Cyclic sulfur ylides derived from gleason-type chiral auxiliaries for the asymmetric synthesis of epoxy amides

Article abstract of DOI:10.1021/jo1025964

Gleason-type chiral auxiliaries were used for the synthesis of a novel class of sulfonium salts, obtained via methylation of the sulfide with Meerwein's salt. The salts were reacted with aldehydes under basic conditions to provide epoxy amides, which were reduced to their corresponding epoxy alcohols in excellent enantiomeric excesses. Interestingly, it was feasible to synthesize both enantiomeric epoxy alcohols depending on which of the sulfonium salts, prepared from L-amino acids (6 and 9 from L-valine or 15 and 16 from L-serine) was employed.

Full text of DOI:10.1021/jo1025964

ARTICLE
pubs.acs.org/joc
Cyclic Sulfur Ylides Derived from Gleason-Type Chiral Auxiliaries for
the Asymmetric Synthesis of Epoxy Amides
Francisco Sarabia,†,* Carlos Vivar-García,† Miguel García-Castro,† and Jorge Martín-Ortiz‡
†Department of Organic Chemistry and ‡Department of Physical Chemistry, Faculty of Sciences, University of Malaga,. Campus de
Teatinos s/n, 29071 Malaga, Spain
S Supporting Information
b
ABSTRACT: Gleason-type chiral auxiliaries were used for the
synthesis of a novel class of sulfonium salts, obtained via
methylation of the sulfide with Meerwein's salt. The salts were
reacted with aldehydes under basic conditions to provide epoxy
amides, which were reduced to their corresponding epoxy
alcohols in excellent enantiomeric excesses. Interestingly, it
was feasible to synthesize both enantiomeric epoxy alcohols
depending on which of the sulfonium salts, prepared from
L-amino acids (6 and 9 from L-valine or 15 and 16 from L-serine)
was employed.
’ INTRODUCTION
the scope of other Gleason-type chiral auxiliaries derived from
other amino acids in the chemistry of sulfur ylides is explored.
Chiral sulfur ylides are proving to occupy a relevant position in
the asymmetric syntheses of epoxides, aziridines, and cyclopro-
panes as evidenced by the flurry of research activity in the past
few years.1 The design of chiral entities in the form of sulfur ylides
offers an interesting alternative to the laureated Sharpless asym-
metric epoxidation2 and, in some cases, may represent a shorter
and even more efficient approach to the corresponding ep-
oxides.3 In this area, particularly interesting are the glycidic
amides whose enantiomeric synthesis by use of sulfur ylides4
or diazoamides5 or via epoxidation of R,β-unsaturated amides6
have received special attention by virtue of their potential
applications in organic synthesis. In fact, we have devoted
significant efforts toward this type of products, synthesized via
stabilized sulfur ylides,7 and demonstrated their utility in the
synthesis of natural bioactive compounds.8 As an extension of
these studies, we have recently reported the design, synthesis and
reactivity of novel chiral sulfur ylides derived from the corre-
sponding sulfonium salts 1 and 2, prepared from L- and D-
methionines respectively, which provided excellent results in the
epoxidation process with respect to chemical and stereochemical
yields (Scheme 1, part a).9 Prompted by these results,10 we
decided to explore new reagents of this type. Inspired by the
commercially available chiral auxiliary 5, prepared and exploited
by Gleason in asymmetric alkylations11,12 and in Mannich-type
reactions,13 we surmised that its corresponding sulfonium salt
could represent a precursor for a bicyclic-type sulfur ylide, a chiral
reagent with exciting prospects in the asymmetric epoxidations of
carbonyl compounds. Toward this aim, we prepared sulfonium
salt 6 by treatment of 5 with Meerwein's salt in 81% yield
(Scheme 1, part b). The present article reports the reactivity of
the sulfonium salt 6 with carbonyl compounds and its synthetic
potential in asymmetric synthesis of epoxyamides. In addition,
’ RESULTS AND DISCUSSION
With sulfonium salt 6 in hand, we proceeded to investigate its
reactivity toward carbonyl compounds and the resulting stereo-
chemical induction. Initial results obtained by reaction of sulfo-
nium salt 6 with simple aromatic and aliphatic aldehydes, under
basic conditions, revealed that both the chemical yields, and the
degrees of stereochemical induction of the resulting epoxyamides
7 were as high as obtained previously with sulfonium salts 1 and
2.9 In some cases, the yields could be improved over the initial
conditions (procedure a) by the addition of DMSO during the
in situ formation of the corresponding ylide (see Table 1, pro-
cedure b). Determination of the absolute stereochemistry was
possible by transformation of the epoxy amides into the corre-
sponding epoxy alcohols by treatment with Super-H.14 Subse-
quent inspection of the physical and spectroscopic properties of
these epoxy alcohols, as well as analysis by GCꢀMS of their
corresponding Mosher esters,15 confirmed the formation of
epoxy alcohols 3 with very high ee (>98%) (Table 1).16
For the sulfonium salts 1 and 2, the stereochemical outcome of
the reaction with aldehydes is defined by the configuration of the
starting R-amino acid; however, for the Gleason-type sulfonium
salt the presence of two chiral centers in its structure made us
wonder which of them could be determining the stereochemical
outcome. To address this question, we decided to prepare the
diastereoisomer of 5 at the aminal functional group. To this aim,
a modification of the original Gleason protocol to prepare sulfide
5 was targeted, which consisted of extended treatment of the
Received: January 2, 2011
Published: March 16, 2011
r
2011 American Chemical Society
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|

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Scheme 1. Design and Synthesis of New Chiral Sulfonium
Salts from Gleason-Type Chiral Auxiliaries
Scheme 2. Synthesis of Epoxy Alcohols 4 from Minor
Diastereoisomer 8
Table 2. Reaction of Sulfur Ylide Derived from Sulfonium
Salt 9 with Aromatic Aldehydes
epoxyamide
epoxyalcohol
(yield %)
entry
aldehyde
PhCHO
(yield %; de %)
1
2
3
4
5
10a (95; >98)a
10b (73; >98)b
10c (63; >98)b
10d (86; >98)b
10e (76; >98)b
4a (34)d
4b (41)c
4c (45)c
4d (38)c
4e (43)d
4-MeC6H4CHO
2-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
Table 1. Reaction of Sulfur Ylide Derived from Sulfonium
Salt 6 with Aldehydes
a 1.0 equiv of 9, 1.0 equiv of a 3.0 M aqueous NaOH or 1.0 equiv of
NatBuO, tBuOH, 25 °C, 3 h; then 1.1 equiv of RCHO, overnight. b 1.0
equiv of 9, 1.0 equiv of a 1.0 M aqueous NaOH, tBuOH/DMSO (10/1),
c
25 °C, 1 h; then 1.1 equiv of RCHO, overnight. 2.5 equiv Super-H,
THF, 0 °C, 0.5 h. d 5.0 equiv LiBH4, THF, 0 f 25 °C, 1.0 h.
to their corresponding epoxyalcohols by the action of Super-H
revealed the opposite stereochemistry (epoxyalcohols 4) to that
obtained from sulfonium salt 6 (Scheme 2).
epoxyamide
epoxyalcohol
(yield %)c
entry
aldehyde
PhCHO
(yield %; de %)
Interestingly, in contrast to the good results obtained with
sulfonium salt 6, aliphatic aldehydes showed a significant differ-
ence in reactivity when reacted with sulfonium salt 9. Thus,
whereas aromatic aldehydes provided good yields and diaster-
eoselectivities in the formation of epoxyamides 10aꢀe, as
described above in Table 2, the aliphatic aldehydes delivered
mixtures of cis/trans epoxyamides in moderate combined yields.
The formation of the cis/trans mixture of epoxyamides, as well as
their ratios were confirmed and determined by their transforma-
tion into the corresponding epoxy alcohols and subsequent
NMR analyses.17 This transformation was carried out by treat-
ment of the inseparable mixtures 10fꢀi:70fꢀi with Super-H to
obtain epoxy alcohols 4fꢀi:30fꢀi, which were separated by
chromatographic methods. Inspection of the spectroscopic and
physical properties of the pure epoxy alcohols, especially their
specific rotations, allowed us to identify them as the trans epoxy
alcohols 4fꢀi and the cis isomers 30fꢀi18 (Scheme 3).
1
2
3
4
5
6
7
8
9
7a (80; >98)a
7b (89; >98)b
7c (73; >98)b
7d (75; >98)b
7e (76; >98)a
7f (41; >98)a
7g (73; >98)a
7h (82; >98)a
7i (79; >98)a
3a (72)
3b (76)
3c (51)
3d (75)
3e (71)
3f (44)
3g (69)
3h (65)
3i (62)
4-MeC6H4CHO
2-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
CH3CH2CHO
(CH3)2CHCHO
Chx-CHO
CH3(CH2)5CHO
a 1.0 equiv of 6, 1.0 equiv of a 3.0 M aqueous NaOH or 1.0 equiv of
NatBuO, tBuOH, 25 °C, 3 h; then 1.1 equiv of RCHO, overnight. b 1.0
equiv of 6, 1.0 equiv of a 1.0 M aqueous NaOH, tBuOH/DMSO (10/1),
c
25 °C, 1 h; then 1.1 equiv of RCHO, overnight. 2.5 equiv Super-H,
THF, 0 °C, 0.5 h.
amino acetal precursor with BF3 OEt2, providing a separable 2:1
3
In addition to the unexpected results found with the aliphatic
aldehydes, another remarkable observation for the epoxy amides
resulting from sulfonium salt 9 was their reductions to the above-
mentioned epoxy alcohols by the action of Super-H, which
proceeded in moderate to poor yields in all cases (Table 2 and
Scheme 3). In order to improve the yield of this reduction, we
investigated other reductive methods including the use of
mixture of diastereoisomers corresponding to the bicyclic sul-
fides 5 and 8, respectively. Subsequent isolation of sufficient
amounts of the minor isomer 8 and subjection to the same
synthetic sequence as for 5 provided sulfonium salt 9
(Scheme 2). This sulfonium salt was then reacted with aromatic
aldehydes under basic conditions to afford epoxyamides 10 in
generally good yields (Table 2). Reduction of these epoxyamides
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Scheme 3. Reaction of Sulfur Ylide Derived from Sulfonium
Salt 9 with Aliphatic Aldehydes
Given these encouraging results, the possibility of extending
this type of sulfonium salts to other L-amino acids led us to
consider L-serine as an interesting starting material to prepare
chiral sulfonium salts that would possess a tail in the form of a
hydroxymethyl group amenable to a linkage to a polyfluorinated
tag26 or attachment to a resin for fluorous or solid phase27
synthesis, respectively. To this aim, we initially examined the
validity of a L-serine derivative, choosing H-Ser(Bn)-OH28 as a
suitable substrate for the synthesis of this class of chiral sulfur
ylides. Thus, O-benzyl L-serine was transformed into the hydroxy
amide 12 by reduction with lithium aluminum hydride to its
corresponding serinol derivative,29 followed by reaction with
ester 11 in the presence of BuLi. According to the modified
Gleason procedure, applied before for L-valine, 12 was treated
with BF3 OEt2 to obtain a separable 2:1 mixture assigned to the
3
diastereoisomers 13 and 14, respectively, in a 70% combined
yield. Subsequent treatment of 13 and 14 with Meerwein's salt
afforded the corresponding sulfonium salts 15 and 16 in 81%
yields for both cases (Scheme 5).
As for sulfonium salts 6 and 9, 15 and 16 were explored as
potential new chiral reagents for the asymmetric synthesis of
epoxy amides. Thus, in a similar procedure as described before
for 6 and 9, 15 and 16 were separately reacted with various
aromatic and aliphatic aldehydes under typical basic conditions.
Not surprisingly, we obtained almost identical results in the
formation of the corresponding epoxy amides 17 and 18 and in
their transformations into the epoxy alcohols 3 and 4, compared
to those obtained with salts 6 and 9. In addition, the same
problems found with aliphatic aldehydes were observed includ-
ing the formation of mixtures of cis/trans epoxyamides 18gꢀh
from sulfonium salt 16 and poor yields in the reduction process
(Table 3).
It is worthy to emphasize that the synthetic value of the
described asymmetric epoxidation methodology lies with the
utility of the resulting epoxyamides together with their corre-
sponding epoxy alcohols, thus representing versatile building
blocks for the stereoselective construction of 1,2-functionalized
systems.30 In fact, for the particular case of glycidic amides, we
have demonstrated their synthetic potential in reactions with
nucleophiles, which display excellent reactivities and regioselec-
tivities at the C-2 position with nitrogen, oxygen, carbon, and
sulfur nucleophiles.8ꢀ10,31
21
LiBH4,19 RedAl,20 LiAlH4 Cp2Zr(H)Cl,22 and LiNH2BH3.23
With exception of LiBH4, which provided results similar to that
using Super-H as the reducing agent, the other agents failed to
provide improved results.
Despite these drawbacks, we concluded that the stereochem-
istry of the chiral center located at the aminal functional group of
the bicyclic system in the sulfonium salt served to control the
stereochemical course of the reaction. In this way, it was feasible
to prepare both enantiomeric epoxy alcohols from a common L-
amino acid.
A theoretical rationale for the observed stereochemical out-
come can be proposed based on the conformational analyses of
sulfur ylides derived from sulfonium salts 6 and 9 (Scheme 4),
which show an unexpected preference for the methyl group on
the sulfur atom to adopt a pseudoaxial disposition.24 Taking into
account the preferred conformations of the sulfur ylides together
with the assumption of a cisoid approach of the aldehyde to the
ylide, with the two polar groups in a near eclipsed orientation,25
make plausible the transition state Iq (path B) as the most
favorable in contrast to the transition state derived from path A.
With the betaine intermediate I formed, the subsequent step
should involve rotation around the CꢀC bond to give the
betaine II with the alkoxy and sulfonium groups in an antiper-
iplanar arrangement, prior to the intramolecular nucleophilic
attack of the alkoxy group to deliver epoxy amide 7.
’ CONCLUSIONS
In conclusion, we have described the synthesis and reactivity
of novel chiral sulfur ylides, based upon the bicyclic ylides
described by us earlier,9 but using Gleason-type chiral auxiliaries
as the chirality source. The results obtained in the formation of
the corresponding epoxy amides were satisfactory in terms of
chemical yields and stereochemical induction, thus illustrating
the synthetic potential that this kind of reagents may offer in
asymmetric synthesis. Interestingly, the extension of this meth-
odology to various L-amino acids in conjuction with the possi-
bility of preparing both diastereoisomers from the same chiral
source represent significant advantages compared with other
asymmetric methodologies, which generally require a pair of
enantiomers to have access to both diastereoisomers. In addition
to these features, the very mild conditions for these reactions are
particularly useful for aromatic aldehydes but not for aliphatic
aldehydes. For these later cases, their reactions with sulfonium
salts 9 and 16 require a more profound and detailed study in
On the other hand, for the reaction of aldehydes with the
sulfur ylide derived from 9, the stereochemical course could
follow a similar path compared to the previous case. However, in
this occasion, an additional steric repulsion present in transition
state IIIq between the aliphatic chain of the starting aldehyde and
the alkyl group of the sulfur ylide could explain the important
preference for this reaction to follow the pathway toward cis
q
epoxides through transition state III0 in which this interaction is
not present. Consequently, this scenario could explain the lack of
diastereoselectivity observed in the formation of the correspond-
ing epoxy amides, where essentially a 1:1 mixture of E:Z epoxy
amides 10 and 70 is observed. The experimental results obtained
for these reactions lend support to the proposed rationale for the
observed stereoselectivity of ylides 6 and 9.
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Scheme 4. Rationale of the Stereochemical Outcome of Reactions of 6 and 9 with Aliphatic Aldehydes
order to extend the methodology to a broader group of carbonyl
compounds.
carried out on 0.25, 0.50, or 1 mm silica gel plates (60F-254). NMR
spectra were recorded on a 400 MHz instrument and calibrated using
residual undeuterated solvent as an internal reference. The following
abbreviations were used to explain the multiplicities: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; band, several overlapping
signals; b, broad. Optical rotations were recorded on a 241 polarimeter.
High resolution mass spectra (HRMS) were recorded on a mass
spectrometer under fast atom bombardment (FAB) conditions.
’ EXPERIMENTAL SECTION
General Techniques. All reactions were carried out under an
argon atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF) was dis-
tilled from sodium benzophenone, and methylene chloride (CH2Cl2)
and benzene (PhH) from calcium hydride. Yields refer to chromato-
graphically and spectroscopically (1H NMR) homogeneous materials,
unless otherwise stated. All solutions used in workup procedures were
saturated unless otherwise noted. All reagents were purchased at highest
commercial quality and used without further purification unless other-
wise stated. All reactions were monitored by thin-layer chromatography
carried out on 0.25 mm silica gel plates (60F-254) using UV light as
visualizing agent and 7% ethanolic phosphomolybdic acid or p-anisal-
dehyde solution and heat as developing agents. Silica gel (60, particle
size 0.040ꢀ0.063 mm) was used for flash column chromatography.
Preparative thin-layer chromatography (PTLC) separations were
Synthesis of Sulfonium Salts. Sulfonium Salt 6. To a solution
of commercially available Gleason auxiliary 5 (747 mg, 3.47 mmol, 1.0
equiv) in dry acetonitrile (12 mL) was added Meerwein salt at room
temperature (636 mg, 4.17 mmol, 1.2 equiv). After 12 h, the reaction was
quenched by the addtion of MeOH (0.2 mL), and the solvents were
evaporated under reduced pressure. To the resulting white solid was
added MeOH (5 mL,) and then the mixture was sonicated for the
dispersion of the salt. The solid was filtered and washed with cooled
MeOH (1 ꢁ 3 mL). After drying under high vacuum, sulfonium salt 6
(887 mg, 81%) was obtained as a white solid: mp 179ꢀ185 °C; [R]25
=
D
þ4.1° (c 0.12, H2O); 1H NMR (400 MHz, DMSO-d6) δ 0.77 (d, J = 6.9
Hz, 3 H), 0.85 (d, J = 7.0 Hz, 3 H), 2.26ꢀ2.48 (m, 2 H), 2.99 (s, 3 H),
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Scheme 5. Synthesis of Sulfonium Salts 15 and 16 from
H-Ser(Bn)-OH
Table 3. Reactions of Sulfur Ylides Derived from Sulfonium
Salts 15 and 16 with Aldehydes
epoxyamide
epoxyalcohol
(yield %)c
entry
aldehyde
PhCHO
(yield %; de %)
1
17a (76; >98)a
17b (60; >98)a
17c (76; >98)a
17d (70; >98)a
17e (50; >98)a
17g (48; >98)a
17h (49; >98)a
17i (51; >98)b
18a (57; >98)b
18b (90; >98)b
18c (60; >98)a
18d (72; >98)a
18e (78; >98)a
18g þ its cis isomer
(77; E:Z 1.3:1)b
18h þ its cis isomer
(83; E:Z 2.1:1)b
3a (96)
2
4-MeC6H4CHO
2-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
(CH3)2CHCHO
Chx-CHO
3b (87)
3
3c (54)
4
3d (73)
5
3e (50)
6
3g (47)
7
3h (69)
8
CH3(CH2)5CHO
PhCHO
3i (85)
9
4a (50)
3.49 (bs, 1 H), 3.65 (dt, J = 12.5, 3.1 Hz, 1 H), 3.75ꢀ3.84 (m, 1 H),
3.93ꢀ4.10 (m, 4 H), 4.66 (d, J = 12.8 Hz, 1 H), 5.53 (d, J = 8.8 Hz, 1 H);
13C NMR (100 MHz, DMSO-d6) δ 15.7, 19.0, 26.4, 27.0, 30.9, 43.9,
61.5, 64.8, 87.8, 158.3. Anal. Calcd for C11H20BF4NO2S: C, 41.66; H,
6.36; N, 4.42. Found : C, 41.30; H, 6.24; N, 4.59.
10
11
12
13
14
4-MeC6H4CHO
2-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
(CH3)2CHCHO
4b (34)
4c (44)
4d (52)
4e (37)
4g þ its cis isomer
(41; E:Z 1.3:1)
4h þ its cis isomer
(45; E:Z 2.1:1)
Cyclic Sulfides 5 and 8. To a dry flask was added LiAlH4 (2.22 g,
55.51 mmol, 1.3 equiv), and the flask was purged under Ar. At 0 °C, dry
THF (150 mL) was added, followed by L-valine (5.0 g, 46.7 mmol, 1.0
equiv) portionwise. The reaction mixture was then heated at reflux for 1
h and after this time cooled to 0 °C. An aqueous KOH solution (4.2 mL,
4.4 M) was carefully added, and then the crude mixture was stirred and
heated under reflux for 30 min. The resulting crude mixture was allowed
to warm to room temperature, filtered through Celite, and washed with
THF. The solvents were then evaporated under reduced pressure to
recover finally L-valinol (4.21 g, 87%) as a yellow oil that was used in the
next reaction without further purification. To a solution of L-valinol
(1.14 g, 11.05 mmol, 1.2 equiv) in dry THF (21 mL) was added n-BuLi
(1.15 mL, 1.6 M in hexanes, 1.84 mmol, 0.2 equiv) at 0 °C. After 10 min
at this temperature, a solution of ester 1111 (1.90 g, 9.21 mmol, 1.0
equiv) in dry THF (5 mL) was added. The mixture was then stirred for
18 h and quenched by the addition of a saturated aqueous NH4Cl
solution. The resulting mixture was extracted three times with EtOAc,
and the combined organic extracts washed with brine, dried over
anhydrous MgSO4, and filtered. The solvents were evaporated under
reduced pressure, and the resulting crude (2.51 g) was used in the next
reaction without further purification. The previous crude product (2.51
g, 9.05 mmol, 1.0 equiv) was dissolved in dry CH2Cl2 (16 mL), and
15
Chx-CHO
a 1.0 equiv of 15 or 16, 1.1 equiv of a 3.0 M aqueous NaOH or 1.1 equiv
of NatBuO, tBuOH, 25 °C, 3 h; then 1.0 equiv of RCHO, overnight. b 1.0
equiv of 15 or 16, 1.0 equiv of a 1.0 M aqueous NaOH, tBuOH/DMSO
(10/1), 25 °C, 1 h; then 1.0 equiv of RCHO, overnight. c 2.5 equiv of
Super-H, THF, 0 °C, 0.5 h.
3.5 Hz, 1 H), 2.24 (dddd, J = 14.1, 4.4, 2.9, 1.3 Hz, 1 H), 2.45 (dtd, J =
14.0, 7.0 3.9 Hz, 1 H), 2.78 (dddd, J = 6.0, 4.8, 3.6, 1.6 Hz, 1 H), 2.94
(ddd, J = 14.4, 12.3, 2.9 Hz, 1 H), 3.18 (dd, J = 14.6, 1.6 Hz, 1 H), 3.26 (d,
J = 14.6 Hz, 1 H), 3.92 (dd, J = 9.1, 2.6 Hz, 1 H), 3.97 (dd, J = 9.1, 6.3 Hz,
1 H), 4.15 (ddd, J = 6.4, 3.7, 2.8 Hz, 1 H), 5.24 (dd, J = 10.0, 0.7 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 15.8, 19.2, 27.5, 29.6, 36.2, 36.5, 61.7,
65.3, 90.2, 167.9. 8: 1H NMR (400 MHz, CDCl3) δ 0.93 (d, J = 6.7 Hz, 3
H), 0.98 (d, J = 6.9 Hz, 3 H), 1.81ꢀ1.98 (m, 2 H), 2.40 (td, J = 13.9, 3.2
Hz, 1 H), 2.78 (td, J = 14.6, 7.0, 3.8 Hz, 1 H), 2.96 (ddd, J = 14.6, 12.8, 2.7
Hz, 1 H), 3.21 (s, 2 H), 3.66 (dd, J = 8.8, 5.6 Hz, 1 H), 3.94 (d, J = 8.8 Hz, 1
H), 4.00 (dd, J = 8.4, 5.6 Hz, 1 H), 5.03 (d, J = 9.7 Hz, 1 H); 13C NMR (100
MHz, D2O) δ 18.9, 30.6, 30.7, 36.5, 36.8, 61.7, 67.4, 89.8, 170.0; FAB
HRMS (NBA) m/e 216.1062, M þ Hþ calcd for C10H17NO2S 216.1058.
Sulfonium Salt 9. Sulfonium salt 9 (409 mg, 70%) was obtained from
sulfide 8 (381 mg, 1.77 mmol) following the same procedure as
BF3 OEt2 (1.4 mL, 11.05 mmol, 1.2 equiv) was added at room
3
temperature. After 96 h, the crude reaction was treated with a saturated
aqueous NaHCO3 solution, which was carefully added until no more
CO2 release was observed. The crude mixture was then extracted three
times with CH2Cl2, and the organic extracts washed with brine, dried
over anhydrous MgSO4, and filtered. After evaporation of the solvent
under reduced pressure, the crude was purified by flash column
chromatography (silica gel, 30% EtOAc to 50% EtOAc in hexanes) to
obtain compounds 532 (747 mg, 38%) and its diastereoisomer 811 (399
mg, 20%) as white solids. 5: 1H NMR (400 MHz, CDCl3) δ 0.80 (d, J =
7.0 Hz, 3 H), 0.86 (d, J = 7.0 Hz, 3 H), 2.05 (dddd, J = 14.1, 12.4, 10.0,
1
described before for 6. 9: white solid; mp 185ꢀ187 °C; H NMR
(400 M þ Hz, DMSO-d6) δ 0.86 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.6 Hz,
3 H), 1.79 (sext, J = 6.8 Hz, 1 H), 1.90 (sext, J = 8.0 Hz, 1 H), 2.65 (d, J =
15.2 Hz, 1 H), 3.01 (s, 3 H), 3.70ꢀ3.80 (m, 3H), 3.96ꢀ4.06 (m, 3 H), 4.62
(d, J = 14.0 Hz, 1 H), 5.29 (d, J = 9.6 Hz, 1 H); 13C NMR (100 MHz,
DMSO-d6) δ 18.8, 19.0, 26.1, 30.2, 31.7, 40.4, 44.2, 62.0, 67.2, 88.0, 161.8.
Anal. Calcd for C11H20BF4NO2S: C, 41.66; H, 6.36; N, 4.42. Found : C,
41.54; H, 6.28; N, 4.53.
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Amide 12. To a dry flask was added LiAlH4 (1.33 g, 33.3. mmol, 1.0
equiv), and the flask was purged under argon. After addition at 0 °C of
dry THF (100 mL), L-benzylserine (5.0 g, 25.6 mmol, 1.0 equiv) was
added portionwise. After completion of the addition, the reaction
mixture was refluxed for 1 h, then cooled to 0 °C and treated with an
aqueous KOH solution (5.0 mL, 4.4 M) which was carefully added. The
resulting suspension was then heated at reflux for 30 min. After this time,
the crude mixture was allowed to recover room temperature, filtered
through Celite, and the solids washed with THF. The solvents were then
evaporated under reduced pressure, to obtain L-benzylserinol (4.28 g,
92%) as a yellow oil that was used in the next reaction without further
purification. To a solution of the resulting aminoalcohol (2.0 g, 11.05
mmol, 1.2 equiv) in dry THF (21 mL) and at 0 °C was added n-BuLi
(1.15 mL, 1.6 M in hexanes, 1.84 mmol, 0.2 equiv) dropwise. After 10
min, a solution of the ester 11 (1.9 g, 9.2 mmol, 1.0 equiv) in dry THF
(5 mL) was added. The mixture was then stirred for 18 h, after which it
was treated with a saturated aqueous NH4Cl solution. The resulting
mixture was extracted three times with EtOAc, and the organic extracts
were washed with brine, dried over anhydrous MgSO4, and filtered. After
evaporation of the solvents under reduced pressure, the resulting crude
was purified by flash column chromatography (silica gel, 100% EtOAc)
to yield compound 12 (2.44 g, 75% over two steps) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 1.85ꢀ1.91 (m, 2 H), 2.57ꢀ2.62 (m, 2 H),
3.18 (s, 2 H), 3.38 (m, 2 H), 3.55 (dd, J = 9.6, 4.7 Hz, 1 H), 3.60ꢀ3.67
(m, 2 H), 3.71ꢀ3.78 (m, 3H), 3.85ꢀ3.89 (m, 1 H), 4.07 (tt, J = 9.2, 4.6
Hz, 1 H), 4.48 (s, 2 H), 4.86 (t, J = 4.5 Hz, 1 H), 7.21ꢀ7.33 (m, 5 H),
7.40 (d, J = 8.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 27.1, 33.2,
36.1. 50.8, 62.5, 64.7, 69.4, 73.1, 102.6, 127.4, 127.6, 128.2, 137.5, 169.0;
FAB HRMS (NBA) m/e 356.1538, M þ Hþ calcd for C17H25NO5S
356.1532.
Sulfonium Salt 16. Sulfonium salt 16 (397 mg, 81%) was obtained
from sulfide 14 (320 mg, 1.49 mmol) following the same procedure as
described before for 6. 16: white solid; mp 147ꢀ149 °C; [R]23D = þ39.2°
(c 0.51, H2O); 1H NMR (400 MHz, DMSO-d6) δ 1.90ꢀ2.00 (m, 1 H),
2.60 (td, J = 15.3, 3.1 Hz, 1 H), 3.01 (s, 3 H), 3.45 (d, J = 5.8 Hz, 2 H),
3.70ꢀ3.76 (m, 2 H), 3.89 (dd, J = 8.6, 6.1 Hz, 1 H), 4.01ꢀ4.05 (m, 2 H),
4.37 (c, J = 5.4 Hz, 1 H), 4.52 (s, 2 H), 4.59 (d, J = 13.7 Hz, 1 H), 5.33 (d,
J = 9.4 Hz, 1 H), 7.28ꢀ7.39 (m, 5 H); 13C NMR (100 MHz, DMSO-d6)
δ 26.2, 31.7, 43.9, 56.0, 67.5, 68.1, 72.3, 88.1, 127.6, 128.4, 138.1, 160.6.
Anal. Calcd for C16H22NO3SBF4 C, 48.66; H, 5.61; N, 3.54; S, 8.11; O,
12.14. Found : C, 48.55; H, 5.48; N, 3.75; S, 7.88; O, 12.35.
Synthesis of Epoxyamides 7, 10, 17, and 18. General
Procedure A. To a suspension of the sulfonium salt (6, 9, 15, or 16)
(1.0 equiv) in tBuOH (0.1 M) was added a 3.0 M aqueous NaOH
solution (1.0 equiv) at room temperature. After 3 h at this temperature, a
solution of aldehyde (1.1 equiv) in tBuOH (0.1 M) was added, and the
resulting reaction mixture was stirred overnight. The crude mixture was
then diluted with AcOEt, and the organic solution was sequentially
washed with saturated aqueous NH4Cl solution and brine. The organic
layer was then separated, dried (MgSO4), and filtered. Concentration
under reduced pressure provided a crude product that was purified by
flash column chromatography (silica gel, AcOEt in hexanes in a range of
20ꢀ50% of AcOEt) to afford the corresponding epoxy amide.
General Procedure B. To a suspension of the sulfonium salt (6, 9, 15
or 16) (1.0 equiv) in tBuOH (0.1 M) was added DMSO (tBuOH/
DMSO: 10/1) followed by a 1.0 M aqueous NaOH solution (1.0 equiv)
at room temperature. After 1 h at this temperature, a solution of
aldehyde (1.1 equiv) in tBuOH (0.1 M) was added, and the resulting
reaction mixture was stirred overnight. After this time the reaction
mixture was worked up in the same way as described above in procedure
A, and the resulting crude product was purified by flash column
chromatography (silica gel, AcOEt in hexanes) to obtain the corre-
sponding pure epoxy amide.
Sulfides 13 and 14. A solution of amide 12 (1.95 g, 5.5 mmol, 1.0
equiv) in CH2Cl2 (10 mL) was treated with BF3 OEt2 (0.84 mL, 6.6
3
mmol, 1.2 equiv) in exactly the same manner as for the L-valinol
derivative, described above, to obtain cyclic sulfides 13 (761 mg, 47%)
Epoxy Amide 7a. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
and 14 (381 mg, 23%) as white solids. 13: mp 92ꢀ96 °C; [R]25
=
D
þ73.5° (c 2.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.99ꢀ2.01 (m,
1 H), 2.19ꢀ2.27 (m, 1 H), 2.73ꢀ2.81 (m, 1 H), 2.92 (ddd, J = 14.9, 12.3,
2.8 Hz, 1 H), 3.16 (s, 2 H), 3.43 (t, J = 8.7 Hz, 1 H), 3.76 (dd, J = 8.9, 3.4
Hz, 1 H), 4.04ꢀ4.13 (m, 2 H), 4.35 (ddt, J = 5.8, 3.4, 2.4 Hz, 1 H), 4.46
(d, J = 11.9 Hz, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 5.21 (dd, J = 10.0, 1.0 Hz,
1 H), 7.23ꢀ7.34 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 29.7, 35.9,
36.4, 56.1, 67.8, 73.2, 89.9, 127.6, 128.3, 137.9, 168.0; FAB HRMS
(NBA) m/e 294.1157, M þ Hþ calcd for C15H19NO3S 294.1164. 14:
mp 91ꢀ95 °C; [R]25D = ꢀ28.4° (c 2.4, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.66ꢀ1.72 (m, 1 H), 2.32 (d, J = 14.2 Hz, 1 H), 2.66 (dt, J =
14.8, 3.7 Hz, 1 H), 2.86 (ddd, J = 14.9, 12.8, 2.5 Hz, 1 H), 3.10 (s, 2 H),
3.37 (t, J = 9.0 Hz, 1 H), 3.57 (dd, J = 9.0, 3.9 Hz, 1 H), 3.71 (dd, J = 8.8,
5.7 Hz, 1 H), 4.08 (d, J = 8.8 Hz, 1 H), 4.33 (dt, J = 9.1, 4.6 Hz, 1 H), 4.45
(d, J = 11.9 Hz, 1 H), 4.48 (d, J = 11.9 Hz, 1 H), 4.97 (d, J = 9.5 Hz,
1 H), 7.14ꢀ7.26 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 30.6,
36.6, 37.2, 56.0, 67.9, 68.4, 73.3, 90.0, 127.7, 128.4, 137.9, 169.3;
FAB HRMS (NBA) m/e 294.1161, M þ Hþ calcd for C15H19NO3S
294.1164.
(80%): colorless oil; [R]30 = þ116.8° (c 0.65, CH2Cl2); H NMR
1
D
(400 MHz, CDCl3) (two rotamers in a 1.5:1 ratio) δ (major) 0.80 (d, J =
6.8 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H), 1.67 (s, 3 H), 1.69ꢀ1.77 (m, 1 H),
1.81ꢀ1.93 (m, 2 H), 2.35ꢀ2.49 (m, 1 H), 2.51ꢀ2.63 (m, 1 H), 3.47 (d,
J = 1.8 Hz, 1 H), 3.95 (dd, J = 9.5, 1.4 Hz, 1 H), 3.99ꢀ4.04 (m, 2 H),
4.14ꢀ4.18 (m, 1 H), 5.59 (dd, J = 8.7, 1.8 Hz, 1 H), 7.24ꢀ7.38 (m, 5 H);
13C NMR (100 MHz, CDCl3) δ (major) 15.2, 15.7, 19.3, 27.5, 29.3,
30.7, 32.5, 34.3, 58.2, 58.4, 60.4, 65.8, 89.9, 125.5, 128.7, 128.9, 135.1,
164.3; FAB HRMS (NBA) m/e 336.1639, M þ Hþ calcd for
C18H25NO3S 336.1633.
Epoxy Amide 7b. Preparation by procedure B and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
1
(89%): colorless oil; [R]25 = þ106.8° (c 1.0, CH2Cl2); H NMR
D
(200 MHz, CDCl3) (two rotamers in a 1.5:1 ratio) δ (major) 0.82 (d, J =
7.2 Hz, 3 H), 0.85 (d, J = 7.2 Hz, 3 H), 1.61ꢀ1.76 (m, 1 H), 1.73 (s, 3 H),
2.04ꢀ2.14 (m, 2 H), 2.33 (s, 3 H), 2.41ꢀ2.66 (m, 2 H), 3.46 (d, J = 2.0
Hz, 1 H), 3.81ꢀ4.09 (m, 3 H), 4.10ꢀ4.22 (m, 1 H), 5.57 (dd, J = 8.6, 1.7
Hz, 1 H), 7.11ꢀ7.17 (m, 4 H); 13C NMR (50 MHz, CDCl3) δ (major)
15.0, 15.2, 19.3, 21.2, 27.5, 29.3, 30.9, 32.5, 34.5, 58.3, 58.5, 60.4, 65.8,
87.7, 90.0, 125.7, 127.9, 129.4, 164.3; FAB HRMS (NBA) m/e 350.1785,
M þ Hþ calcd for C19H27NO3S 350.1790.
Sulfonium Salt 15. Sulfonium salt 15 (687 mg, 81%) was obtained
from sulfide 13 (634 mg, 2.16 mmol) following the same procedure as
described before for 6. 15: white solid; mp 142ꢀ144 °C; [R]25
=
D
þ17.5° (c 0.4, H2O); 1H NMR (400 MHz, DMSO-d6) δ 2.23ꢀ2.40 (m,
2 H), 2.91 (s, 3 H), 3.28 (t, J = 8.6 Hz, 2 H), 3.54ꢀ3.65 (m, 1 H),
3.66ꢀ3.77 (m, 1 H), 3.87ꢀ3.97 (m, 2 H), 3.99ꢀ4.05 (m, 1 H),
4.12ꢀ4.20 (bs, 1 H), 4.36ꢀ4.53 (m, 3 H), 5.41 (d, J = 7.1 Hz, 1 H),
7.18ꢀ7.33 (m, 5 H); 13C NMR (100 MHz, DMSO-d6) δ 26.2, 30.5,
43.6, 56.0, 66.7, 67.3, 72.2, 87.6, 127.5, 128.2, 138.0, 158.6. Anal.
Calcd for C16H22NO3SBF4 C, 48.66; H, 5.61; N, 3.54; S, 8.11; O,
12.14. Found : C, 48.51; H, 5.38; N, 3.78; S, 7.97; O, 12.55.
Epoxy Amide 7c. Preparation by procedure B and purification by flash
column chromatography (silica gel, 30% EtOAc in hexanes) (73%):
colorless oil; [R]25D = þ62.5° (c 1.1, CH2Cl2); 1H NMR (400 MHz,
CDCl3) (two rotamers in a 1.6:1 ratio) δ (major) 0.84 (d, J = 7.0 Hz, 3
H), 0.88 (d, J = 6.7 Hz, 3 H), 1.68ꢀ1.74 (m, 1 H), 1.74 (s, 3 H),
1.74ꢀ2.00 (m, 2 H), 2.36 (s, 3 H), 2.40ꢀ2.65 (m, 2 H), 3.37 (d, J = 1.9
Hz, 1 H), 3.94 (dd, J = 9.5, 1.1 Hz, 1 H), 4.00ꢀ4.06 (m, 1 H), 4.14ꢀ4.21
(m, 1 H), 4.21 (d, J = 1.8 Hz, 1 H), 5.61 (dd, J = 8.8, 1.8 Hz, 1 H),
3144
dx.doi.org/10.1021/jo1025964 |J. Org. Chem. 2011, 76, 3139–3150

The Journal of Organic Chemistry
ARTICLE
7.10ꢀ7.28 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ (major) 15.6,
18.7, 19.3, 29.3, 30.6, 32.6, 34.3, 56.4, 57.3, 60.3, 65.6, 89.9, 123.8, 126.3,
128.4, 130.1, 133.4, 136.2, 164.5; FAB HRMS (NBA) m/e 350.1779, M
þ Hþ calcd for C19H27NO3S 350.1790.
Epoxy Amide 7i. Preparation by procedure A and purification by flash
column chromatography (silica gel, 20% EtOAc in hexanes) (79%):
colorless oil; [R]25D = þ12.5° (c 0.15, CH2Cl2); 1H NMR (400 MHz,
CDCl3) (two rotamers in a 1.6:1 ratio) δ (major) 0.86 (t, J = 6.6 Hz, 3
H), 0.88 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 1.23ꢀ1.39 (m,
7 H), 1.40ꢀ1.59 (m, 3 H), 1.64ꢀ1.73 (m, 1 H), 1.88ꢀ1.93 (m, 1 H),
2.09 (s, 3 H), 2.30ꢀ2.40 (m, 1 H), 2.51ꢀ2.61 (m, 2 H), 3.10 (ddd, J =
6.2, 4.6, 1.8 Hz, 1 H), 3.22 (d, J = 1.9 Hz, 1 H), 3.83 (d, J = 11.9 Hz, 1 H),
3.99ꢀ4.06 (m, 2 H), 5.54 (dd, J = 8.7, 1.8 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ (major) 14.0, 14.6, 18.6, 22.9, 24.5, 28.1, 29.3, 29.6,
31.5, 31.7, 34.4, 53.0, 56.3, 60.4, 69.4, 87.6, 165.0; FAB HRMS (NBA)
m/e 344.2264, M þ Hþ calcd for C18H32NO3S 344.2259.
Epoxy Amide 7d. Preparation by procedure B and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(75%): colorless oil; [R]25D = þ127.3° (c 1.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) (tworotamersin a1.5:1 ratio) δ(major) 0.81 (d, J= 6.9 Hz,
3 H), 0.84 (d, J = 6.9 Hz, 3 H), 1.64ꢀ1.78 (m, 1 H), 1.73 (s, 3 H),
1.80ꢀ1.93 (m, 2 H), 2.35ꢀ2.64 (m, 2 H), 3.46 (d, J = 1.9 Hz, 1 H), 3.78
(s, 3 H), 3.97 (d, J = 1.8 Hz, 1 H), 3.99ꢀ4.04 (m, 2 H), 4.13ꢀ4.18 (m, 1
H), 5.57 (dd, J = 8.8, 1.8 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ (major) 15.8, 19.3, 27.5, 29.2,
30.7, 32.5, 34.4, 55.3, 58.2, 60.4, 61.1, 65.8, 89.9, 114.2, 127.0, 160.1, 164.5;
FAB HRMS (NBA) m/e 366.1745, M þ Hþ calcd for C19H27NO4S
366.1739.
Epoxy Amide 10a. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(95%): colorless oil; [R]25 = ꢀ178.5 (c 0.6, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.6:1 ratio) δ (major) 0.98 (d, J =
6.7 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 1.77ꢀ1.91 (m, 2 H), 1.93ꢀ2.03
(m, 1 H), 2.13 (s, 3 H), 2.44ꢀ2.51 (m, 1 H), 2.58ꢀ2.71 (m, 1 H), 3.53
(s, 1 H), 3.71 (dd, J = 7.7, 5.8 Hz, 1 H), 3.77 (t, J = 7.1 Hz, 1 H), 4.05 (d,
J = 8.8 Hz, 1 H), 4.15 (s, 1 H), 5.36 (dd, J = 7.9, 1.6 Hz, 1 H), 7.30ꢀ7.38
(m, 5 H); 13C NMR (100 MHz, CDCl3) δ (major) 15.2, 18.7, 19.8, 29.3,
31.2, 33.7, 57.3, 57.7, 61.9, 68.5, 89.6, 125.7, 128.7, 128.9, 135.4, 165.8;
FAB HRMS (NBA) m/e 336.1628, M þ Hþ calcd for C18H25NO3S
336.1633.
Epoxy Amide 7e. Preparation by procedure A and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes)
1
(76%): colorless oil; [R]25 = þ127.5° (c 1.1, CH2Cl2); H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.5:1 ratio) δ (major) 0.84 (d, J =
6.9 Hz, 3 H), 0.88 (d, J = 6.9 Hz, 3 H), 1.71ꢀ1.80 (m, 1 H), 1.79 (s, 3 H),
1.84ꢀ1.96 (m, 2 H), 2.37ꢀ2.67 (m, 2 H), 3.45 (d, J = 1.8 Hz, 1 H), 4.00
(d, J = 1.8 Hz, 1 H), 4.01ꢀ4.08 (m, 2 H), 4.16ꢀ4.20 (m, 1 H), 5.60 (dd,
J = 8.8, 1.8 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ (major) = 15.2, 19.3, 29.2, 30.6, 32.6,
34.5, 57.5, 58.0, 60.4, 61.2, 65.8, 89.9, 109.5, 126.9, 129.0, 133.7, 134.7,
163.9; FAB HRMS (NBA) m/e 370.1241 M þ Hþ calcd for
C18H24ClNO3S 370.1244.
Epoxy Amide 10b. Preparation by procedure B and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(73%): colorless oil; [R]25 = ꢀ130.5 (c 0.5, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.7:1 ratio) δ (major) 0.95 (d, J =
6.7 Hz, 3 H), 1.03 (d, J = 6.9 Hz, 3 H), 1.75ꢀ1.88 (m, 2 H), 1.92ꢀ2.01
(m, 1 H), 2.11 (s, 3 H), 2.34 (s, 3 H), 2.42ꢀ2.51 (m, 1 H), 2.56ꢀ2.69
(m, 1 H), 3.51 (d, J = 1.7 Hz, 1 H), 3.68 (dd, J = 7.9, 5.7 Hz, 1 H), 3.74
(dd, J = 8.8, 5.5 Hz, 1 H), 4.03 (d, J = 8.4 Hz, 1 H), 4.09 (d, J = 1.7 Hz, 1
H), 5.34 (dd, J = 8.1, 2.4 Hz, 1 H), 7.13ꢀ7.20 (m, 4 H); 13C NMR (100
MHz, CDCl3) δ (major) 15.2, 18.8, 19.8, 21.2, 29.2, 31.2, 33.7, 57.2,
57.7, 61.9, 68.5, 89.5, 125.7, 129.4, 132.3, 138.9, 166.0; FAB HRMS
(NBA) m/e 350.1792, M þ Hþ calcd for C19H27NO3S 350.1790.
Epoxy Amide 10c. Preparation by procedure B and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
Epoxy Amide 7f. Preparation by procedure A and purification by flash
column chromatography (silica gel, 20% EtOAc in hexanes) (41%):
colorless oil; [R]25D = þ49.8° (c 0.95, CH2Cl2); 1H NMR (400 MHz,
CDCl3) (two rotamers in a ∼ 2:1 ratio) δ (major) 0.82ꢀ0.90 (m, 3 H),
0.88 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 0.97ꢀ1.05 (m, 2 H),
1.54ꢀ1.81 (m, 1 H), 1.86ꢀ2.13 (m, 2 H), 2.08 (s, 3 H), 2.29ꢀ2.40 (m, 1
H), 2.49ꢀ2.63 (m, 1 H), 3.09 (dt, J = 6.3, 2.0 Hz, 1 H), 3.25 (d, J = 2.0
Hz, 1 H), 4.00 (dd, J = 10.0, 4.9 Hz, 1 H), 4.05 (dd, J = 10.0, 3.5 Hz, 1 H),
4.10ꢀ4.15 (m, 1 H), 5.54 (dd, J = 8.8, 1.8 Hz, 1 H); 13C NMR (100
MHz, CDCl3) (major) δ 9.5, 15.7, 19.4, 24.5, 29.3, 30.9, 32.6, 43.3, 54.1,
59.7, 60.2, 65.7, 89.8, 165.6; FAB HRMS (NBA) m/e 288.1630, M þ Hþ
calcd for C14H25NO3S 288.1633.
(63%): colorless oil; [R]25 = ꢀ117.0 (c 0.5, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.7:1 ratio) δ (major) 0.99 (d, J =
6.7 Hz, 3 H), 1.05 (d, J = 7.0 Hz, 3 H), 1.78ꢀ1.87 (m, 1 H), 1.89ꢀ2.06
(m, 2 H), 2.14 (s, 3 H), 2.40 (s, 3 H), 2.44ꢀ2.55 (m, 1 H), 2.59ꢀ2.72
(m, 1 H), 3.45 (d, J = 1.8 Hz, 1 H), 3.73ꢀ3.81 (m, 2 H), 4.08 (d, J = 8.8
Hz, 1 H), 4.31 (d, J = 1.8 Hz, 1 H), 5.40 (dd, J = 8.1, 2.6 Hz, 1 H),
7.17ꢀ7.28 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ (major) 14.9,
15.9, 18.6, 19.3, 29.4, 30.6, 34.3, 56.4, 60.3, 61.1, 65.6, 87.6, 123.9, 126.2,
128.3, 130.1, 133.4, 136.2, 164.5; FAB HRMS (NBA) m/e 350.1786, M
þ Hþ calcd for C19H27NO3S 350.1790.
Epoxy Amide 7g. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(73%): colorless oil; [R]25 = þ39.8° (c 1.1, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.8:1 ratio) δ (major) 0.86 (d, J =
6.9 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H), 1.00 (d,
J = 6.8 Hz, 3 H), 1.61ꢀ1.72 (m, 2 H), 1.99ꢀ2.11 (m, 1 H), 2.07 (s, 3 H),
2.27ꢀ2.37 (m, 1 H), 2.48ꢀ2.61 (m, 2 H), 2.93 (dd, J = 6.3, 1.8 Hz, 1 H),
3.27 (d, J = 1.8 Hz, 1 H), 3.94ꢀ4.01 (m, 1 H), 4.00 (d, J = 5.8 Hz, 1 H),
4.03ꢀ4.07 (m, 1 H), 5.53 (dd, J = 8.7, 1.7 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ (major) 15.5, 18.1, 18.6, 19.4, 29.2, 29.9, 30.7, 32.6,
34.9, 53.3, 60.2, 63.5, 65.6, 89.8, 165.6; FAB HRMS (NBA) m/e
302.1798 M þ Hþ calcd for C15H27NO3S 302.1790.
Epoxy Amide 10d. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes)
(86%): colorless oil; [R]25 = ꢀ264.9 (c 0.7, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.7:1 ratio) δ (major) 0.97 (d, J =
6.7 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 1.73ꢀ1.92 (m, 2 H), 1.94ꢀ2.02
(m, 1 H), 2.12 (s, 3 H), 2.43ꢀ2.53 (m, 1 H), 2.57ꢀ2.70 (m, 1 H), 3.52
(d, J = 1.6 Hz, 1 H), 3.71 (dd, J = 7.8, 5.7 Hz, 1 H), 3.76 (dd, J = 8.8, 5.6
Hz, 1 H), 3.80 (s, 3 H), 4.03 (s, 1 H), 4.09 (d, J = 1.2 Hz, 1 H), 5.35 (dd,
J = 8.0, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.22 (d, J = 8.5 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ (major) 15.2, 18.7, 19.8, 29.2, 31.2,
33.7, 55.3, 57.2, 57.6, 61.9, 68.5, 89.5, 114.2, 127.1, 160.2, 166.1; FAB
HRMS (NBA) m/e 366.1742, M þ Hþ calcd for C19H27NO4S
366.1739.
Epoxy Amide 7h. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
1
(82%): colorless oil; [R]25 = þ29.2° (c 0.88, CH2Cl2); H NMR
D
(400 MHz, CDCl3) (two rotamers in a 1.5:1 ratio) δ (major) 0.86
(d, J = 6.9 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 1.04ꢀ1.25 (m, 5 H),
1.60ꢀ1.82 (m, 5 H), 1.87ꢀ1.95 (m, 1 H), 2.07 (s, 3 H), 2.27ꢀ2.38 (m, 1
H), 2.49ꢀ2.61 (m, 2 H), 2.93 (dd, J = 6.3, 2.0 Hz, 1 H), 3.29 (d, J = 2.0
Hz, 1 H), 3.94ꢀ4.01 (m, 1 H), 4.00 (d, J = 6.2 Hz, 1 H), 4.03ꢀ4.07
(m, 1 H), 5.23 (dd, J = 8.7, 1.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ (major) 15.6, 19.4, 25.4, 25.5, 26.0, 28.7, 29.1, 29.5, 30.7, 32.6, 39.3,
53.1, 60.2, 62.7, 65.6, 89.8, 165.7; FAB HRMS (NBA) m/e 342.2096,
M þ Hþ calcd for C18H31NO3S 342.2103.
Epoxy Amide 10e. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes)
(76%): colorless oil; [R]25 = ꢀ152.5 (c 0.5, CH2Cl2); 1H NMR
D
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(400 MHz, CDCl3) (two rotamers in a 1.6:1 ratio) δ (major) 0.98 (d, J =
6.7 Hz, 3 H), 1.05 (d, J = 6.2 Hz, 3 H), 1.78ꢀ2.05 (m, 3 H), 2.13 (s, 3 H),
2.43ꢀ2.54 (m, 1 H), 2.58ꢀ2.71 (m, 1 H), 3.47 (d, J = 1.6 Hz, 1 H), 3.69
(dd, J = 7.9, 5.7 Hz, 1 H), 3.78 (dd, J = 8.9, 5.4 Hz, 1 H), 4.06 (d, J = 9.0
Hz, 1 H), 4.14 (d, J = 1.1 Hz, 1 H), 5.35 (dd, J = 7.5, 1.8 Hz, 1 H), 7.25 (d,
J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3)
δ (major) 15.2, 18.7, 19.8, 29.3, 31.3, 33.7, 57.4, 62.0, 68.5, 89.6, 127.0,
129.0, 134.8, 165.5; FAB HRMS (NBA) m/e 370.1239 M þ Hþ calcd
for C18H24ClNO3S 370.1244.
Epoxy Amide 10f. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes) (54%
combined yield of 10f together with its cis isomer 70f): colorless oil;
[R]25D = ꢀ48.9 (c 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) (mixture
of E:Z isomers in a 1.3:1 proportion and the E isomer as two rotamers in
a 1.9:1 ratio) δ (E isomer, major rotamer) 0.90ꢀ1.03 (m, 9 H),
1.57ꢀ1.81 (m, 3 H), 1.92ꢀ2.00 (m, 2 H), 2.10 (s, 3 H), 2.57ꢀ2.64
(m, 2 H), 3.16 (s, 1 H), 3.27 (s, 1 H), 3.70ꢀ3.82 (m, 2 H), 4.05 (d, J = 8.8
Hz, 1 H), 5.29 (d, J = 7.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
(major) 9.7, 15.1, 18.7, 19.7, 24.5, 29.3, 31.1, 33.8, 53.2, 59.1, 62.0, 68.4,
89.5, 167.1; FAB HRMS (NBA) m/e 288.1628, M þ Hþ calcd for
C14H25NO3S 288.1633.
(m, 2 H), 2.11 (s, 3 H), 2.38ꢀ2.49 (m, 1 H), 2.51ꢀ2.65 (m, 1 H), 3.33
(dd, J = 9.2, 6.5 Hz, 1 H) 3.37ꢀ3.43 (m, 2 H), 3.59 (d, J = 1.9 Hz, 1 H),
3.96ꢀ4.03 (m, 2 H), 4.05 (d, J = 1.9 Hz, 1 H), 4.28 (d, J = 12.1 Hz, 1 H),
4.33 (d, J = 12.1 Hz, 1 H), 5.56 (dd, J = 8.9, 1.9 Hz, 1 H), 7.21ꢀ7.28 (m,
6 H), 7.30ꢀ7.36 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ (major)
15.2, 29.3, 30.7, 55.3, 58.2, 67.9, 70.5, 73.5, 89.6, 125.7, 127.7, 128.0,
128.5, 128.7, 127.8, 128.9, 135.4, 164.8; FAB HRMS (NBA) m/e
414.1745, M þ Hþ calcd for C23H27NO4S 414.1739.
Epoxy Amide 17b. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(60%): colorless oil; [R]25 = þ136.0 (c 1.5, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 2.3:1 ratio) δ (major) 1.65ꢀ1.75
(m, 2 H), 2.07 (s, 3 H), 2.30 (s, 3 H), 2.33ꢀ2.46 (m, 1 H), 2.48ꢀ2.60
(m, 1 H), 3.30 (dd, J = 9.2, 6.3 Hz, 1 H) 3.34ꢀ3.41 (m, 2 H), 3.53 (d, J =
1.9 Hz, 1 H), 3.90ꢀ3.95 (m, 2 H), 3.97 (d, J = 1.7 Hz, 1 H), 4.18ꢀ4.27
(m, 2 H), 5.52 (dd, J = 8.9, 1.9 Hz, 1 H), 6.99ꢀ7.03 (m, 1 H), 7.09ꢀ7.11
(m, 4 H), 7.18ꢀ7.23 (m, 3 H), 7.25ꢀ7.29 (m, 1 H); 13C NMR (100
MHz, CDCl3) δ (major) 15.2, 21.2, 29.3, 30.7, 55.2, 58.3, 67.9, 70.5,
73.5, 89.6, 125.7, 127.7, 128.0, 128.4, 129.3, 132.3, 137.1, 138.7, 164.9;
FAB HRMS (NBA) m/e 428.1908, M þ Hþ calcd for C24H29NO4S
428.1896.
Epoxy Amide 17c. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(76%): colorless oil; [R]25D = þ71.8 (c 2.0, CH2Cl2); 1H NMR (400
MHz, CDCl3) (two rotamers in a 2.1:1 ratio) δ (major) 1.71ꢀ1.82 (m,
2 H), 2.12 (s, 3 H), 2.39 (s, 3 H), 2.41ꢀ2.66 (m, 2 H), 3.38ꢀ3.49 (m, 2
H), 3.53 (d, J = 1.9 Hz, 1 H), 4.07ꢀ4.12 (m, 3 H), 4.25 (d, J = 1.9 Hz, 1
H), 4.34 (s, 2 H), 5.59 (dd, J = 8.9, 1.9 Hz, 1 H), 7.07ꢀ7.12 (m, 1 H),
7.13ꢀ7.28 (m, 6 H), 7.31ꢀ7.37 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ (major) 15.2, 18.9, 29.3, 30.5, 55.1, 56.2, 57.2, 67.8, 70.3, 73.5,
89.5, 124.1, 126.2, 127.7, 128.4, 130.1, 133.5, 136.4, 137.0, 165.0; FAB
HRMS (NBA) m/e 428.1905, M þ Hþ calcd for C24H29NO4S
428.1896.
Epoxy Amide 10g. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes) (57%
combined yield of 10g together with its cis isomer 70g): colorless oil;
[R]25D = ꢀ43.4 (c 0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) (mixture
of E:Z isomers in a 1.3:1 proportion and the E isomer as two rotamers in
a 1.6:1 ratio) δ (E isomer, major rotamer) 0.86ꢀ1.12 (m, 12 H),
1.52ꢀ1.70 (m, 1 H), 1.74ꢀ1.85 (m, 1 H), 1.90ꢀ2.01 (m, 2 H), 2.10 (s, 3
H), 2.58ꢀ2.69 (m, 2 H), 2.99 (d, J = 6.5 Hz, 1 H), 3.30 (s, 1 H),
3.63ꢀ3.81 (m, 2 H), 4.05 (d, J = 8.4 Hz, 1 H), 5.31 (dd, J = 3.8 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ (major) 15.2, 18.7, 18.9, 20.0, 26.5,
29.3, 30.0, 31.0, 34.1, 52.6, 54.1, 62.0, 68.5, 89.3, 166.7; FAB HRMS
(NBA) m/e 302.1786 M þ Hþ calcd for C15H27NO3S 302.1790.
Epoxy Amide 10h. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes) (86%
combined yield of 10h together with its cis isomer 70h): colorless oil;
[R]25D = ꢀ37.2 (c 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) (mixture
of E:Z isomers in a 1.4:1 proportion and the E isomer as two rotamers in
a 1.7:1 ratio) δ (E isomer, major rotamer) 0.90ꢀ1.06 (m, 6 H),
1.11ꢀ1.40 (m, 7 H), 1.66ꢀ1.87 (m, 5 H), 1.93ꢀ2.02 (m, 2 H), 2.11
(s, 3 H), 2.57ꢀ2.68 (m, 2 H), 3.00 (dd, J = 6.6, 1.8 Hz, 1 H), 3.33 (d, J =
1.9 Hz, 1 H), 3.63ꢀ3.78 (m, 2 H), 4.06 (d, J = 8.4 Hz, 1 H), 5.30ꢀ5.33
(m, 1 H); 13C NMR (100 MHz, CDCl3) δ (major) 15.2, 18.7, 25.3, 25.5,
26.0, 28.8, 29.1, 29.2, 29.5, 31.0, 35.6, 39.4, 52.4, 53.7, 62.1, 68.5, 89.3,
166.8; FAB HRMS (NBA) m/e 342.2106, M þ Hþ calcd for
C18H31NO3S 342.2103.
Epoxy Amide 10i. Preparation by procedure B and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes) (77%
combined yield of 10i together with its cis isomer 70i): colorless oil; 1H
NMR (400 MHz, CDCl3) (mixture of E:Z isomers in a 1.4:1 proportion
and the E isomer as two rotamers in a 2:1 ratio) δ (E isomer, major
rotamer) 0.85 (t, J = 6.9 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.04 (d, J =
6.9 Hz, 3 H), 1.21ꢀ1.36 (m, 7 H), 1.40ꢀ1.50 (m, 2 H), 1.54ꢀ1.65 (m, 1
H), 1.72ꢀ1.84 (m, 1 H), 1.91ꢀ2.00 (m, 2 H), 2.09 (s, 3 H), 2.55ꢀ2.67
(m, 2 H), 3.17 (td, J = 5.3, 1.1 Hz, 1 H), 3.25 (d, J = 1.2 Hz, 1 H),
3.69ꢀ3.82 (m, 2 H), 4.05 (d, J = 8.7 Hz, 1 H), 5.30 (dd, J = 7.9, 2.3 Hz, 1
H), 7.22ꢀ7.36 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ (major) 14.0,
15.2, 15.8, 19.3, 22.5, 25.7, 27.6, 28.9, 29.3, 29.5, 30.8, 31.6, 54.4, 55.1,
58.8, 65.7, 87.7, 89.9, 165.6; FAB HRMS (NBA) m/e 344.2261, M þ Hþ
calcd for C18H32NO3S 344.2259.
Epoxy Amide 17d. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(70%): colorless oil; [R]25 = þ123.0 (c 1.6, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 2.3:1 ratio) δ (major) 1.67ꢀ1.76
(m, 2 H), 2.09 (s, 3 H), 2.36ꢀ2.50 (m, 1 H), 2.50ꢀ2.63 (m, 1 H),
3.30ꢀ3.44 (m, 2 H), 3.57 (d, J = 1.9 Hz, 1 H), 3.77 (s, 3 H), 3.91ꢀ4.04
(m, 2 H), 3.97 (d, J = 1.7 Hz, 1 H), 4.25 (s, 2 H), 4.44ꢀ4.56 (m, 1 H),
5.54 (dd, J = 8.9, 1.8 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.03ꢀ7.08 (m, 1
H), 7.15 (d, J = 8.7 Hz, 2 H), 7.21ꢀ7.34 (m, 4 H); 13C NMR (100 MHz,
CDCl3) δ (major) 15.2, 29.2, 30.7, 55.2, 58.1, 67.9, 70.5, 73.5, 89.5,
114.2, 127.1, 127.7, 127.9, 128.4, 160.1, 165.0; FAB HRMS (NBA) m/e
444.1856, M þ Hþ calcd for C24H29NO5S 444.1845.
Epoxy Amide 17e. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(50%): colorless oil; [R]25 = þ105.7 (c 1.6, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 2.8:1 ratio) δ (major) 1.60ꢀ1.75
(m, 2 H), 2.07 (s, 3 H), 2.33ꢀ2.48 (m, 1 H), 2.49ꢀ2.61 (m, 1 H), 3.30
(dd, J = 9.2, 6.9 Hz, 1 H), 3.35 (dd, J = 9.9, 3.1 Hz, 1 H), 3.51 (d, J = 1.8
Hz, 1 H), 3.92ꢀ3.97 (m, 1 H), 3.97 (d, J = 1.7 Hz, 1 H), 4.05 (dd, J = 9.2,
5.3 Hz, 1 H), 4.24 (s, 2 H), 4.40ꢀ4.54 (m, 1 H), 5.52 (dd, J = 8.9, 1.8 Hz,
1 H), 6.98ꢀ7.03 (m, 1 H), 7.09 (d, J = 8.5 Hz, 2 H), 7.14ꢀ7.31 (m, 6 H);
13C NMR (100 MHz, CDCl3) δ (major) 15.2, 29.2, 30.6, 55.3, 58.0,
67.8, 70.6, 73.5, 89.6, 127.0, 127.7, 128.0, 128.5, 129.0, 134.0, 136.9,
164.6; FAB HRMS (NBA) m/e 448.1356, M þ Hþ calcd for
C23H26ClNO4S 448.1349.
Epoxy Amide 17g. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(48%): colorless oil; [R]25D = þ47.2 (c 1.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) (two rotamers in a 2.4:1 ratio) δ (major) 0.86 (d, J = 7.0
Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 1.59ꢀ1.71 (m, 1 H), 2.04 (s, 3 H),
2.26ꢀ2.36 (m, 1 H), 2.44ꢀ2.60 (m, 3 H), 2.88 (dd, J = 6.2, 2.0 Hz, 1 H),
Epoxy Amide 17a. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(76%): colorless oil; [R]25 = þ127.0 (c 1.9, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 2.3:1 ratio) δ (major) 1.66ꢀ1.79
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3.26 (d, J = 2.0 Hz, 1 H), 3.43 (bs, 1 H), 3.99ꢀ4.09 (m, 2 H), 4.25ꢀ4.33
(m, 1 H), 4.48 (s, 2 H), 5.46 (dd, J = 8.9, 1.9 Hz, 1 H), 7.21ꢀ7.32 (m, 5
H); 13C NMR (100 MHz, CDCl3) δ (major) 18.2, 29.3, 55.0, 53.2, 55.3,
63.5, 67.9, 70.4, 73.6, 89.4, 127.8, 128.0, 128.4, 128.6, 166.0; FAB HRMS
(NBA) m/e 380.1905, M þ Hþ calcd for C20H29NO4S 380.1896.
Epoxy Amide 17h. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(49%): colorless oil; [R]25D = þ48.9 (c 0.7, CH2Cl2); 1H NMR (400
MHz, CDCl3) (two rotamers in a 2.8:1 ratio) δ (major) 0.93ꢀ1.33 (m,
6 H), 1.50ꢀ1.78 (m, 8 H), 2.06 (s, 3 H), 2.42ꢀ2.63 (m, 2 H), 3.30 (d, J =
2.0 Hz, 1 H), 3.41ꢀ3.47 (m, 2 H), 4.00ꢀ4.10 (m, 1 H), 4.26ꢀ4.35 (m, 2
H), 4.49 (s, 2 H), 5.47 (dd, J = 8.8, 1.7 Hz, 1 H), 7.22ꢀ7.35 (m, 5 H);
13C NMR (100 MHz, CDCl3) δ (major) 15.2, 25.4, 25.6, 26.0, 28.8,
29.0, 29.2, 29.7, 30.7, 30.9, 38.9, 53.0, 55.1, 62.4, 68.0, 70.4, 73.6, 89.4,
127.8, 128.6, 137.3, 166.1; FAB HRMS (NBA) m/e 420.2215, M þ Hþ
calcd for C23H33NO4S 420.2209.
Epoxy Amide 17i. Preparation by procedure B and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(51%): colorless oil; 1H NMR (400 MHz, CDCl3) (two rotamers in a
2.4:1 ratio) δ (major) 0.86 (t, J = 6.9 Hz, 3 H), 1.14ꢀ1.36 (m, 9 H),
1.62ꢀ1.74 (m, 1 H), 1.84ꢀ2.02 (m, 2 H), 2.08 (s, 3 H), 2.48ꢀ2.61 (m, 2
H), 3.03 (dt, J = 8.0, 2.0 Hz, 1 H), 3.23 (d, J = 2.0 Hz, 1 H), 3.41ꢀ3.49
(m, 2 H), 3.60ꢀ3.73 (m, 1 H), 4.07 (s, 2 H), 4.51 (s, 2 H), 5.51 (dd, J =
8.8, 1.7 Hz, 1 H), 7.23ꢀ7.35 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ
(major) 15.2, 16.5, 18.3, 18.5, 19.7, 23.2, 23.3, 29.1, 29.3, 29.8, 30.8, 53.2,
55.0, 63.5, 67.9, 70.4, 73.5, 73.6, 83.3, 89.4, 127.7, 127.8, 128.1, 128.5,
128.6, 137.4, 165.9; FAB HRMS (NBA) m/e 422.2371, M þ Hþ calcd
for C23H35NO4S 422.2365.
127.7, 128.0, 128.3, 128.5, 130.1, 133.7, 136.3, 137.2, 166.3; FAB HRMS
(NBA) m/e 428.1892, M þ Hþ calcd for C24H29NO4S 428.1896.
Epoxy Amide 18d. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(72%): colorless oil; [R]25 = ꢀ77.8° (c 1.5, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 4.1:1 ratio) δ (major) 1.77ꢀ1.84
(m, 1 H), 2.11 (s, 3 H), 2.36ꢀ2.44 (m, 1 H), 2.55ꢀ2.60 (m, 2 H), 3.52
(dd, J = 9.4, 6.6 Hz, 1 H), 3.58 (dd, J = 9.3, 7.5 Hz, 1 H), 3.81 (s, 3 H),
3.85 (dd, J = 9.1, 5.6 Hz, 1 H), 3.90 (d, J = 1.9 Hz, 1 H), 3.98 (d, J = 1.9
Hz, 1 H), 4.00 (d, J = 9.1 Hz, 1 H), 4.20 (dd, J = 12.7, 6.5 Hz, 1 H), 4.55
(s, 2 H), 5.36 (dd, J = 7.4, 2.4 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 2 H), 7.18 (d,
J = 8.7 Hz, 2 H), 7.29ꢀ7.37 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ
(major) 15.2, 28.7, 33.6, 55.3, 55.6, 57.2, 57.6, 68.6, 71.0, 73.5, 89.6,
114.1, 127.2, 127.7, 128.0, 128.5, 137.3, 160.2, 166.3; FAB HRMS
(NBA) m/e 444.1849, M þ Hþ calcd for C24H29NO5S 444.1845.
Epoxy Amide 18e. Preparation by procedure A and purification by
flash column chromatography (silica gel, 30% EtOAc in hexanes)
(78%): colorless oil; [R]25 = ꢀ79.7° (c 1.7, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 4.6:1 ratio) δ (major) 1.82ꢀ1.90
(m, 1 H), 2.17 (s, 3 H), 2.43ꢀ2.51 (m, 1 H), 2.62ꢀ2.67 (m, 2 H), 3.59
(dd, J = 9.3, 6.3 Hz, 1 H), 3.65 (dd, J = 9.1, 8.1 Hz, 1 H), 3.94 (dd, J = 9.2,
5.8 Hz, 1 H), 3.96 (d, J = 1.8 Hz, 1 H), 4.06 (d, J = 8.9 Hz, 1 H), 4.08 (d,
J = 1.8 Hz, 1 H), 4.25 (dd, J = 12.8, 6.3 Hz, 1 H), 4.61 (s, 2 H), 5.43 (dd,
J = 7.5, 2.3 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.30ꢀ7.44 (m, 7 H); 13
C
NMR (100 MHz, CDCl3) δ (major) 15.2, 28.6, 33.4, 55.7, 57.0, 57.3,
68.6, 71.0, 73.5, 89.6, 127.1, 127.7, 128.0, 128.5, 128.8, 133.9, 134.6,
137.1, 165.8; FAB HRMS (NBA) m/e 448.1343, M þ Hþ calcd for
C23H26ClNO4S 448.1349.
Epoxy Amide 18g. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes) (77%
combined yield of 18g together with its cis isomer): colorless oil; H
Epoxy Amide 18a. Preparation by procedure B and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(57%): colorless oil; [R]25D = ꢀ83.2 (c 1.5, CH2Cl2); 1H NMR (400
MHz, CDCl3) (two rotamers in a 4:1 ratio) δ (major) 1.76ꢀ1.87 (m, 1
H), 2.11 (s, 3 H), 2.37ꢀ2.48 (m, 1 H), 2.56ꢀ2.61 (m, 2 H), 3.52 (dd, J =
9.4, 6.6 Hz, 1 H), 3.58 (dd, J = 9.3, 7.6 Hz, 1 H), 3.86 (dd, J = 9.1, 5.7 Hz,
1 H), 3.91 (d, J = 1.9 Hz, 1 H), 4.01 (d, J = 9 0.1 Hz, 1 H), 4.04 (d, J = 1.8
Hz, 1 H), 4.20 (dd, J = 12.7, 6.5 Hz, 1 H), 4.55 (s, 2 H), 5.37 (dd, J = 7.5,
2.4 Hz, 1 H), 7.25ꢀ7.37 (m, 10 H); 13C NMR (100 MHz, CDCl3) δ
(major) 15.2, 28.7, 33.6, 55.6, 57.3, 57.7, 68.6, 70.9, 73.5, 89.6, 125.8,
127.7, 128.0, 128.5, 128.6, 128.8, 130.1, 135.4, 137.3, 166.2; FAB HRMS
(NBA) m/e 414.1735, M þ Hþ calcd for C23H27NO4S 414.1739.
Epoxy Amide 18b. Preparation by procedure B and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
1
NMR (400 MHz, CDCl3) (mixture of E:Z isomers in a 1.3:1 proportion
and the E isomer as two rotamers in a 4:1 ratio) δ (E isomer, major
rotamer) 0.96 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H), 1.63 (td, J =
13.5, 6.8 Hz, 1 H), 1.68ꢀ1.79 (m, 1 H), 1.92ꢀ2.09 (m, 2 H), 2.06 (s, 3
H), 2.26ꢀ2.36 (m, 1 H), 2.51ꢀ2.55 (m, 2 H), 2.88 (dd, J = 6.5, 2.0 Hz, 1
H), 3.45ꢀ3.54 (m, 2 H), 3.54 (d, J = 1.9 Hz, 1 H), 4.06 (dd, J = 13.3, 9.0
Hz, 1 H), 4.18 (dt, J = 12.8, 6.5 Hz, 1 H), 4.52 (d, J = 11.8 Hz, 1 H), 4.57
(d, J = 11.9 Hz, 1 H), 5.28 (dd, J = 7.6, 2.5 Hz, 1 H), 7.26ꢀ7.35 (m, 5 H);
13C NMR (100 MHz, CDCl3) δ (major) 16.6, 19.6, 23.16, 23.24, 29.1,
29.7, 39.3, 53.2, 55.1, 63.5, 68.0, 70.4, 73.5, 83.2, 89.4, 127.8, 128.1,
128.6, 137.3, 166.1; FAB HRMS (NBA) m/e 380.1889, M þ Hþ calcd
for C20H29NO4S 380.1896.
(90%): colorless oil; [R]25 = ꢀ61.3° (c 1.4, CH2Cl2); 1H NMR
D
Epoxy Amide 18h. Preparation by procedure B and purification by
flash column chromatography (silica gel, 50% EtOAc in hexanes) (83%
combined yield of 18h together with its cis isomer): colorless oil;
(400 MHz, CDCl3) (two rotamers in a 4.3:1 ratio) δ (major) 1.73ꢀ1.82
(m, 1 H), 2.09 (s, 3 H), 2.34 (s, 3 H), 2.34ꢀ2.43 (m, 1 H), 2.53ꢀ2.58
(m, 2 H), 3.49 (dd, J = 9.3, 6.6 Hz, 1 H), 3.55 (dd, J = 9.2, 7.6 Hz, 1 H),
3.83 (dd, J = 9.1, 5.7 Hz, 1 H), 3.88 (d, J = 1.9 Hz, 1 H), 3.97ꢀ3.99 (m, 2
H), 4.17 (dd, J = 12.9, 6.7 Hz, 1 H), 4.52 (s, 2 H), 5.34 (dd, J = 7.5, 2.4
Hz, 1 H), 7.09ꢀ7.18 (m, 4 H), 7.26ꢀ7.36 (m, 5 H); 13C NMR (100
MHz, CDCl3) δ (major) 15.2, 21.2, 28.7, 33.5, 55.6, 57.2, 57.7, 68.6,
70.9, 73.5, 89.6, 125.8, 127.7, 128.0, 128.5, 129.3, 132.3, 138.8, 166.3;
FAB HRMS (NBA) m/e 428.1905, M þ Hþ calcd for C24H29NO4S
428.1896.
[R]25 = ꢀ12.3° (c 2.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
D
(mixture of E:Z isomers in a 2.1:1 proportion and the E isomer as two
rotamers in a 4.6:1 ratio) δ (E isomer, major rotamer) 1.01ꢀ1.26 (m,
7 H), 1.59ꢀ1.81 (m, 6 H), 1.90ꢀ2.06 (m, 2 H), 2.06 (s, 3 H), 2.26ꢀ2.36
(m, 1 H), 2.49ꢀ2.55 (m, 2 H), 2.88 (dd, J = 8.6, 2.0 Hz, 1 H), 3.50 (dd,
J = 11.4, 4.1 Hz, 1 H), 3.55 (d, J = 2.1 Hz, 1 H), 4.05 (dd, J = 13.7, 9.1 Hz,
1 H), 4.52 (d, J = 12.6 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 5.28 (dd, J =
7.3, 2.2 Hz, 1 H), 7.27ꢀ7.35 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ
(major) 15.2, 25.0, 25.3, 26.0, 28.6, 29.0, 29.4, 33.8, 39.4, 52.5, 54.0, 62.4,
68.7, 70.6, 73.5, 89.2, 127.7, 128.0, 128.5, 137.2, 166.8;); FAB HRMS
(NBA) m/e 420.2212, M þ Hþ calcd for C23H33NO4S 420.2209.
Synthesis of Epoxy Alcohols 3 and 4. General Procedure A.
To a solution of epoxyamide 7, 17, 10, or 18 (1.0 equiv) in dry THF (0.1
M) was added Super-H (1 M in THF, 2.5 equiv) at 0 °C. The mixture
was stirred for 30 min at this temperature prior to be quenched by
carefully addition of a saturated aqueous of NH4Cl solution. Dilution
with diethyl ether was followed by separation of both phases, and the
aqueous phase was extracted twice with more diethyl ether. The organic
Epoxy Amide 18c. Preparation by procedure A and purification by
flash column chromatography (silica gel, 20% EtOAc in hexanes)
(60%): colorless oil; [R]25 = ꢀ24.2° (c 1.9, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) (two rotamers in a 4.4:1 ratio) δ (major) 1.76ꢀ1.84
(m, 1 H), 2.12 (s, 3 H), 2.37ꢀ2.45 (m, 1 H), 2.40 (s, 3 H), 2.55ꢀ2.61
(m, 2 H), 3.52 (td, J = 8.2, 1.7 Hz, 1 H), 3.58 (ddd, J = 9.1, 7.4, 1.6 Hz, 1
H), 3.76 (d, J = 1.9 Hz, 1 H), 3.86 (ddd, J = 8.9, 5.6, 1.6 Hz, 1 H), 4.06 (d,
J = 9.0 Hz, 2 H), 4.19 (d, J = 1.7 Hz, 1 H), 4.24 (t, J = 6.5 Hz, 1 H),
4.51ꢀ4.58 (m, 2 H), 5.39 (dt, J = 7.5, 1.8 Hz, 1 H), 7.17ꢀ7.21 (m, 4 H),
7.23ꢀ7.35 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ (major) 15.2,
18.9, 28.8, 33.6, 55.7, 55.9, 56.5, 68.7, 70.7, 73.5, 89.6, 124.4, 126.2,
3147
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The Journal of Organic Chemistry
ARTICLE
layer was washed with brine, dried over anhydrous MgSO4, and filtered.
The solvents were then removed by evaporation under reduced pres-
sure, and the crude product purified by flash column chromatography
(silica gel, 20% f 50% AcOEt in hexanes) to obtain pure epoxy alcohol.
Epoxy Alcohol 3a. 72% from epoxy amide 7a, 96% from epoxy amide
17a. Identical physical and spectroscopic data as reported in the
literature.33
Epoxy Alcohols 4g:30g. 45% combined yield from a 1.3:1 mixture of
epoxy amides 10g:70g, 41% combined yield from a 1.3:1 mixture of
epoxy amides 18g:170g. Separation by flash column chromatography
(silica gel, 20% AcOEt in hexanes) provided pure epoxy alcohols 4g
(25%) and 30g (20%). 4g: Identical physical and spectroscopic data as
reported in the literature.42 30g: Identical physical and spectroscopic data
as reported in the literature:18b Rf = 0.47 (silica gel, 50% AcOEt in
hexanes); [R]25D = ꢀ25.6 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.96 (d, J = 6.9 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 1.43ꢀ1.53 (m, 1 H),
2.72 (dd, J = 9.4, 4.4 Hz, 1 H), 3.18 (dt, J = 7.3, 4.3 Hz, 1 H), 3.68 (dd,
J = 12.2, 7.1 Hz, 1 H), 4.04 (dd, J = 12.0, 4.5 Hz, 1 H).
Epoxy Alcohol 3b. 76% from epoxy amide 7b, 87% from epoxy amide
17b. Identical physical and spectroscopic data as reported in the literature.34
Epoxy Alcohol 3c. 51% from epoxy amide 7c, 54% from epoxy amide
17c. 3c: colorless oil; Rf = 0.50 (silica gel, 50% AcOEt in hexanes);
[R]25 = ꢀ0.63 (c 1.0, CH2Cl2); IR (neat) νmax: 3395, 3023, 2919,
Epoxy Alcohols 4h:30h. 45% combined yield from a 2.1:1 mixture of
epoxy amides 18h:170 h.
D
2868 cmꢀ1;1H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.12 (m, 4 H), 4.05
(d, J = 2.3 Hz, 1 H), 3.85ꢀ3.78 (m, 1 H), 3.88 (d, J = 2.2 Hz, 1 H), 3.77
(ddd, J = 12.7, 7.6, 3.9 Hz, 1 H), 3.21 (dt, J = 4.0, 2.3 Hz, 1 H), 2.33 (s, 3
H), 1.92 (dd, J = 7.6, 5.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 18.7,
53.5, 61.2, 61.4, 124.2, 126.0, 127.7, 129.7, 134.9, 135.8; FAB HRMS
(NBA) m/e 187.0737, M þ Naþ calcd for C10H12O2 187.0735.
Epoxy Alcohol 3d. 75% from epoxy amide 7d, 73% from epoxy amide
17d. Identical physical and spectroscopic data as reported in the
literature.35
Epoxy Alcohols 4i:30i. 52% combined yield from a 1.4:1 mixture of
epoxy amides 10i:70i. Separation by flash column chromatography
(silica gel, 20% AcOEt in hexanes) provided pure epoxy alcohols 4i
(30%) and 30i (22%). 4i: Identical physical and spectroscopic data as
reported in the literature:38 white foam; Rf = 0.39 (silica gel, 30% AcOEt
1
in hexanes); [R]25 = ꢀ22.5° (c 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 0.88 (t, J = 7.0 Hz, 3 H), 1.25ꢀ1.37 (m, 6 H), 1.41ꢀ1.46 (m, 2
H), 1.54ꢀ1.59 (m, 2 H), 1.89 (dd, J = 6.5, 6.1 Hz, 1 H), 2.92 (dt, J = 4.9,
2.5 Hz, 1 H), 2.95 (dt, J = 5.7, 2.5 Hz, 1 H), 3.61 (ddd, J = 11.5, 7.0, 4.4
Hz, 1 H), 3.90 (ddd, J = 12.6, 5.3, 2.6 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 22.4, 25.8, 28.9, 31.5, 31.6, 56.0, 58.7, 61.9. 30i: Identical
physical and spectroscopic data as reported in the literature:18d white
Epoxy Alcohol 3e. 71% from epoxy amide 7e, 50% from epoxy amide
17e. Identical physical and spectroscopic data as reported in the
literature.36
Epoxy Alcohol 3f. 44% from epoxy amide 7f. Identical physical and
spectroscopic data as reported in the literature.37
foam; Rf = 0.43 (silica gel, 30% AcOEt in hexanes); [R]25 = ꢀ2.9°
D
(c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J = 6.9 Hz, 3
H), 1.28ꢀ1.48 (m, 6 H), 1.48ꢀ1.76 (m, 5 H), 3.06 (ddd, J = 6.8, 5.5, 4.4
Hz, 1 H), 3.18 (dt, J = 6.9, 4.2 Hz, 1 H), 3.71 (ddd, J = 12.1, 6.8 Hz, 1 H),
3.84ꢀ3.92 (m, 1 H).
Epoxy Alcohol 3g. 69% from epoxy amide 7g, 47% from epoxy amide
17g. Identical physical and spectroscopic data as reported in the
literature.18c
Epoxy Alcohol 3h. 65% from epoxy amide 7h, 69% from epoxy amide
17h. Identical physical and spectroscopic data as reported in the
literature.18c
Epoxy Alcohol 3i. 62% from epoxy amide 7i, 85% from epoxy amide
17i. Identical physical and spectroscopic data as reported in the
literature.38
General Procedure B. A solution of epoxyamide 10 (1.0 equiv) in dry
THF (0.1 M) was treated with LiBH4 (2 M in THF, 5.0 equiv) at 0 °C to
allowed to reach room temperature. The mixture was stirred for 1 h at
this temperature and then quenched by carefully addition of a saturated
aqueous of NH4Cl solution. Dilution with diethyl ether was followed by
separation of both phases and the aqueous phase was extracted twice
with more diethyl ether. The organic layer was washed with brine, dried
over anhydrous MgSO4 and filtered. The solvents were then removed by
evaporation under reduced pressure, and the crude product purified by
flash column chromatography (silica gel, 20% f 50% AcOEt in
hexanes) to obtain pure epoxy alcohol.
Epoxy Alcohol 4a. 50% from epoxy amide 18a. Identical physical and
spectroscopic data as reported in the literature.39
Epoxy Alcohol 4b. 41% from epoxy amide 10b, 34% from epoxy
amide 18b. Identical physical and spectroscopic data as reported in the
literature.34
Epoxy Alcohol 4c. 45% from epoxy amide 10c, 44% from epoxy
amide 18c. [4c]: colorless oil; Rf = 0.50 (silica gel, 50% AcOEt in
hexanes); [R]25D = þ0.59 (c 1.0, CH2Cl2); IR (neat) νmax 3395, 3023,
2919, 2868 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.12 (m, 4 H),
4.05 (d, J = 2.3 Hz, 1 H), 3.85ꢀ3.78 (m, 1 H), 3.88 (d, J = 2.2 Hz, 1 H),
3.77 (ddd, J = 12.7, 7.6, 3.9 Hz, 1 H), 3.21 (dt, J = 4.0, 2.3 Hz, 1 H), 2.33
(s, 3 H), 1.92 (dd, J = 7.6, 5.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
18.7, 53.5, 61.2, 61.4, 124.2, 126.0, 127.7, 129.7, 134.9, 135.8; FAB
HRMS (NBA) m/e 187.0742, M þ Naþ calcd for C10H12O2 187.0735.
Epoxy Alcohol 4d. 38% from epoxy amide 10d, 52% from epoxy
amide 18d. Identical physical and spectroscopic data as reported in the
literature.35
Epoxy Alcohol 4a. 34% from epoxy amide 10a. Identical physical and
spectroscopic data as reported in the literature.39
Epoxy Alcohol 4e. 43% from epoxy amide 10e. Identical physical and
spectroscopic data as reported in the literature.40
Epoxy Alcohols 4h:30h. 41% combined yield from a 1.4:1 mixture of
epoxy amides 10 h:70h). Separation by flash column chromatography of
the crude obtained of the reduction of the mixture 10 h:70h (silica gel,
20% AcOEt in hexanes) provided pure epoxy alcohols 4h (24%) and 30h
(17%). 4h: Identical physical and spectroscopic data as reported in the
literature.18c 30h: Identical physical and spectroscopic data as reported in
the literature:18c Rf = 0.55 (silica gel, 50% AcOEt in hexanes); [R]25
=
D
þ5.6 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.09ꢀ1.27 (m, 6
H), 1.60ꢀ1.76 (m, 5 H), 1.96 (bd, 1 H), 2.79 (dd, J = 9.4, 4.3 Hz, 1 H),
3.18 (dt, J = 7.5, 4.3 Hz, 1 H), 3.68 (ddd, J = 15.5, 12.0, 7.4 Hz, 1 H), 3.85
(ddd, J = 15.5, 12.0, 4.5 Hz, 1 H).
Epoxy Alcohol 4e. 37% from epoxy amide 18e. Identical physical and
spectroscopic data as reported in the literature.40
Epoxy Alcohols 4f:30f. 42% combined yield from a 1.3:1 mixture of
epoxy amides 10f:70f. Separation by flash column chromatography
(silica gel, 20% AcOEt in hexanes) provided pure epoxy alcohols 4f
(24%) and 30f (18%). 4f: Identical physical and spectroscopic data as
reported in the literature.41 30f: Identical physical and spectroscopic data
as reported in the literature:18a Rf = 0.42 (silica gel, 40% AcOEt in
’ ASSOCIATED CONTENT
hexanes); [R]25 = þ13.0 (c 0.6, CH2Cl2); 1H NMR (400 MHz,
S
Supporting Information. Experimental procedures and
b
D
spectroscopic data of all new compounds, as well as 1H- and 13
C
CDCl3) δ 1.07 (t, J = 7.5 Hz, 3 H), 1.49ꢀ1.71 (m, 2 H), 3.03 (dd, J = 6.9,
6.0, 4.4 Hz, 1 H), 3.19 (dt, J = 7.0, 4.2 Hz, 1 H), 3.70 (dd, J = 12.1, 6.9 Hz,
1 H), 3.88 (dd, J = 12.0, 3.7 Hz, 1 H).
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
3148
dx.doi.org/10.1021/jo1025964 |J. Org. Chem. 2011, 76, 3139–3150

The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519.
Corresponding Author
*Fax: 34-952 131941. E-mail: frsarabia@uma.es.
(16) See Supporting Information for details of the analyses by HPLC
and GCꢀMS for the determination of the ee's.
(17) The NMR spectra of epoxyamides 10fꢀi showed great com-
plexity due to the presence of not only a mixture of Z:E epoxyamides but
also the existence of rotamers around the amide bond. These
complex spectra were quite simplified when the epoxyamides were
transformed into their corresponding epoxyalcohols, allowing confirma-
tion by 1H NMR spectra the presence of a mixture of cis:trans
epoxyalcohols whose proportions were determined directly from the
crude reactions.
’ ACKNOWLEDGMENT
This work was financially supported by Ministerio de
Educaciꢀon y Ciencia (CTQ2007-66518), Junta de Andalucía
(FQM-03329), CNIO (Spanish National Cancer Research Cen-
ter) and a fellowship from Fundaciꢀon Ramꢀon Areces (M.G.-C.).
We thank Dr. J. I. Trujillo from Pfizer (Groton, CT) for
assistance in the preparation of this manuscript. We thank the
NMR and SM facilities of Malaga and Granada Universities,
respectively, for spectroscopic assistances.
(18) cis epoxy alcohols 30f, 30g, 30h, and 30i have been described in
the following articles, respectively: (a) Souliꢀe, J.; Pꢀericaud, F.; Lallemand,
J. Y. Tetrahedron: Asymmetry 1995, 6, 1367–1374. (b) Tsuboi, S.; Furutani,
H.; Utaka, M.; Takeda, A. Tetrahedron Lett. 1987, 28, 2709–2712. (c) Li,
X.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 16126–16127. (d) Burke, C. P.;
Shi, Y. Org. Lett. 2009, 11, 5150–5153.
(19) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990,
20, 307–312.
(20) Hayashi, M.; Terashima, S.; Koga, K. Tetrahedron 1981,
37, 2797–2803.
(21) (a) Tessier, A.; Pytkowicz, J.; Brigaud, T. Angew. Chem., Int. Ed.
2006, 45, 3677–3681. (b) Lubin, H.; Tessier, A.; Chaume, G.; Pytkowicz, J.;
Brigaud, T. Org. Lett. 2010, 12, 1496–1499.
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a system in solution by means of a PCM (polarizable continuum model),
choosing ethanol as solvent.
(25) This eclipsed orientation of both polar groups is supported
by rigorous and extensive theoretical studies of this reaction under-
taken by Aggarwal et al.: Aggarwal, V. K.; Jeremy, J. N.; Richardson, J.
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