A highly stereoselective synthesis of glycidic amides based on a new class of chiral sulfonium salts: Applications in asymmetric synthesis

Article abstract of DOI:10.1002/chem.201201332

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98 %). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

Full text of DOI:10.1002/chem.201201332

DOI: 10.1002/chem.201201332
A Highly Stereoselective Synthesis of Glycidic Amides Based on a New Class
of Chiral Sulfonium Salts: Applications in Asymmetric Synthesis
Francisco Sarabia,* Carlos Vivar-Garcꢀa, Miguel Garcꢀa-Castro, Cristina Garcꢀa-Ruiz,
Francisca Martꢀn-Gꢁlvez, Antonio Sꢁnchez-Ruiz, and Samy Chammaa[a]
In memory of Professor Rafael Suau
Abstract: A new type of chiral sulfoni-
um salts that are characterized by a bi-
cyclic system has been designed and
synthesized from a-amino acids. Their
corresponding ylides, which were pre-
pared by basic treatment of the sulfoni-
hydes to provide trans-epoxy amides in
reasonable to very good yields and ex-
cellent stereoselectivities (>98%). The
obtained epoxy amides were found to
be useful as synthetic building blocks.
Thus, they were reduced into their cor-
responding epoxy alcohols and subject-
ed to oxirane-ring-opening reactions
with different types of nucleophiles.
Keywords: amides
synthesis natural products
oxiranes · ylides
·
asymmetric
·
·
um salts, reacted smoothly with
a
broad array of simple and chiral alde-
Introduction
amides, which display exquisite regiocontrol for the C2 posi-
tion in reactions with nucleophiles.[13] Our extensive experi-
ence in this field,[14] which initially focused on carbohy-
drates[15] and later became extended to other types of syn-
thetic endeavors,[16] prompted us to investigate the asymmet-
ric version of this reaction by designing a new class of
chiral-amide-stabilized sulfur ylides. With amide-stabilized
sulfur ylides, the chirality can be introduced in the amide
fragment (type A, Scheme 1), which, in our own experi-
ence[17] and in the experience of some other precedents,[18]
did not successfully result in the enantiomeric formation of
the oxirane ring. Alternatively, ylides of type B (Scheme 1)
have been well-studied and employed in the literature to
give excellent enantiomeric excesses in various cases. A
third case, which has not been studied so far, can be repre-
sented by cyclic sulfur ylides of type C, for which we expect
a high degree of diastereoselection in their reactions with
carbonyl compounds owing to the presence of a chiral bicy-
clic system. These new chiral sulfur ylides should yield
epoxy amides of the type depicted in Scheme 1 and offer di-
verse synthetic possibilities, including oxirane-ring-opening
reactions that are combined with the reduction or hydrolysis
of the amide functionality. To this end, appropriately func-
tionalized a-amino acids would represent suitable starting
points for the construction of these bicyclic systems through
the cyclization of the a-amino acid in the form of an amino
alcohol and the intramolecular formation of the sulfur-ylide
functionality through a sulfonium-salt precursor by the in-
troduction of a methylthiol group. With these requirements
in mind, commercially available amino acids l-methionine,
(S)-methyl-l-cysteine, and l-proline could represent the pre-
cursors of their corresponding sulfur ylides (1–3, Scheme 1).
Herein, we report in detail our studies in this area, part of
which has been reported recently,[19] as well as the scope and
In the realm of asymmetric synthesis, methods that are di-
rected towards the stereoselective construction of an oxirane
ring[1] constitute an important area of research, owing to the
versatility and usefulness of this functional group.[2] Among
the flurry of asymmetric methods that have been developed
to date, there is no doubt that the Sharpless asymmetric ep-
oxidation reaction,[3] which rendered its inventor the Nobel
Prize, has occupied a privileged position, being recognized
as one of the most important and most powerful reactions in
organic synthesis by virtue of its high efficiency and general-
ity for the enantiocontrolled synthesis of oxirane rings.[4] In
the exploration of new methods for asymmetric epoxidation,
chiral sulfur ylides[5] have emerged as efficient synthetic
tools not only for the asymmetric syntheses of epoxides[6]
but also for aziridines[7] and cyclopropanes.[8] In this sense,
the contributions by Aggarwal’s group[9] have reaped the
benefits of this type of reagent in the synthesis of natural
products[10] and drug-like compounds.[11] Amide-stabilized
sulfur ylides[12] are particularly useful for three reasons: 1)
they only require very mild conditions and simple proce-
dures for their reactions with carbonyl compounds, 2) they
show high diastereocontrol in favor of the trans epoxides,
and 3) the synthetic potential of the resulting glycidic
[a] Prof. Dr. F. Sarabia, C. Vivar-Garcꢀa, Dr. M. Garcꢀa-Castro,
C. Garcꢀa-Ruiz, F. Martꢀn-Gꢁlvez, Dr. A. Sꢁnchez-Ruiz,
Dr. S. Chammaa
Department of Organic Chemistry
Faculty of Sciences, University of Malaga
Campus de Teatinos s/n. 29071 Malaga (Spain)
Fax : (+34)952-131941
E-mail: frsarabia@uma.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201332.
15190
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FULL PAPER
Scheme 2. Synthesis of bicyclic sulfonium salts 8, 9, 12, and 14. Reagents
and conditions: a) NaBH4 (2.4 equiv), I2 (1.0 equiv), THF, reflux, 24 h,
66% for both amino acids; b) CSA (0.05 equiv), molecular sieves (4 ꢃ),
Scheme 1. Design of a new class of cyclic sulfur ylides that are derived
from a-amino acids.
acetone, reflux, 12 h, 99% for compounds
4 and 5; c) ClCH2COCl
(1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 08C, 0.5 h; d) NaClO4 (1.1 equiv),
acetone, 408C, 48 h, or 5 days at 258C, 70% after recrystallization from
MeOH for compounds 8 and 9 from compounds 4 and 5, respectively, or
50% for compound 12 from compound 10; e) Me3OBF4 (1.3 equiv),
CH3CN, 258C, 12 h, 73%.
limitations of these synthetic tools in asymmetric syntheses.
Furthermore, we demonstrate their application in the con-
struction of a plethora of different scaffolds of particular in-
terest and potential utility in natural-product synthesis.[20]
were precursors of sulfur ylides 1 and 2, l-methionine and
(S)-methyl-l-cysteine were subjected to treatment with
NaBH4 in the presence of iodine,[21] followed by reaction
with acetone under acidic catalysis with camphorsulfonic
acid (CSA), to obtain compounds 4 and 5, respectively. The
reactions of both compounds with 2-chloroacetyl chloride
furnished 2-chloroacetamides 6 and 7, which were not isolat-
ed but treated with sodium perchlorate in acetone to obtain,
after crystallization, cyclic sulfonium salts 8 and 9 in 70 and
75% overall yield from compounds 4 and 5, respectively.
For ylide 3, the synthesis of its corresponding sulfonium salt
precursor was achieved through two different routes that
both started from l-proline. In the first route, l-proline was
transformed into the known methylsulfide (10),[22] which,
after a similar treatment to that described above for com-
pounds 4 and 5, was transformed into sulfonium salt 12
through 2-chloroacetamide 11. Alternatively, l-proline was
subjected to the procedure described by Ishibashi[23] to
obtain sulfide 13, which, following methylation with Meer-
wein’s salt, furnished sulfonium salt 14 (Scheme 2).
Results and Discussion
Design, synthesis, and reactivity of cyclic sulfur ylides:
Having designed a new potential class of chiral sulfur ylides
(compounds 1–3), we began their syntheses from the corre-
sponding commercially available amino acids (Scheme 2).
Thus, for the synthesis of sulfonium salts 8 and 9, which
Abstract in Spanish: Un nuevo tipo de sales de sulfonio qui-
rales, caracterizadas por contener un sistema bicꢀclico, ha
sido diseÇado y sintetizado desde a-amino ꢁcidos. Sus corres-
pondientes iluros, preparados por tratamiento bꢁsico de las
sales de sulfonio, reaccionaron suavemente con una amplia
gama de aldehidos simples y quirales para dar las epoxiami-
das trans en rendimientos desde razonables a muy buenos, y
estereoselectividad excelente estimada en mꢁs de un 98%.
Las epoxiamidas obtenidas probaron ser ffltiles building
blocks. Asꢀ, Østas fueron reducidas a sus correspondientes
epoxialcoholes y, ademꢁs, fueron sometidas a reacciones de
apertura del anillo de oxirano con diferentes tipos de nucleó-
filos.
It is important to highlight that sulfonium salts 8 and 9
were isolated as single diastereoisomers, which was essential
for obtaining high asymmetric induction in the reactions
with aldehydes.[12f] In contrast, sulfonium salts 12 and 14
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F. Sarabia et al.
were obtained as 3:2 mixtures of diastereoisomers that
could not be separated by crystallization. This result may ex-
plain the lower efficiency in reactivity and diastereoselectivi-
ty shown by these sulfonium salts compared with salts 8 and
9. The diastereomeric purities of all of these sulfonium salts
(8, 9, 12, and 14) were determined by NMR spectroscopy
and the absolute configurations of salts 8 and 9 were estab-
lished by a combination of NMR spectroscopy (NOE ex-
periments and J values) and theoretical studies, because we
could not obtain suitable crystals for X-ray analysis. Thus,
for sulfonium salt 8, we observed NOE correlations between
the methyl group on the sulfur atom and both hydrogen
atoms on the CH2 group at the C5 position, as well as with
one of the hydrogen atoms at the C3 position (Figure 1). In
hydrogen atom at the C5 position, which was revealed by
the J value of 10.6 Hz.
With all of these chiral sulfonium salts in hand, we pro-
ceeded to investigate the reactivities of their corresponding
ylides with aldehydes, paying special attention to the d.e. of
the products to assess the potential utility of these chiral
salts in asymmetric synthesis. We initiated this study with
the in situ preparation of ylides 1–3 by treatment of their
corresponding sulfonium salts (8, 9, and 12 or 14) with an
aqueous solution of NaOH in tBuOH, followed by the addi-
tion of the aldehyde to afford their corresponding epoxy
amides (16, 17, and 18) in various chemical yields and dia-
stereoselectivities, depending on which sulfonium salt was
employed. For the determination of the diastereomeric
ratios, the resulting crude products were analyzed by NMR
spectroscopy and by GCMS, which revealed a high degree
of stereoselectivity. Remarkably, sulfonium salt 8, which was
derived from l-methionine, afforded the best results with
both aromatic and aliphatic aldehydes, with diastereomeric
excesses of greater than 98%. Thus, the corresponding
epoxy amides (16a–f) were isolated as single diastereoisom-
ers by NMR spectroscopy, which indicated an excellent
level of stereochemical control, as confirmed by the deter-
mination of their absolute stereochemistry and the measure-
ment of their enantiomeric purities (see below). In contrast,
sulfonium salts 9, 12, and 14 afforded lower yields of their
corresponding epoxy amides (17 and 18), albeit with high di-
astereomeric excesses (>98% for compounds type 17, 85%
for compounds type 18; Table 1).
For the determinations of their absolute configurations
and their enantiomeric excesses, epoxy amides 16–18 were
transformed into their corresponding epoxy alcohols (19 and
ent-19) by either a sequential reduction with Red-Al and
sodium borohydride[25] or by treatment with super hy-
dride,[26] which resulted in higher yields (Table 2). A meas-
urement of their specific rotations and a comparison with
literature data allowed us to establish the absolute stereo-
chemistry of epoxy alcohols 19 as (2R,3R) and ent-19 as
(2S,3S). On the other hand, to quantify the enantiomeric
purity of the resulting epoxides, we analyzed the epoxy alco-
hols by HPLC on a chiral column,[27] which established that
the enantiomeric excesses were greater than 98% for the
epoxy alcohols that were derived from epoxy amides 16 and
17 and 85% for those that were produced from epoxy
amides 18. In addition, the formation of Mosher esters,[28] by
treatment of epoxy alcohols 19 and ent-19 with (R)-(+)-a-
methoxy-a-trifluoromethyl or (R)-(+)-a-methyl phenylace-
tic acids in the presence of 1-(3-dimethylaminopropyl)-3-
Figure 1. Assignment of the stereochemistry at the sulfur atom of sulfoni-
um salts 8 and 9 by NOE correlations.
addition, the J values between hydrogen atom HA and the
bridgehead hydrogen atom (HB) and between hydrogen
atom HA and hydrogen atom HC at the C5 position (10.5
and 12.6 Hz respectively) indicate an antiperiplanar arrange-
ment of these atoms. All of this spectroscopic information
would agree with an S configuration at the sulfur atom in a
twist-shaped conformation. Indeed, this conformation was
revealed to be the preferred one following an extensive mo-
lecular-modeling study.[24] On the other hand, the absence of
NOEs between the methyl group on the sulfur atom and the
bridgehead hydrogen atom or between the methyl groups of
the gem-dimethyl unit in the oxazolidine ring with different
hydrogen atoms on the molecule should rule out the oppo-
site configuration at the sulfur atom in the different possible
minimum conformations (chair-, boat-, or twist-types). For
sulfonium salt 9, the NOE between the methyl group on the
sulfur atom and one of the hydrogen atoms at the C5 posi-
tion was in agreement with an S configuration at the sulfur
atom in a twist-type conformation, with an antiperiplanar ar-
rangement between the bridgehead hydrogen atom and the
ethylcarbodiimide
(EDCI)/4-(dimethylamino)pyridine
(DMAP) and subsequent GCMS analysis led us to the same
results.
In light of these encouraging results, we decided to
embark on an extensive study with sulfonium salt 8, which
provided the best results of all of the tested sulfonium salts,
thereby further extending their use to a broader range of al-
dehydes to explore the scope and limitations of this chiral
reagent as a useful tool for asymmetric epoxidation reac-
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Highly Stereoselective Synthesis of Glycidic Amides
FULL PAPER
Table 1. Reactions of sulfur ylides that were derived from sulfonium
salts 8, 9, 12, and 14 with aldehydes.
tions. To this end, various aromatic and aliphatic aldehydes
were chosen and reacted with the in situ sulfur ylide that
was generated from compound 8 under basic conditions
(Table 3). According to our obtained results, this method
was found to be general and efficient in terms of chemical
and stereochemical yields. Only in the case of 2-salicylalde-
hyde (Table 3, entry 7), it was not possible to isolate the cor-
responding epoxy amide (16m); instead, cyclization product
20 was obtained. In contrast, dialdehyde 15o (Table 3,
entry 9) afforded diepoxy amide 16o in 58% yield and dia-
ldehyde 15p (Table 3, entry 10) provided compound 21 in
56% yield, which was subjected to acetylation (into com-
pound 22) to confirm its structure. In this case, we rational-
ized the formation of compound 21 as an intramolecular re-
action of a new sulfur ylide (Y), which is generated from be-
taine intermediate X, with the second aldehydic group that
is present in the molecule (Scheme 3). Only for aldehyde
Entry
Aldehyde
C6H5CHO
Sulfonium
salt
Epoxy
Yield
[%]
d.e.
[%]
amide[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
8
9
16a
17a
18a
16b
17b
18b
16c
17c
18c
16d
17d
18d
16e
17e
18e
16 f
17 f
18 f
75
53
55
79
40
43
70
50
43
85
36
50
61
23
47
74
73
82
>98
>98
85
>98
>98
85
>98
>98
85
>98
>98
85
>98
>98
85
>98
>98
85
12 or 14
8
9
12 or 14
8
9
12 or 14
8
9
12 or 14
8
9
2-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
CH3CH2CHO
ChxCHO
12 or 14
8
9
12 or 14
[a] Reagents and conditions: Sulfonium salt 8, 9, 12, or 14 (1.0 equiv),
aqueous solution of NaOH (3.0m, 1.0 equiv), tBuOH, 258C, 1 h, then al-
dehyde 15 (1.0 equiv), 258C, overnight.
Table 2. Reduction of epoxy amides 16, 17, and 18 into epoxy alcohols
19 and ent-19.
Scheme 3. Rationale for the formation of compound 21.
15v (Table 3, entry 16), it was disappointing to find that the
corresponding epoxy amide (16v) was not formed; instead,
a complex mixture of decomposition products was formed.
This discouraging—although not surprising—result was as-
cribed to the basic conditions under which the reactions
were conducted, which favored the elimination of the
alkoxy group at the b-position of the starting aldehyde. To
circumvent this complication, we attempted to modify the
reaction conditions by using other bases, such as a phospha-
ꢀ
Entry
Epoxy amide
R
Epoxy alcohol
Yield [%]
1
2
3
4
5
6
7
8
9
16a
17a
18a
16b
16c
16d
16e
16 f
17 f
18 f
C6H5
C6H5
C6H5
2-MeC6H4
4-MeOC6H4
4-ClC6H4
CH3CH2
cyclohexyl
cyclohexyl
cyclohexyl
19a
19a
ent-19a
19b
77[a], 57[b]
75[a], 65[b]
65[a], 60[b]
73[a]
19c
19d
19e
19 f
83[a]
72[a]
65[a], 62[b]
98[a]
(NMe2)3, EtP2)[29]
zene-type base (e.g., EtN=PACHTNUGRTENNUG(NMe2)2 N=PACHUTNGTRENNGUN
or 1,8-diazabicycloACTHNUTRGNEUNG
[5.4.0]undec-7-ene (DBU),[30] and also by
19 f
ent-19 f
72[a]
the prior formation of the ylide by treatment of compound 8
with NaH in CH3CN, followed by reaction with the corre-
sponding aldehyde. However, in all of these cases, the re-
sults were similarly disappointing. Fortunately, when we at-
tempted a two-phase method,[31] as developed in our group,
10
55[a]
Reagents and conditions: [a] Super hydride (3.0 equiv), THF, 08C, 0.5 h;
[b] (i) Red-Al (0.6 equiv), THF, ꢀ108C, 0.5 h; (ii) NaBH4 (8.0 equiv),
MeOH, 08C, 15 min. Red-Al=sodium bis(2-methoxyethoxy)aluminum-
hydride.
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F. Sarabia et al.
Yield d.e.
Table 3. Reactions of sulfur ylide that was derived from sulfonium salt 8
with various aldehydes.
Table 3. (Continued)
Entry Aldehyde
Epoxy amide[a]
[%]
[%]
26
27
28
ACHTUNGTRNE(NUNG dec.)
16g’
76
44
>98
>98
Entry Aldehyde
Epoxy amide[a]
Yield d.e.
16h’
16i’
[%]
[%]
Aromatic aldehydes
29
92
>98
1
2
3
4
5
6
4-O2NC6H4CHO
4-AcNHC6H4CHO
3-IC6H4CHO
2-BrC6H4CHO
2,6-(CH3)2C6H3CHO
16g
16h
16i
16j
16k
16l
84
63
82
99
46
65
>98
>98
>98
>98
>98
>98
30
31
32
16j’
16kꢂ
16l’
63
25
35
>98
>98
>98
ꢁ
2-HC CC6H4CHO
7
2-HOC6H4CHO
65
>98
Reagents and conditions: [a] Sulfonium salt 8 (1.0 equiv), aqueous solu-
tion of NaOH (3.0m, 1.0 equiv), tBuOH, 258C, 1 h, then aldehyde 15
(1.0 equiv), 258C, overnight; [b] aldehyde 15 (1.0 equiv), sulfonium salt 8
(1.2 equiv), aqueous solution of NaOH (3.0m, 1.0 equiv), CH2Cl2/water
(1:1), 258C, 48 h. TBDPS=tert-butyldiphenylsilyl, Ac=acyl.
20
16n
16o
8
9
69
58
>98
>98
1,3-OHCC6H4CHO
1,2-OHCC6H4CHO
the desired epoxy amide (16v) was obtained in 71% yield.
Aldehydes in their hemiacetal form (Table 3, entry 17) were
also reactive enough towards sulfonium salt 8 to obtain
epoxy amide 16w in a good 77% yield. In addition and par-
ticularly interesting were the results with a,b-unsaturated al-
dehydes (Table 3, entries 18–23), for which their corre-
sponding epoxy amides (16x–c’) were obtained in good
yields instead of the expected cyclopropyl derivatives. In a
different set of reactions, we extended these studies to in-
clude various commercially available heterocyclic aldehydes
(Table 3, entries 24–32). The resulting epoxy amides (16d’–
l’) were obtained in modest to reasonably good yields and
with a high degree of diastereoselectivity, except for furfural
(Table 3, entry 26), for which the corresponding epoxy
amide (16 f’) was not detected; instead, a complex mixture
of decomposition products was observed.
10
Aliphatic aldehydes
11
12
13
14
15
16
PhCH2CHO
16q
16r
16s
74
93
56
72
47
71
>98
>98
>98
>98
>98
>98
CH
CH
CH
CH
3A
3A(CH2)10CHO
3A(CH2)12CHO
3A(CH2)14CHO
G
E
16t
C
16u
TBDPSOCH2CH2CHO
16v[b]
Hemiacetal
17
77
>98
16w
To complete this study on the reactivity of these cyclic
sulfonium salts, their corresponding ylides were exposed to
propargylic aldehydes, in particular, to commercial phenyl-
propargyl aldehyde (23). Surprisingly, in contrast to the ex-
pected propargyl epoxide, dialkyne 24 was obtained in 47%
yield, together with a complex mixture of unidentified prod-
ucts. To confirm this new and intriguing result, we per-
formed the reactions of propargyl aldehydes 23 and 25 with
a simple ylide, such as N,N-dimethyl-2-(dimethylsulfuranyli-
dene)acetamide, which was derived from sulfonium salt 26,
to obtain dialkynes 27 and 28 in 50 and 55% yield, respec-
tively, thereby showing an interesting reaction mode of
sulfur ylides with propargylic aldehydes. To rationalize
these results, we postulate a mechanism (Scheme 4) in
which, after the formation of the betaine intermediate,
proton transfer should give a hydroxy ylide. This ylide inter-
a,b-Unsaturated aldehydes
18
19
(E)-PhCH=CHCHO
1-cyclohexencarboxalde-
hyde
16x
16y
50
52
>98
>98
20
21
2-methylpropenal
(E)-(CH3)2CHCH=
CHCHO
16z
16a’
70
76
>98
>98
22
23
(E)-TMSCH=CHCHO
16b’
16c’
79
60
>98
>98
(E)-CH
3ACHTUNGTRENNUNG(CH2)12CH=
CHCHO
Heterocyclic aldehydes
24
16d’
16e’
55
34
>98
>98
25
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Highly Stereoselective Synthesis of Glycidic Amides
FULL PAPER
(19–22% yield), albeit with excellent stereoselectivities (>
98%).[32]
To rationalize the resulting stereoselectivity in the reac-
tions of these sulfur ylides with carbonyl compounds, we
had to address two stereochemical issues: 1) the preferential
formation of epoxy amides 16 over the other trans diaster-
eoisomer and 2) the exclusive formation of trans-epoxy
amides over their cis isomers. To answer the first question,
the resulting stereochemistry of epoxy amides 16 should be
defined during the first addition step. Thus, this addition
must proceed on the more accessible enantiotopic face of
the ylide, for which we have to establish the configuration at
the sulfur atom and the preferred conformation for sulfur
ylide 1.[33] In light of this fact, we assumed that the stereo-
chemistry at the sulfur atom of ylide 1 remains the same
with respect to its precursor, sulfonium salt 8, by taking into
account that the energy barrier for the inversion of configu-
ration of ylides is high. In addition, this assumption was ex-
perimentally supported by the formation of sulfur ylide 1,
followed by quenching with acetic acid to afford sulfonium
salt 8b with similar diastereomeric purity to the starting ma-
terial 8a, that is, no epimerization was observed (Scheme 5).
As a consequence, considering the S configuration at the
sulfur atom for ylide 1, it is probably a conformational
change to a boat-like conformation, in which an orthogonal
disposition of the lone pairs of electrons on the carbon and
sulfur atoms should stabilize this conformation. This ration-
ale of the stereochemical outcome for the addition step
would then support a convex approach as the most favora-
ble pathway, in contrast to the transition state that is derived
from a concave approach, which would exhibit important
steric hindrance between the starting aldehyde, with the
pseudoaxial methyl group of the sulfur ylide and one of the
methyl groups of the gem-dimethyl unit. Combining this
convex approach with a preferred cisoid arrangement be-
tween the reactants, in which the two polar groups are in an
almost eclipsed orientation,[34] ylide 1 could attack the alde-
hyde on its re or si faces. Attack on the re face, through
transition state [I’]°, should deliver epoxy amides 16’ via in-
termediates [I’] and [II’]. The fact that compounds type 16’
were not detected in the reaction could be easily explained
by unfavorable steric interactions between the R group of
the aldehyde and one of the methyl groups of the gem-di-
methyl unit of the acetal moiety in transition state [I’]°. In
contrast, attack on the si face of the aldehyde should be
completely favored. According to this theory, syn-betaine in-
termediate [I] would be formed and the subsequent step
Scheme 4. Reactions of the sulfur ylides that are derived from sulfonium
salts 8 or 26 with propargyl aldehydes, and a proposed mechanism for the
formation of the diynes. Reagents and conditions: a) sulfonium salt 8
(1.2 equiv), aqueous solution of NaOH (3.0m, 1.2 equiv), tBuOH, 258C,
1 h, then aldehyde 23 (1.0 equiv), 258C, overnight, 47%; b) sulfonium
salt 26 (1.3 equiv), aqueous solution of NaOH (20%, 1.3 equiv), aldehyde
23 or 25 (1.0 equiv), CH2Cl2, 258C, 2 h, 55% for compound 27 or 50%
for compound 28.
mediate could then evolve towards a vinyl sulfonium salt,
after the elimination of the hydroxy group, and, finally, into
the resulting diyne through an elimination process that is
promoted by the basic conditions under which this reaction
is performed.
Having gathered all of this chemistry and having demon-
strated the synthetic value of these chiral reagents, the possi-
bility of obtaining the corresponding enantiomerically pure
epoxy amides with identical chemical and stereochemical ef-
ficiency required the formation of the enantiomer of sulfoni-
um salt 8, for which commercially available d-methionine
was required. Thus, ent-8 was prepared and reacted with var-
ious aromatic, aliphatic, and heterocyclic aldehydes to
obtain the corresponding epoxy amides (ent-16) in similar
yields and diastereoselectivities as for salt 8 (for experimen-
tal details, see the Supporting Information).
After widely covering the reactivity of this class of chiral
sulfur ylides towards a broad array of aldehydes, we planned
to extend this chemistry to ketones. Initial results revealed
that the reactions of sulfonium salts 8 or ent-8 with simple
ketones were more problematic under Aggarwal’s condi-
tions. In fact, the reactions of acetone and cyclohexanone
with sulfur ylides that are derived from salts 8 and ent-8 af-
forded very poor yields of the corresponding epoxy amides
ꢀ
(pathway a) should involve rotation around the C C bond
to give betaine [II], in which the alkoxy and sulfonium
groups are in an antiperiplanar arrangement, prior to the in-
tramolecular nucleophilic attack of the alkoxy group to de-
liver the expected epoxy amides that would correspond to
cis-16, which were not detected either. The high barrier for
ring closure ([II]!16’) establishes this process as the rate-
determining step and, considering that the betaine forma-
tion is reversible (as demonstrated in crossover experiments
by Aggarwal’s group), makes this pathway nonproductive,
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F. Sarabia et al.
instead reverting back to the starting aldehyde and ylide.
From intermediate [I], we could then consider an alternative
pathway (b) based on the basicity of the alkoxy group,
which could abstract the acidic proton at the position a to
the carbonyl group to obtain an ylide intermediate, [III].
This transient ylide could be protonated by the more acces-
sible convex face to form intermediate anti-betaine [IV],
which would finally evolve into trans-epoxides 16
(Scheme 5).
Among all of the epoxy amides prepared, epoxy amides
16i and 16j allowed further transformations taking advant-
age of the presence of a halogen atom in the aromatic ring
of the molecule. Thus, we considered Sonogashira[35] and
Suzuki[36] couplings as a way of obtaining more elaborated
epoxy amides and, therefore, a manner of increasing the
complexity of the structures. For example, Sonogashira and
Suzuki couplings of 16i provided the compounds 29–32 in
general good yields. In contrast, epoxy amide 16j did not
react under Sonogashira conditions, likely due to steric fac-
tors. Fortunately, Suzuki reactions of 16j with different bor-
onic esters provided the corresponding coupling products 33
and 34. It was interesting that under conventional conditions
for Sonogashira and Suzuki couplings the epoxide was not
affected at all. However, when the Suzuki coupling was car-
ried out at higher temperatures and by using Cs2CO3 as
base, the epoxide amide suffered a rearrangement to its cor-
responding a-keto amide 35 (Scheme 6).
Reactions of sulfonium salts 8 and ent-8 with chiral alde-
hydes: After an extensive study of these chiral reagents, in
particular those that are derived from l- and d-methionine
in the form of sulfonium salts 8 and ent-8, in their reactions
with simple aldehydes, we decided to extend our investiga-
tions to the reactions of enantiomeric sulfonium salts 8 and
ent-8 with more complex chiral aldehydes (Table 4), with
the synthesis of natural compounds in mind. Thus, aldehydes
36–45 were reacted with sulfonium salts 8 or ent-8 to obtain
epoxy amides 46–55 in generally good yields and excellent
stereoselectivities. Notable problems arose owing to the
presence of alkoxy groups at the b-position of the starting
aldehydes (e.g., aldehydes 39 and 40), as was anticipated
from previous results (Table 3, entry 16). In these cases, the
yields of the desired epoxy amides (49 and 50) were remark-
ably improved by using the two-phase method. The efficien-
cy and generality that was displayed by these sulfur ylides in
their reactions with chiral aldehydes, even for mismatched
pairs (consider the reactions of aldehydes 39 and 40 with
salt 8), is worth noting. On the other hand, we have demon-
strated that many of these aldehydes (e.g., aldehydes 36–40,
43) displayed poor diastereoselectivity in their reactions
with achiral sulfonium salt 26,[37] which enhances the syn-
thetic value of these chiral reagents. The reduction of all of
these epoxy amides with super hydride afforded their corre-
sponding epoxy alcohols 56–65, the spectroscopic and physi-
cal properties of which were consistent with those that were
obtained by Sharpless asymmetric epoxidation.[38] These
epoxy alcohols offer diverse synthetic possibilities for the
Scheme 5. Mechanism of the epoxidation reaction and a theoretical ra-
tionale of the stereochemical outcome.
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Chem. Eur. J. 2012, 18, 15190 – 15201

Highly Stereoselective Synthesis of Glycidic Amides
FULL PAPER
Therefore, taking into account the wide array of scaffolds
that are potentially accessible from the resulting epoxy
amides, we devised synthetic applications towards natural
products with molecular architectures that are accessible
from epoxides through regio- and stereocontrolled opening
reactions with nucleophiles. In fact, we have already applied
these chiral reagents for the asymmetric synthesis of benga-
mides and their related analogues,[20a] as well as for the total
synthesis of natural cyclodepsipeptides Globomycin and SF-
1904 A5.[20b] Potentially, natural products that contain 1,2-
functionalized systems, such as polypropionate-derived
chains or amino alcohols, represent some of the many exam-
ples of structural motifs that are accessible by using this new
method. To demonstrate this synthetic potential, we targeted
the bioactive compounds sphingosine and sphinganine.
Sphingosine is a component of sphingolipids,[46] which are
important structural and functional molecules that are found
in the membranes of all eukaryotic cells and are involved in
many essential biological processes, such as immune re-
sponse, cell recognition, adhesion, and apoptosis.[47] On the
other hand, sphinganine is a key precursor in the biosynthe-
sis of ceramides and sphingolipids.[48] In addition, sphinga-
nine itself inhibits protein kinase C.[49,50] In both cases,
epoxy amide precursors 16u and 16c’ were treated with am-
monia to smoothly obtain their corresponding ring-opened
products 66 and 67 in 72 and 75% yield, respectively, with
complete regio- and stereoselectivity. With both products in
hand, we attempted the direct reduction of the 2-amino-
ring-opened products. Thus, compounds 66 and 67 were
treated with H3NBH3 in the presence of lithium diisopropy-
lamide (LDA).[51] To our delight, after a reaction time of
8 h, the reduction products, which corresponded to the ex-
pected sphinganine (68) and sphingosine (69), were obtained
in reasonable 68 and 65% yield, respectively (Scheme 7).
As mentioned above, typical polypropionate frameworks
could be accessed by using this new method. To confirm the
validity of this synthetic application, epoxy amide ent-50,
which was obtained from the reaction of aldehyde 39 with
Scheme 6. Transformations of epoxy amides 16k and 16l by using palladi-
ꢀ ꢁ
um chemistry. Reagents and conditions: a) TMS C CH (1.5 equiv), CuI
(0.2 equiv), TEA (2.0 equiv), [PdACTHNUTGRNE(UNG PPh3)4] (0.1 equiv), CH2Cl2, 258C, 8 h,
72% for compound 29; b) boronic acid pinacol ester (1.2 equiv), Tl2CO3
(2.0 equiv), [Pd(dpephos)Cl2] (0.3 equiv), THF/water (3:1), 508C, over-
ACHTUNGTRENNUNG
night, 75% for compound 30, 68% for compound 31, 75% for compound
32, 73% for compound 33, 67% for compound 34; c) boronic acid pina-
col ester (1.2 equiv), Cs2CO3 (2.0 equiv), [PdACTHNUTRGNE(UNG dpephos)Cl2] (0.3 equiv),
1,4-dioxane/water (3:1), 1408C, overnight, 55% for compound 35.
dpephos=bis[(2-diphenylphosphino)phenyl] ether, TMS=trimethylsilyl,
TEA=triethylamine.
synthesis of natural products. For example, epoxy alcohol 56
represents an advanced intermediate for the synthesis of the
immunosuppressive agent stevastelin C3.[39] Epoxy alcohol
57 could be useful in the synthesis of the antitumoral agent
pironetin.[40] Epoxy alcohol 58 can be used for the synthesis
of the pheromone invictolide[41] or the lipidic chain that is
contained in antiviral agent celebeside C.[42] On the other
hand, epoxy alcohols 59, 60, and 62, as well as diepoxyalco-
hol 61, may be of general use in the synthesis of natural
products that belong to the polypropionate biosynthetic
pathway.[43] Epoxy alcohol 63 can provide access to the 2,3-
epimer analogue of bengamide E by following the same syn-
thetic sequence that we have already delineated for natural
bengamide E.[44] Finally, epoxy alcohols 64 and 65 represent
key precursors for the synthesis of marine-fused polycyclic-
ether-type toxins.[45]
Scheme 7. Asymmetric syntheses of sphinganine (68) and sphingosine
(69). Reagents and conditions: a) aqueous solution of NH3 (30%,
5.0 equiv), MeOH, 708C, 8 h, 72% for compound 66, 75% for compound
67; b) LDA (7.0 equiv), H3NBH3 (7.0 equiv), THF, 08C!258C, 0.5 h,
then compound 66 or 67 (1.0 equiv), 258C, overnight, 68% for compound
68, 65% for compound 69.
Synthetic applications: We have demonstrated the versatility
and utility of the synthesized glycidic amides in the opening
of the oxirane ring with a variety of nucleophiles in a com-
pletely regio- and stereoselective manner, thereby giving
access to a broad range of 1,2-difunctionalized products.
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F. Sarabia et al.
Table 4. Reactions of sulfur ylides that were derived from sulfonium salts 8 and ent-8 with various chiral aldehydes.
Entry
Aldehyde
Sulfonium salt
Epoxy amide
Yield [%] d.e. [%]
Epoxy alcohol[c]
Yield [%]
79
1
8
60
60
>98
36
37
46[a]
56
57
2
8
80
77
47[a]
3
4
5
6
7
8
ent-8
70
71
62
80
50
72
85
>98
>98
>98
>98
>98
65
75
75
97
71
86
38
39
40
41
42
48[a]
49[b]
50[b]
51[a]
52[a]
58
59
60
61
62
8
8
ent-8
ent-8
ent-8
43
53[a]
63
9
8
8
75
70
>98
>98
89
92
44
45
54[a]
64
65
10
55[a]
Reagents and conditions: [a] Method 1: Sulfonium salt 8 or ent-8 (1.0 equiv), aqueous solution of NaOH (3.0m, 1.0 equiv), tBuOH, 258C, 1 h, then alde-
hyde (1.0 equiv), 258C, overnight; [b] method 2: aldehyde (1.0 equiv), sulfonium salt 8 or ent-8 (1.2 equiv), aqueous solution of NaOH (3.0m, 1.2 equiv),
CH2Cl2/water (1:1), 258C, 48 h; [c] super hydride (3.0 equiv), THF, 08C, 0.5 h. TBS=tert-butyldimethylsilyl.
sulfonium salt ent-8 in 67% yield, was reacted with
Me2CuLi, followed by protection of the resulting opened
product to give silyl ether 70 in 73% overall yield. Reduc-
tion with super hydride, followed by oxidation with
TEMPO/BAIB,[52] provided aldehyde 72, which, on reaction
with achiral sulfur ylide N,N-dimethylcarboxymethylene di-
methylsulfurane, furnished a diastereomeric mixture of the
corresponding epoxy amides in 83% combined yield and an
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Highly Stereoselective Synthesis of Glycidic Amides
FULL PAPER
approximately 9:1 ratio[53] in favor of the Felkin–Anh dia-
stereoisomer (73). Subsequent opening of epoxy amide 73
with lithium dimethylcuprate efficiently provided the
opened product 74 in 87% yield, which was protected as the
corresponding acetal 76, through diol 75, and reduced to al-
cohol 77 (Scheme 8). This compound represents a stereo-
plore the synthetic potential of these chiral reagents, their
reactivities towards a large variety of aromatic, aliphatic,
heterocyclic, and a,b-unsaturated aldehydes were investigat-
ed. In addition, an extensive study with chiral aldehydes was
performed that allowed the generation of a broad range of
epoxy amides with high potential for the synthesis of various
natural products. Thus, the rapid and efficient syntheses of
natural sphingosine and sphinganine are described, as well
as the synthesis of typical polypropionate fragments.
The synthetic utility of these reagents and the synthetic
potential of their corresponding epoxy amides for asymmet-
ric access to important building blocks by regioselective nu-
cleophilic epoxide opening have been clearly demonstrated.
Compared with other methods that involve chiral sulfur
ylides, the method reported herein offers several advantages,
such as ease of preparation, the ready availability of both
enantiomers, generally good reactivity towards both aromat-
ic and aliphatic aldehydes, and an excellent degree of ster-
eoselectivity. New synthetic applications of the described
epoxy amides are currently being investigated with a partic-
ular emphasis on applications to the total synthesis of natu-
ral products of biological interest.
Acknowledgements
This work was financially supported by the Ministerio de Ciencia e Inno-
vaciꢄn (CTQ2010-16933) and the Consejerꢀa de Educaciꢄn y Ciencia of
Junta de Andalucꢀa (FQM-03329). C.G.R. and F.M.G. thank the Minister-
io de Educaciꢄn y Ciencia and Junta de Andalucꢀa, respectively, for fel-
lowships. We thank Dr. J. I. Trujillo for assistance in the preparation of
this manuscript. We thank the Unidad de Espectroscopꢀa de Masas of
Universidad de Granada and the NMR facility of Unidad de Nano-
Imagen of Centro Andaluz de Nanomedicina y Biotecnologꢀa (BION-
AND, Technology Park of Andalucꢀa, Mꢁlaga) for assistance with the de-
termination of exact mass and NMR spectroscopic analysis, respectively.
Scheme 8. Stereoselective synthesis of the polypropionate frameworks.
Reagents and conditions: a) Me2CuLi (5.0 equiv), THF, 08C, 8 h;
b) TBSOTf (1.5 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, 08C, 0.5 h, 73%
over two steps; c) LiEt3BH (3.0 equiv), THF, 08C!258C, 8 h, 78%;
d) BAIB (3.0 equiv), TEMPO (0.3 equiv), CH2Cl2, 08C, 0.5 h, 98%;
e) Me2S=CHCONMe2 (4.0 equiv), CH2Cl2, 258C, 12 h, 83% for com-
pound 73 together with its b-epoxide isomer (9:1); f) Me2CuLi
(5.0 equiv), THF, 08C, 8 h, 87%; g) CSA (0.4 equiv), CH2Cl2/MeOH
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Conclusion
In conclusion, we have described the synthesis, reactivity,
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15200
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Highly Stereoselective Synthesis of Glycidic Amides
FULL PAPER
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Received: April 19, 2012
Revised: August 31, 2012
Published online: October 18, 2012
Chem. Eur. J. 2012, 18, 15190 – 15201
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15201