated al- lyst may also be inhibited by forming a competing
iminium intermediate with the (formylmethylene)tri-
phenylphosphorane.
After 4 h of vigorously stirring, the reaction was
quenched and the corresponding 2,4-diepoxy alde-
hyde 15e was isolated in 42% yield with>10:1 dr and
97% ee [Eq. (1)].
The one-potchiral amine 10-catalyzed asymmetric
tandem epoxidation-Wittig reaction allowed for the
synthesis of a,b-unsaturated 4-epoxide 14e, which was
isolated in 56% yield with>10:1 dr and 97% ee [Eq.
Scheme 2. The one-pot direct organocatalytic asymmetric
tandem asymmetric synthesis of 2,4-diepoxy aldehydes.
(2)]. Notably, a one-pot double organocatalytic asym-
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Scheme 3. The one-pot direct organocatalytic asymmetric cascade epoxidation-Mannich reaction that is centered on iminium
and enamine catalysis.
Scheme 4. One-pot direct organocatalytic asymmetric cascade epoxidation-Mannich reactions.
metric tandem epoxidation-Wittig reaction allowed reactions proceed with high chemo- and enantioselec-
for the synthesis of 4,6-diepoxy-a,b-unsaturated alde- tivity.
hyde 16e with high stereoselectivity [Eq. (3)]. Thus,
For instance, PMP-protected 4-amino-5-epoxy
the one-pot organocatalytic asymmetric epoxidation- ketone 17a was synthesized in one-step in 75% yield
Wittig reaction sequences represents a simple and with 19:1 dr and>95% ee. The use of (R)-proline en-
highly useful route for the synthesis of functional a,b- abled the formation of the other diasterisomer 17aa
unsaturated 4-epoxides and 2,4-diepoxides. We also but low diastereoselectivity (Scheme 4 bottom). The
decided to investigate whether the concepts of imini- novel one-pot organocatalytic asymmetric cascade re-
um and enamine catalysis could be combined in a action represents a simple way of getting access to
novel one-pot direct organocatalytic cascade asym- valuable chiral synthons with high stereocontrol.
metric epoxidation-Mannich reaction (Scheme 3).[26]
Moreover, the results demonstrated that the employ-
Hence, aldehydes 1 (0.25 mmol) were reacted with ment of two different organocatalysts with orthogonal
hydrogen peroxide (1.2 equivs.) in the presence of a chemoselectivity can be a very powerful synthetic
catalytic amount of catalyst 10 (10 mol%) in CHCl3 strategy.
(1 mL) (Scheme 4 top). After 4 h of vigorous stirring
DMSO (1 mL), acetone (0.5 mL), p-anisidine (1.1
equivs.), and a catalytic amount of (S)-proline 3 (30 Mechanism
mol%) were added to the reaction mixture. Proline
was utilized as an additional organocatalyst, since cat- The stereochemistry of the chiral amine-catalyzed
alyst 10 was a poor catalyst for the one-pot three- asymmetric epoxidation reactions was established by
component Mannich reactions with ketones as comparison of the optical rotation of aldehyde 2a
donors.[28] The reactions were quenched after 16 h and with the literature {[a]D25: ꢀ30.1 (c 1.6, CHCl3); Lit.
the corresponding PMP (p-methoxyphenyl) protected ent-2a [a]23: +14.3 (c 0.48, CHCl3)[4]} which revealed
2-keto-4-amino-5-epoxides 17 were isolated in high that the sDtereochemistry of the 2-epoxy aldehyde 2a
yields and enantiomeric excesses together with a derived by chiral pyrrolidine derivative 5, 6, 10 and 12
small amount of the aldol product from the reaction catalysis was (2S,3R). The opposite enantiomer ent-2a
between acetone and 2-epoxy aldehyde 2. Thus, the was furnished by (S)-proline, (S)-prolinol and proline-
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tetrazole 4 catalysis. The plausible mechanism of the
The stereochemistry of the chiral diamine 5- and 6-
amine-catalyzed asymmetric epoxidation reactions is catalyzed asymmetric epoxidation was explained by a
depicted in Scheme 1. Accordingly, the reaction starts combination of shielding of the Si-face of the chiral
with iminium activation of the a,b-unsaturated alde- iminium and enamine intermediates. In the case of
hydes by the chiral pyrrolidine or proline followed by (S)-proline, opposite facial attack occurs on the per-
stereoselective nucleophilic conjugate attack on the b- oxygen by the plausible transition state III that results
carbon resulting in an enamine derivative. Next, the in formation of ent-2.
chiral enamine performs a nucleophilic attack on the
peroxygen, followed by hydrolysis of the resulting
iminium intermediate. The reverse mechanism has
been observed in chiral pyrrolidine-catalyzed tandem
a-aminoxylation-Michael reactions[11j,k,l] and aza-
Diels–Alder[15a] reactions with a,b-unsaturated ke-
tones, which further supports the proposed reaction
mechanism. We also most recently found that cata-
lysts 10 and 12 catalyze the enantioselective a-oxida-
Investigation of the enantiomeric excess of 2-epox-
tion of aldehydes with O2 via a catalytic enamine yaldehyde 2a as a function of the optical purity of the
mechanism.[21] The remarkable change of reactivity by catalyst 10 revealed
slightly positive effect
1
a
TMS protection of the diarylprolinols such as 9 was (Figure 1). We also found that the reaction is possibly
explained by prevention of aminal formation with the first order with respect to the catalyst (Figure 2). In
substrate [Eq. (4)] or product and increased hydro- addition, the rate and consequently the conversion of
the reaction decreased at lower optical purity of the
catalyst (Figure 3). Thus, the barely noticeable posi-
tive non-linear effect in Figure 1 may be due to an in
situ kinetic resolution of catalyst 10 by the chiral 2-
epoxy aldehyde 2a.[30]
Conclusions
phobicity of the corresponding diarylprolinols 10 and
12, which improves the rate of iminium formation In summary, we have shown that several simple chiral
with aldehydes 1. This is in accordance with other pyrrolidine derivatives and amino acid-derived imida-
protected diarylprolinol-catalyzed asymmetric trans- zolidinones catalyze the direct asymmetric epoxida-
formations.[19,20] Moreover, the same effects are due to tion of a,b-unsaturated aldehydes with peroxides. In
the rate acceleration when comparing protected proli- particular, TMS-protected diarylprolinols such as 10
nol 14 with prolinol 13. The beneficial hydrophobic and 12 were excellent catalysts and furnished the cor-
effect[29] also explains the rate acceleration and in- responding 2-epoxy aldehydes in high yields, diaster-
creased enantioselectivity of the 10-catalyzed asym- eo- and enantioselectivities (91–98% ee). Notably, the
metric epoxidation of a,b-unsaturated aliphatic alde- diarylprolinol 10-catalyzed asymmetric epoxidation
hydes with hydrogen peroxide in aqueous media.
reaction with hydrogen peroxide was efficient and
The high enantioselectivity observed for the asym- highly enantioselective in water or water alcohol solu-
metric epoxidation reactions with catalysts 10 and 12 tions. In addition, highly stereoselective one-pot orga-
is plausibly due to stabilization of the configuration of nocatalytic asymmetric tandem epoxidation-Wittig re-
the iminium ion intermediate as well as efficient action sequences were developed. The one-pot cata-
shielding of the Si-face of the chiral iminium and en- lytic asymmetric tandem epoxidation-Wittig reactions
amine intermediates by the bulky aryl groups via the were done in an iterative fashion and gave 2,4-di-
plausible intermediates I and II, respectively. The sta- epoxy aldehydes or a,b-unsaturated 4-epoxy aldehydes
bilization of the enamine intermediate II is supported in good yield and enantiomeric excess. Moreover, a
by the high trans-selectivity of the asymmetric epoxi- novel organocatalytic asymmetric cascade epoxida-
dation reactions with 10 and 12.
tion-Mannich reaction was developed. The catalytic
enantioselective cascade reaction assembled 2-keto-4-
amino-5-epoxides in an asymmetric fashion with high
diastereo- and enantioselectivities. The organocatalyt-
ic epoxidation reactions proceed via a plausible com-
bined iminium and enamine mechanism. Further-
more, the high enantioselectivity observed for the
asymmetric epoxidation reactions with catalysts 10
1218
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Adv. Synth. Catal. 2007, 349, 1210 – 1224

Asymmetric Epoxidation of a,b-Unsaturated Aldehydes
FULL PAPERS
&
Figure 1. The enantiomeric excess of 2-epoxy aldehyde 2a as a function of the enantiomeric excess of the (S)-10 ( )-cata-
lyzed direct asymmetric epoxidation of 1a.
&
Figure 2. The initial rate Vi [mmol/
A
(mol%, 10 mol%=25 mmol/mL). The initial rates have at least been collected 3 times and averaged.
and 12 is possibly due to efficient stabilization of the Experimental Section
configuration of the iminium ion intermediate as well
as efficientshielding of the Si-face of the chiral imini- General Methods
um and enamine intermediates by the bulky aryl
Chemicals and solvents were either purchased puriss p. A.
groups. The ability of natural amino acids to catalyze
the reaction suggest that the amine-catalyzed asym-
metric epoxidation of a,b-unsaturated aldehydes
from commercial suppliers or purified by standard tech-
niques. For thin-layer chromatography (TLC), silica gel
plates Merck 60 F254 were used and compounds were vi-
sualized by irradiation with UV light and/or by treatment
[31]
mightbe presentin Nature.
with
a solution of phosphomolybdic acid (25 g), Ce-
Adv. Synth. Catal. 2007, 349, 1210 – 1224
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1219

Gui-Ling Zhao etal.
FULL PAPERS
&
^
Figure 3. The amountof 2-epoxy aldehyde 2a formed (%) when enantiopure catalyst (S)-10 ( ) and (S)-10 with 10% ee ( ),
respectively, were used as the catalysts for the organocatalytic asymmetric epoxidation of 1a.
.
A
(CDCl3, 125 MHz): d=2.4, 25.1, 28.0, 47.3, 65.5, 83.3, 126.8,
127.0, 128.0, 129.0, 146.0, 147.0.
Catalysts 12 and 14 were prepared by the same proce-
dure.
followed by heating or by treatment with a solution of p-ani-
saldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid
(10 mL), and ethanol (900 mL) followed by heating. Flash
chromatography was performed using silica gel Merck 60
(particle size 0.040–0.063 mm), H NMR and 13C NMR spec-
General Procedure for the Organocatalytic
Asymmetric Epoxidation of a,b-Unsaturated
Aldehydes with H2O2 Catalyzed by 10 and 12
tra were recorded on a Varian AS 400. Chemical shifts are
given in d relative to tetramethylsilane (TMS), the coupling
constants J are given in Hz. The spectra were recorded in
CDCl3 as solvent at room temperature, TMS served as inter-
To a stirred solution of 10 or 12 (10 mol%) in CHCl3
nal standard (d=0 ppm) for H NMR, and CDCl3 was used
(2 mL) was added aldehyde
1 (0.25 mmol) and H2O2
as internal standard (d=77.0 ppm) for 13C NMR. GC was
carried out using a Varian 3800 GC Instrument. Chiral GC-
column used: CP-Chirasil-Dex CB 25 m”0.32 mm. HPLC
was carried out using a Waters 2690 Millennium with photo-
diode array detector. Optical rotations were recorded on a
Perkin Elemer 241 polarimeter (l=589 nm, 1 dm cell).
High-resolution mass spectra (ESI) were obtained with a
Bruker MicrOTOF spectrometer. The spectral data of chiral
products 2a are known.[4]
(0.3 mmol, 50% aqueous solution). The reaction was vigo-
rously stirred at room temperature for the times shown in
the Tables. The crude reaction mixture was passed through a
silica gel column (pentane/EtOAc or toluene/EtOAc mix-
tures) to give oxirane-2-carbaldehydes 2 or the temperature
of the reaction mixture was decreased to 08C and MeOH
(1 mL) and excess NaBH4 was added. The reaction was
quenched by addition of EtOAc and aqueous solution of
NH4Cl. The organic layer was dried, concentrated and the
crude productpurified by silica-gel column chromaot graphy
(toluene/EtOAc mixtures) to give the corresponding 2-
epoxy alcohols 13.
Preparation of Catalyst 10
The commercially available catalyst 9 (1 g, 3.95 mmol) was
readily protected with TMSOTf (1.1 g, 5.1 mmol) in the
presence of TEA (0.51 g, 5.1 mmol) in CH2Cl2 (20 mL) at
08C. The reaction mixture was stirred at room temperature
for 17 h and quenched with water (10 mL). The aqueous
layer was extracted with CH2Cl2 (3”15 mL). The combined
organic extracts were stirred with NaHCO3 for 15 min,
dried over anhydrous Na2SO4 and concentrated under
vacuum after filtration. Purification with silica gel column
chromatography (EtOAc:pentane, 1:7!1:3) furnished 10 as
General Procedure for the Chiral amine 10-Catalyzed
Asymmetric Epoxidation of a,b-Unsaturated
Aldehydes with SPC or UHP
To a stirred solution of 10 (10 mol%) in solvent(2 mL) was
added aldehyde
1
(0.25 mmol) and SPC or UHP
(0.38 mmol+50 mL H2O). The reaction mixture was vigo-
rously stirred at room temperature for the time shown in
the Tables and monitored by chiral-phase GC analyses or
NMR analysis. The crude reaction mixture was passed
through a silica gel column (pentane/EtOAc or toluene/
EtOAc mixtures) to give oxirane-2-carbaldehydes 2 or the
temperature of the reaction mixture was decreased to 08C
1
a thick oil; yield: 1.3 g (99%). H NMR (CDCl3, 400 MHz):
d=ꢀ0.03 (s, 9H), 1.53–1.71 (m, 4H), 2.81–2,93 (m, 2H),
4.09 (t, J=7.0 Hz, 1H), 7.22–7.53 (m, 10H); 13C NMR
1220
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Adv. Synth. Catal. 2007, 349, 1210 – 1224

Asymmetric Epoxidation of a,b-Unsaturated Aldehydes
FULL PAPERS
and MeOH (1 mL) and excess NaBH4 was added. The reac-
tion was quenched by addition of EtOAc and aqueous solu-
tion of NH4Cl. The organic layer was dried, concentrated
and the crude product purified by silica-gel column chroma-
tography (toluene/EtOAc mixtures) to give the correspond-
ing 2-epoxy-alcohols 13.
54.9, 61.0, 62.5, 127.0, 128.7, 134.1, 135.2; The ee was deter-
mined by HPLC on Daicel Chiralpak OJ column, with iso-
hexane/i-PrOH (92:8) as the eluent: Rt (min)=25.283
(major enantiomer); 28.964 (minor enantiomer). [a]2D5:
+32.3 (c 1.0, CHCl3).
AHCTREUNG
[(2R,3R)-3-(4-bromophenyl)oxiran-2-yl]methanol (13f):[35]
A
1H NMR (400 MHz, CDCl3): d=2.20 (br s, 1H), 3.16–3.18
(m, 1H), 3.79 (dd, J=3.6, 12.8 Hz, 1H), 3.89 (d, J=2.0 Hz,
1H), 4.03 (dd, J=2.4, 12.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H),
7.47 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
53.9, 61.0, 62.5, 122.2, 127.3, 131.6, 135.8; The ee was deter-
mined by HPLC on Daicel Chiralpak OJ column, with iso-
(CDCl3, 400 MHz): d=9.20 (d, J=6.1 Hz, 1H), 7.39–7.29
(m, 5H), 4.17 (d, J=1.8 Hz, 1H), 3.46 (dd, J=1.8, 6.1 Hz,
1H); 13C NMR (CDCl3, 125 MHz): d=196.7, 134.2, 129.2,
128.8 (2C), 125.7 (2C), 62.9, 56.6; The formation and enan-
tiomeric excess of 2a was determined on a Chromasil CP-
Chirasil-Dex CB-column. Temperature program: 708C t o hexane/i-PrOH (92:8) as the eluent: Rt (min)=28.07 (major
1608C, rate; 108Cminꢀ1, hold 1 min, 1608C to 2008C, rate;
808Cminꢀ1, hold 5 min. Rt (min)=major enantiomer
8.04 min, minor enantiomer 8.12 min; [a]2D5: ꢀ30.1 (c 1.6,
CHCl3) {Lit .ent-2a, [a]23: +14.3 (c 0.48, CHCl3, 94% ee)[9]};
MALDI-TOF-MS: m/Dz=171.0423; C9H8NO2 (M+Na+:
calcd.: 171.0422); IR (film): n=3038, 2823, 1732 cmꢀ1
enantiomer); 32.89 (minor enantiomer); [a]2D5: +23.1 (c 1.0,
CHCl3).
AHCTREUNG
[(2R,3R)-3-(4-Nitrophenyl)oxiran-2-yl]methanol (13g):[36]
1H NMR (400 MHz, CDCl3): d=2.20 (br s, 1H), 3.18–3.20
(m, 1H), 3.85 (d, J=12.8 Hz, 1H), 4.04–4.08 (m, 2H), 7.44
(d, J=8.8 Hz, 2H), 8.18 (d, J=8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=54.3, 60.7, 63.0, 123.7, 126.4, 144.4,
147.8; The ee was determined by HPLC on Daicel Chiralpak
OJ column, with isohexane/i-PrOH (92:8) as the eluent: Rt
(min)=80.50 (major enantiomer); 91.98 (minor enantio-
mer); [a]2D5: +25.0 (c 1.0, CHCl3).
A
(2b):[32a,b]
1H NMR (300 MHz, CDCl3): d=0.97 (t, J=7.2 Hz, 3H),
1.46–4.54 (m, 2H), 1.60–1.68 (m, 2H), 3.12 (dd, J=6.3,
1.8 Hz, 1H), 3.22 (dt, J=5.4, 1.8 Hz, 1H), 9.00 (d, J=
6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=13.9, 19.3,
33.3, 56.7, 59.2, 198.6; The enantiomeric excess was deter-
mined on a Chromasil CP-Chirasil-DexCB column, temper-
ature program: 70–1308C, rate: 78Cminꢀ1, hold 1 min, 130–
2008C, rate: 808Cminꢀ1, hold 7 min. Major isomer: tR =
4.799 min; minor isomer: tR =4.906 min; [a]2D5: ꢀ41.3 (c 1.0,
CHCl3).
A
(13h):
1H NMR (300 MHz, CDCl3): d=2.25 (br s, 1H), 3.20–3.22
(m, 1H), 3.85 (dd, J=3.6, 12.9 Hz, 1H), 4.04–4.09 (m, 2H),
7.46–7.56 (m, 1H), 7.60–7.68 (m, 1H), 8.07–8.19 (m, 2H);
13C NMR (75 MHz, CDCl3): d=54.3, 60.7, 62.8, 120.6, 123.1,
129.5, 131.7, 139.2, 148.4; The ee was determined by HPLC
on Daicel Chiralpak OJ column, with isohexane/i-PrOH
(92:8) as the eluent: Rt (min)=69.60 (major enantiomer);
72.45 (minor enantiomer). [a]2D5: + 40.2 (c 1.0, CHCl3). HR-
ACHTREUNG
(2S,3R)-3-Butyloxirane-2-carbaldehyde (2c):[32c] 1H NMR
(400 MHz, CDCl3): d=0.90–0.94 (m, 3H), 1.35–1.46 (m,
4H), 1.63–1.68 (m, 2H), 3.13 (dd, J=2.0, 6.0 Hz, 1H), 3.21–
3.24 (m, 1H), 9.01 (d, J=6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): <it>d</it>=13.84, 22.31, 27.84, 30.88, 56.77,
59.15, 198.49; The ee was determined on a Chromasil CP-
MS
196.0604; IR (film): n=3265, 2922, 1520 cmꢀ1.
[(2R,3R)-3-(naphthalen-1-yl)oxiran-2-yl]methanol (13i):[37]
(ESI): m/z= 196.0605, calcd. for [M+H]+ (C9H10NO4):
ACHTREUNG
AHCTREUNG
Chirasil-Dex CB-column. Temperature program: 708C t o 1H NMR (300 MHz, CDCl3): d=1.96 (br s, 1H), 3.32–3.33
1308C, rate; 78Cminꢀ1, hold 1 min, 1308C to 2008C, rate;
808Cminꢀ1, hold 7 min. Rt (min)=5.32 (major enatiomer);
5.43(minor enationer); [a]2D5: ꢀ26.5 (c 0.56, CHCl3).
(m, 1H), 3.86 (dd, J=6.6, 12.9 Hz, 1H), 4.07–4.12 (m, 2H),
7.32–7.50 (m, 3H), 7.80–7.84 (m, 4H); 13C NMR (75 MHz,
CDCl3): d=55.8, 61.2, 62.5, 122.9, 123.9, 125.2, 125.4, 126.2,
126.4, 126.5, 127.8, 128.1, 128.4; The ee was determined by
HPLC on Daicel Chiralpak OJ column, with isohexane/i-
PrOH (92:8) as the eluent: Rt (min)=93.11 (minor enantio-
mer); 101.29 (major enantiomer). [a]2D5: +20.8 (c 1.0,
CHCl3).
A
3-formyloxirane-2-carboxylate
(2d):[33]
1H NMR (400 MHz, CDCl3): d=1.34 (t, J=7.3 Hz, 3H),
3.76 (dd, J=1.8, 6.8 Hz, 1H), 3.77 (d, J=1.8 Hz, 1H), 4.23
(m, 2H), 9.05 (d, J=6.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=14.0, 50.8, 57.5, 62.6, 166.1, 195.0; The ee was
determined on a Chromasil CP-Chirasil-Dex CB-column.
Temperature program: 708C t o 858C, rate; 58Cminꢀ1, hold
20 min, Rt (min)=17.6 (major enatiomer); 18.9 (minor ena-
tioner); [a]2D5: ꢀ33.7 (c 0.61, CHCl3).
AHCTRE[UNG (2R,3R)-3-(Benzyloxymethyl)oxiran-2-yl]methanol
(13j):[38] 1H NMR (400 MHz, CDCl3): d=2.02 (br s, 1H),
3.09–3.10 (m, 1H), 3.22–3.24 (m, 1H), 3.53 (dd, J=5.6,
12.0 Hz, 1H), 3.63 (dd, J=4.0, 12.0 Hz, 1H), 3.77 (dd, J=
2.8, 8.4 Hz, 1H), 3.92 (dd, J=3.2, 12.8 Hz, 1H), 4.52–4.61
(m, 2H), 7.27–7.37 (m, 5H); 13C NMR (100 MHz, CDCl3):
d=54.2, 55.7, 61.1, 69.6, 73.3, 127.7, 127.8, 128.4, 137.7; The
ee was determined by HPLC on Daicel Chiralpak OJ
column, with isohexane/i-PrOH (95:5) as the eluent: Rt
(min)=142.79 (major enantiomer); 160.97 (minor enantio-
mer). [a]2D5: +10.5 (c 1.0, CHCl3).
ACHTREUNG(2S,3R)-3-(4-Chlorophenyl)-oxirane-2-carbaldehyde (2e):
1H NMR (400 MHz, CDCl3): d=3.40 (dd, J=1.8, 6.0 Hz,
1H), 4.15 (d, J=1.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.35
(d, J=8.4 Hz, 2H), 9.17 (d, J=6.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=56.4, 63.1, 127.3 (2C), 129.3 (2C),
133.0, 135.3, 196.8; The ee was determined after NaBH4 re-
duction to the alcohol 13e. [a]2D5: ꢀ38.0 (c 1.7, CHCl3). IR
(film): n=3437, 2827, 1728 cmꢀ1.
(R)-(3,3-Dimethyloxiran-2-yl)methanol (13k):[39] 1H NMR
(400 MHz, CDCl3): d=1.30 (s, 3H), 1.33 (s, 3H), 2.19 (br s,
1H), 2.95–2.99 (m, 1H), 3.66 (dd, J=6.8, 12.0 Hz, 1H), 3.82
(dd, J=4.0, 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
18.8, 24.7, 58.9, 61.4, 63.8; The ee was determined on a
Chromasil CP-Chirasil-Dex CB-column. Temperature pro-
ACHTREUNG[(2R,3R)-3-(4-Chlorophenyl)oxiran-2-yl]methanol
(13e):[34] 1H NMR (300 MHz, CDCl3): d=2.33 (br s, 1H),
3.15–3.18 (m, 1H), 3.78 (dd, J=3.9, 12.9 Hz, 1H), 3.90 (d,
J=1.8 Hz, 1H), 4.03 (dd, J=2.1, 12.9 Hz, 1H), 7.18–7.20 (m,
2H), 7.30–7.32 (m, 2H); 13C NMR (75 MHz, CDCl3): d=
Adv. Synth. Catal. 2007, 349, 1210 – 1224
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Gui-Ling Zhao etal.
FULL PAPERS
gram: 608C to 1008C, rate: 28Cminꢀ1, hold 1 min, 1008C t o CDCl3): d=3.15 (dd, J=3.2, 2.0 Hz, 1H), 3.23 (dd, J=3.2,
2008C, rate; 1008Cminꢀ1, hold 3 min. Rt (min)=14.839
(minor enatiomer); 15.421 (major enationer); [a]2D5: +10.2 (c
1.0, CHCl3).
2.0 Hz, 1H), 3.68 (dd, J=6.8, 2.0 Hz, 1H), 3.89 (d, J=
2.0 Hz, 1H), 6.44 (dd, J=16.0, 7.6 Hz, 1H), 6.57 (dd, J=
16.0, 6.8 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.33 (d, J=
8.4 Hz, 2H), 9.59 (d, J=7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=53.9, 55.8, 58.5, 59.2, 127.1, 129.1, 134.5, 134.6,
142.7, 150.7, 192.3. [a]2D5: +56.7 (c 0.6, CHCl3). HR-MS
(ESI): m/z=251.0458, calc. for [M+H]+ (C13H12ClO3):
251.0469. IR (film): n=3479, 2925, 1694 cmꢀ1.
Typical Procedure for the One-Pot Organocatalytic
Tandem Asymmetric Epoxidation-Wittig Reaction
To a stirred solution of 10 (10 mol%) in CHCl3 (2 mL) was
added aldehyde 1 (0.25 mmol) and H2O2 (0.3 mmol, 50%
aqueous solution). After 4 h (formylmethylene)triphenyl-
phosphorane (0.3 mmol) was added and the reaction mix-
ture was stirred for 1 h. Next, the crude reaction mixture
was directly loaded onto a silica gel column and chromatog-
raphy with pentane/EtOAc (10/1) gave (E)-3-[(2R,3R)-3-(4-
Typical Procedure for the One-Pot Organocatalytic
Asymmetric Cascade Epoxidation-Mannich Reaction
To a stirred solution of 10 (10 mol%) in CHCl3 (1 mL) was
added aldehyde 1 (0.25 mmol) and H2O2 (0.3 mmol, 50%
aqueous solution). After 4 h of vigorous stirring DMSO
(1 mL), acetone (0.5 mL), p-anisidine (0.28 mmol), and a
catalytic amount of (S)-proline 3 or ent-3 (30 mol%) were
added to the reaction mixture. The one-pot reaction mixture
was stirred for 16 h and quenched by extraction with brine
and EtOAc. The combined organic layers were dried with
Na2SO4, filtered, concentrated and purified by silica-gel
column chromatography (toluene/EtOAc) to give the corre-
sponding PMP protected amino epoxides 17 as yellow oils.
17a: 1H NMR (400 MHz, CDCl3): d=2.20 (s, 3H), 2.84
(d, J=6.5 Hz, 2H), 3.23 (t, J=4.7 Hz, 1H), 3.76 (s, 3H),
3.89 (d, J=2.1 Hz, 1H), 4.21 (m, 1H), 6.63 (d, J=9.1 Hz,
2H), 6.80 (d, J=9.0 Hz, 2H), 7.17–7.33 (m, 5H); 13C NMR
(100 MHz, CDCl3): d=30.9, 46.1, 49.2, 55.9, 56.7, 64.2,
115.1, 115.3, 125.8, 128.4, 129.0, 137.0, 140.8, 152.8, 207.1;
[a]2D5: +21.9 (c 1.0, CHCl3); MALDI-TOF-MS: m/z=
334.1420, calcd. for C19H21NO3 (M+Na+): 334.1419. IR
(film): n=3434, 1645 cmꢀ1.
chlorophenyl)oxiran-2-yl]acrylaldehyde (14e) as
a light
yellow oil: 1H NMR (400 MHz, CDCl3): d=3.53–3.55 (m,
1H), 3.87 (d, J=1.6 Hz, 1H), 6.43 (ddd, J=16.0, 8.0, 0.8 Hz,
1H), 6.66 (dd, J=16.0, 6.8 Hz, 1H), 7.22–7.27 (m, 2H),
7.33–7.35 (m, 2H), 9.61 (d, J=8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=60.8, 61.1, 127.4, 129.3, 134.3, 134.5,
135.1, 151.2, 192.6; [a]2D5: +228.9 (c 1.0, CHCl3). HR-MS
(ESI): m/z=209.0360, calcd. for [M+H]+ (C11H10ClO2):
209.0364. IR (film): n=3646, 3418, 1645 cmꢀ1.
Typical Procedure for the One-Pot Organocatalytic
Asymmetric Tandem Epoxidation-Wittig Reaction
To a stirred solution of 10 (10 mol%) in CHCl3 (2 mL) was
added aldehyde 1 (0.25 mmol) and H2O2 (0.3 mmol, 50%
aqueous solution). After 4 h (formylmethylene)triphenyl-
phosphorane (0.3 mmol) was added and the reaction mix-
ture was stirred for 1 h. Next, an additional amount of cata-
lyst 10 (10 mol%) and H2O2 (1.2 equivs.) were added. After
4 h of vigorously stirring, the crude reaction mixture was di-
rectly loaded onto a silica gel column and chromatography
with pentane/EtOAc (10/1) gave (2R,3S,2’S,3’R)-3’-(4-chloro-
17g: 1H NMR (400 MHz, CDCl3): d=2.21 (s, 3H), 2.87
(m, 2H), 3.21 (t, J=2.2 Hz, 1H), 3.76 (s, 3H), 3.99 (d, J=
2.0 Hz, 1H), 4.23 (m, 1H), 6.61 (d, J=9.0 Hz, 2H), 6.81 (d,
J=8.9 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 8.17 (d, J=8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=30.9, 46.1, 48.9, 55.9,
56.0, 64.8, 115.2, 115.4, 124.0, 126.6, 140.5, 144.7, 148.1,
153.1, 206.9; [a]2D5: +26.8 (c 1.0, CHCl3). HR-MS (ESI):
m/z=357.1445, calcd for [M+H]+ C19H22N2O5: 357.1445. IR
(film): n=3401, 1642 cmꢀ1.
phenyl)-[2,2’]bioxiranyl-3-carbaldehyde (15e) as
a light
yellow oil. 1H NMR (400 MHz, CDCl3): d=3.11 (dd, J=
1.6 Hz, 2.0 Hz, 1H), 3.45–3.48 (m, 2H), 3.88 (d, J=1.6 Hz,
1H), 7.18–7.20 (m, 2H), 7.30–7.34 (m, 2H), 9.10 (d, J=
6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=54.0, 55.6,
56.3, 58.6, 127.0, 128.9, 134.0, 134.6, 196.6; [a]2D5: +75.1 (c
1.0, CHCl3); MALDI-TOF-MS: m/z=247.0139; calcd. for
C11H9ClO3 (M+Na+): 247.0138. IR (film): n=3508, 3019,
1732 cmꢀ1.
17l: 1H NMR (400 MHz, CDCl3): d=2.20 (s, 3H), 2.85
(m, 2H), 3.17 (t, J=2.2 Hz, 1H), 3.75 (s, 3H), 3.92 (d, J=
2.1 Hz, 1H), 4.20 (m, 1H), 6.60 (d, J=9.0 Hz, 2H), 6.79 (d,
J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.5 Hz,
2H); 13C NMR (100 MHz, CDCl3): <it>d</it>=30.8,
46.1, 48.9, 55.9, 56.0, 64.6, 115.1, 115.3, 126.4, 132.51, 140.5,
141.2, 142.7, 153.0, 206.9; [a]2D5: +41.2 (c 1.0, CHCl3). HR-
MS (ESI): m/z=337.1544, calcd. for [M+H]+ C20H21N2O3:
337.1547. IR (film): n=3391, 1660 cmꢀ1.
Typical Procedure for the One-Pot Organocatalytic
Asymmetric Tandem Double Epoxidation-Wittig
Reaction
1
To a stirred solution of 10 (10 mol%) in CHCl3 (2 mL) was
added aldehyde 1 (0.25 mmol) and H2O2 (0.3 mmol, 50%
aqueous solution). After 4 h the (formylmethylene)triphe-
nylphosphorane (0.3 mmol) was added and the reaction mix-
ture was stirred for 1 h. Next, an additional amount of cata-
lyst 10 (10 mol%) and H2O2 (1.2 equivs.) were added. After
4 h of vigorously stirring, the (formylmethylene)triphenyl-
phosphorane (0.3 mmol) was again added and the reaction
mixture stirred for 1 h. Next, the crude reaction mixture was
directly loaded onto a silica gel column and chromatography
with pentane/EtOAc (6/1) gave the a,b-unsaturated-4,6-di-
epoxy aldehyde 16e as lightyellow oil. 1H NMR (400 MHz,
17aa: H NMR (400 MHz, CDCl3): d=2.18 (s, 3H), 2.84
(d, J=6.0 Hz, 2H), 3.22 (t, J=2.4 Hz, 1H), 3.73 (s, 3H),
3.89 (d, J=2.0 Hz, 1H), 4.40 (m, 1H), 6.67 (d, J=9.0 Hz,
2H), 6.80 (d, J=9.0 Hz, 2H), 7.19–7.32 (m, 5H); 13C NMR
(100 MHz, CDCl3): d=31.0, 46.1, 49.3, 56.0, 56.8, 64.2,
115.2, 116.2, 126.6, 128.7, 130.5, 136.8, 140.8, 153.1, 207.1;
MALDI-TOF-MS: m/z=334.1419, calcd. for C19H21NO3
(M+Na+): 334.1419. IR (film): n=3434, 1645 cmꢀ1.
1222
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Adv. Synth. Catal. 2007, 349, 1210 – 1224

Asymmetric Epoxidation of a,b-Unsaturated Aldehydes
FULL PAPERS
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T. Sumiya, T. Urushima, M. Shoji, D. Hashizume, H.
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Acknowledgements
Support by Stockholm University is gratefully acknowledged.
We thank the Swedish National Research council, the Swed-
ish Research Council for Environment, Agricultural Sciences
and Spatial Planning, Carl-Trygger and Lars Hierta Founda-
tion for financial support.
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