Peracid dependent stereoselectivity and functional group contribution to the stereocontrol of epoxidation of (E)-alkene dipeptide isosteres

Article abstract of DOI:10.1016/j.tet.2006.01.095

Twelve Boc-protected phenylalanyl-phenylalanine and phenylalanyl-glycine trans-vinyl isosteres were epoxidised with magnesium monoperoxyphtalate hexahydrate (MMPP) and trifluoroperacetic acid, and the results have been compared with those from earlier stu

Full text of DOI:10.1016/j.tet.2006.01.095

Tetrahedron 62 (2006) 3600–3609
Peracid dependent stereoselectivity and functional group
contribution to the stereocontrol of epoxidation of (E)-alkene
dipeptide isosteres
Daniel Wiktelius,a Wei Berts,b Annika Jenmalm Jensen,b Joachim Gullbo,c Stina Saitton,a
d
Ingeborg Csoregh and Kristina Luthman
a,
*
¨
a
¨
¨
Department of Chemistry, Medicinal Chemistry, Goteborg University, SE-412 96 Goteborg, Sweden
bBiovitrum AB, Medicinal Chemistry, PO Box 6443, SE-751 37 Uppsala, Sweden
cDepartment of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
dDepartment of Structural Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden
Received 19 October 2005; revised 9 January 2006; accepted 26 January 2006
Abstract—Twelve Boc-protected phenylalanyl-phenylalanine and phenylalanyl-glycine trans-vinyl isosteres were epoxidised with
magnesium monoperoxyphtalate hexahydrate (MMPP) and trifluoroperacetic acid, and the results have been compared with those from
earlier studies on epoxidations with m-CPBA. The alkenes were synthesised in high yields with high E/Z-selectivities using either the Julia or
Schlosser reactions. The formation of threo isomers was favoured in all epoxidation reactions except with CF3CO3H on substrates containing
two allylic/homoallylic functional groups directing the peracid to opposite faces of the alkene. The switch to erythro selectivity observed
with CF3CO3H is suggested to emanate from coordination to the allylic ester functionalities via hydrogen bond donation from the peracid.
The other peracid reagents seem to be preferentially coordinated to the allylic carbamate function. The contribution of individual functional
groups to the stereopreference was also investigated.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselective epoxidation of structurally more complex
alkenes. In these studies, Boc-protected phenylalanyl-
phenylalanine (Phe-Phe) and phenylalanyl-glycine (Phe-
Gly) derived epoxides (2a–l, 3a–l) were synthesised by
m-CPBA treatment of the Phe-Phe and Phe-Gly vinyl
isosteres 1a–l, possessing two stereogenic centres and
different oxygen containing functional groups at the
C-terminus of the pseudo-dipeptide (Scheme 1).5 The
reactions are highly stereoselective with the formation of
threo isomers being favoured.
Stereoselective epoxidation reactions have been studied
experimentally1,2 and theoretically3 to a great extent over the
years. Peracids are still commonly used, although several
novel epoxidation reagents have been developed.4 However,
these new, usually metal-based reagents, have mainly been
studied using simpler mono- or non-functionalised alkenes.
In a project aimed at the synthesis and use of functionalised
dipeptidomimetics we have for some time studied the
g: R=CH2OH, R1=Bn, R2=H
h: R=CH2OH, R1=Bn, R2=Bn
i: R=CH2OAc, R1=H, R2=H
j: R=CH2OAc, R1=H, R2=Bn
k: R=CH2OAc, R1=Bn, R2=H
l: R=CH2OAc, R1=Bn, R2=Bn
a: R=COOMe, R1=H, R2=H
b: R=COOMe, R1=H, R2=Bn
c: R=COOMe, R1=Bn, R2=H
d: R=COOMe, R1=Bn, R2=Bn
e: R=CH2OH, R1=H, R2=H
f: R=CH2OH, R1=H, R2=Bn
Epoxidation
O
O
+
R
R
R
BocNH
BocNH
BocNH
R2
R2
R2
R1
R1
R1
1a-1l
2a-2l (threo)
3a-3l (erythro)
Scheme 1.
Keywords: Epoxidation; Peracid; Dipeptidomimetics; Stereoselectivity; Allylic functional group; Coordination.
*
Corresponding author. Tel.: C46 31 7722894; fax: C46 31 7723840; e-mail: luthman@chem.gu.se
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.095

D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
3601
The stereoselectivity has been suggested to originate from
cooperative coordination of m-CPBA to the allylic
carbamate and a suitably positioned ester or alcohol
group.6–8
of methyltrioctylammonium chloride as phase-transfer
catalyst. Throughout, the epoxidation reactions with
MMPP were much slower than those using m-CPBA, the
alcohol derivatives 1e–h being the most reactive (Table 1,
entries 5–8). Epoxidation of methyl ester 1a with MMPP
proceeded in only ca. 50% yield even after extensively
prolonged reaction times (17 days). No products were
observed in epoxidation of 1b–d and acetate 1k after 7 days.
The rate of MMPP epoxidations has been proposed to
increase after addition of pyridine to the reaction medium.11
However, in our hands, the reactions became more sluggish
in the presence of catalytic amounts (0.1 equiv) of either
pyridine or 4-dimethylaminopyridine or when using
pyridine as the solvent. Due to the low rates of reaction of
the ester derivatives, we did not consider it practical to
perform the epoxidations on any other acetate derivative in
the series.
In a preliminary study on epoxidation of six Phe-Phe vinyl
isosteres, we used trifluoroperacetic acid (generated from
urea hydrogen peroxide (UHP) and trifluoroacetic anhy-
dride) as oxidant in addition to m-CPBA.9 It was found that
the stereoselectivity was strongly dependent on the choice
of peracid and the functionalities flanking the alkene,
presumably by formation of different hydrogen bonding
patterns between the peracid and the alkenes. Differences in
stereoselectivity between the two peracids have been
reported with cyclic alkenes containing one directing
functional group.10 To gain further understanding of these
phenomena, we have made a more extensive study
including more alkene substrates, and also added mono-
peroxyphthalate hexahydrate (MMPP), a peracid presumed
to possess different hydrogen bonding properties compared
to m-CPBA and trifluoroperacetic acid. A new method for
the synthesis of b,g-unsaturated esters based on the
Schlosser reaction is also disclosed.
The threo/erythro ratios of products in the MMPP
epoxidations were about the same as those in reactions
using m-CPBA (Table 1). Thus, the results indicate that the
phthalic acid motif itself does not contribute to a change in
the reagent–substrate hydrogen bonding interaction
compared to m-CPBA. Consequently, the diastereoselec-
tivity of the MMPP epoxidations may be rationalised by
assuming the same influence of cooperative coordination as
in the reactions with m-CPBA. This coordination may also
explain the increased reactivity of the alcohols (1e–h)
compared to the esters since additional hydrogen bonding
between the substrate and the peracid should lead to an
increased stability of the transition state.
2. Results and discussion
2.1. Peracid epoxidation
2.1.1. Epoxidation of 1a–h and 1k with MMPP. MMPP
has been suggested as a replacement for m-CPBA in
epoxidations and other oxidation reactions. MMPP has
similar chemical properties to m-CPBA but it is considered
safer to use in both small- and large-scale reactions.11 We
expected that MMPP might exhibit different hydrogen
bonding properties to m-CPBA due to the additional ortho-
positioned carboxylate. Compounds 1a–h and 1k were
treated with MMPP in a two-phase system consisting of
chloroform and water at room temperature in the presence
2.1.2. Epoxidation of 1a–l with trifluoroperacetic acid.
Trifluoroperacetic acid11 can be generated in situ from urea-
hydrogen peroxide (UHP) and trifluoroacetic anhydride.
Substrates 1a–l were epoxidised at 0 8C using a mixture of
UHP, trifluoroacetic anhydride, and Na2HPO4 in CH2Cl2.
Throughout, the trifluoroperacetic acid epoxidations were
faster than the reactions with m-CPBA.
Table 1. Reaction conditions, yields and stereochemical results from epoxidations of the olefinic substrates 1a–la
NHBoc
O
NHBoc
Epoxidation
method A, B, Ca
NHBoc
R
R
R
+
R2
R2
R2
O
R1
R1
R1
3a-3l (erythro)
1a-1l
2a-2l (threo)
Entry
Substrate
R
R1
R2
Ratio 2:3 (threo:erythro)b
Isolated yield (%)
Reaction time (h)
A
Bc
C
A
Bc
C
A
Bc
C
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
COOMe
COOMe
COOMe
COOMe
CH2OH
CH2OH
CH2OH
CH2OH
CH2OAc
CH2OAc
CH2OAc
CH2OAc
H
H
Bn
Bn
H
H
Bn
H
Bn
H
Bn
H
Bn
H
Bn
H
88:12
e
89:11
62:38
91:9
84:16
37:63
87:13
87:13
85:15
48:52
88:12
78:22
82:18
36:64
76:24
61:39
46d
0e
81
80
77
90
68
89
89
94
87
84
80
84
79
75
81
86
78
63
82
76
53
71
81
67
408
168
168
168
24
26
30
24
48
44
40
24
12
6
5
5
12
45
24
48
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
e
e
0e
88:12
88:12
60:40
87:13
76:24
83:17
68:32
86:14
79:21
0e
79:21
63:37
88:12
64:36
57
71
76
70
H
Bn
Bn
H
H
Bn
Bn
9
10
11
12
1j
1k
1l
e
0e
168
Bn
a A: MMPP, (C8H17)3NMeCl, CHCl3/H2O, rt; B: m-CPBA, CH2Cl2, rt; C: CF3CO3H, CH2Cl2, 0 8C.
b The relative ratios of epoxide isomers were determined by HPLC and NMR spectroscopy of the crude reaction product.
c Data on m-CPBA epoxidations are taken from Ref. 5c.
d 54% starting material was recovered after 408 h.
e No products were obtained even after long reaction times.

3602
D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
Most substrates followed the general trend affording mainly
threo epoxide isomers in yields comparable to those obtained
with m-CPBA, but a somewhat lower diastereoselectivity was
obtained (Table 1). Interestingly, two substrates (methyl ester
1b and acetate 1j) afforded preferentially erythro products
with threo/erythro diastereomeric ratios of 37:63, and 36:64,
respectively. In contrast, m-CPBA epoxidation of 1b and 1j
produced epoxides in a diastereomeric ratio of 62:38, and
68:32, respectively (Table 1, entries 2 and 10). In the
trifluoroperacetic acid epoxidation reaction of the alcohol
derivative 1f, which has the same absolute configuration at
the stereogenic centres as the ester derivatives 1b and 1j,
stereoselectivity was essentially lost; however, the difference
in threo/erythro ratio from that obtained with m-CPBA was
small (Table 1, entry 6).
The observed change of stereoselectivity for 1b and 1j
indicates that the threo directing effect of the allylic
carbamate is weaker with trifluoroperacetic acid and that
the directing effect from the ester group is dominating. To
gain further information on the directing role of each
functionality, compounds 8a–e having only one directing
functional group, were synthesised and epoxidised.
2.2. Directing effect contribution of allylic functional
groups to the stereoselectivity of m-CPBA and
trifluoroperacetic acid in epoxidation reactions
2.2.1. Synthesis of the alkenes 8a–e. To investigate the
relative influence of the different functional groups on the
stereoselectivity, analogues of 1 with only one functionality
were synthesised and epoxidised. In previous studies,5a,b we
have relied on the Julia olefination reaction14 as a reliable
method for the construction of (E)-alkene peptide isosteres
(i.e., 1). The reaction has good E-selectivity, whilst
preserving the stereochemistry at C-5. The method
was suitable also for the synthesis of the alkenes 8a–d
(Scheme 2) and the allylic carbamate 8e (Table 2) as
described previously.5c The anion of sulfone 5 and
DIBAL$OMe-activated aldehyde 65b were reacted followed
by desulfonylation and deprotection to give the E/Z-isomers
of allylic alcohol 8a in a ratio of 88:12 and 33% total yield.
By-products were formed if the reaction time was
prolonged. An isomeric mixture of by-products from the
epoxidation reaction of 1b with trifluoroperacetic acid was
separated by column chromatography and the structures of
the isomers were determined by NMR spectroscopy to be
oxazolidinone derivatives 4a and 4b,12 probably formed via
an intramolecular ring opening of the corresponding
epoxides by the carbamate carbonyl oxygen. The epoxide
ring opening is probably catalysed by trifluoroacetic acid
generated in the epoxidation reaction. The minor oxazoli-
dinone isomer (4b) was analysed by X-ray crystallo-
graphy,13 which established the stereochemistry at C-4
and C-5 (Fig. 1). The 4S,5S stereochemistry also established
that 4b was formed from the threo epoxide isomer 1b. Both
the threo and erythro epoxides can undergo the cyclisation/
ring opening reaction to form oxazolidinones, but the
reaction rate of the erythro isomer seems to be considerably
higher than that of the threo isomer since a change in the
threo/erythro ratio of epoxides was observed over time.
Epoxidation of 1b gave after 30 min a threo/erythro ratio of
2:3, which changed to 2:1 after 120 min. This is probably
due to formation of by-products preferentially from the
erythro isomer. A decrease of the temperature in
the trifluoroperacetic acid epoxidation suppressed the
by-product formation, that is, epoxidation of 1f produced
10–20% of by-products at 0 8C but no by-products were
observed when the reaction was run at K78 8C.
The Julia reaction has some disadvantages as the procedure
is laborious, and desulfonylation is accomplished using
sodium amalgam. To avoid the hazardous handling of
molten sodium and mercury, an alternative phosphorous
ylide based strategy for forming the double bond from
similar components was investigated. A standard Wittig
reaction between the ylide generated from deprotonation of
phosphonium salt 715 with n-butyllithium and aldehyde 6
(Scheme 2) was expected16 to give predominantly the
Z-isomer of 8a which was indeed found to be the case, the
resulting E/Z-ratio was 12:88. An increased reaction
temperature may sometimes give higher E-selectivity in
the Wittig reaction;16 performing the reaction at 0 8C
resulted in a slightly higher yield of (E)-8a (E/Z 22:78).
To gain further E-selectivity, the Schlosser modification16
of the Wittig reaction was tried (Scheme 2). Deprotonation
of 7 with n-butyllithium at K78 8C and addition of aldehyde
6, was followed by a second equivalent of n-butyllithium at
K41 8C and the b-oxido ylide was protonated with tert-
butanol. No improvement of the E-selectivity was found, the
E/Z-ratio was 19:81. Attempts to further optimise the
reaction by trying different temperatures were made, but it
was not until the base was changed to phenyllithium that
any change in selectivity was found, the E/Z-ratio was
essentially reversed to 87:13 and the alcohol 8a was
obtained in 61% total yield (Scheme 2). An explanation of
the dependence of E-selectivity on the choice of alkyl-
lithium was presented by Schlosser and co-workers during
the course of this study.17
OH
OH
COOMe
COOMe
HN
HN
O
O
O
O
4a
4b
O2
C1
C21
C20
O3
C2
C19
C16
C10
C11
C15
C14
O1
C9
C8
C3
C17
C12
C4
C18
C5
C6
C7
O4
N1
C13
Alcohol 8a was further transformed into acetate 8b and
trifluoroacetate 8c by treatment with acetic anhydride and
trifluoroacetic anhydride, respectively (Scheme 2). Methyl
ester 8d was prepared by oxidation of 8a in two steps, first
with the Dess–Martin periodinane to the corresponding
O5
Figure 1. Perspective ORTEP view of the crystal structure of 4b (CCDC
no. 102769),13 showing 50% probability displacement ellipsoids. Hydro-
gens are included to clarify the absolute configuration of chiral atoms.

D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
3603
OH
a
b
PPh3Br
SO2Ph
c
OTBDMS
5
7
O
OTBDMS
H
(±)-6
OAc
(±)-8b
d
6
O
3
1
5
e
f
COOMe
2
H
OCOCF3
OH
4
7
(±)-8c
(±)-8d
(±)-8a
Scheme 2. Reagents, reaction conditions and yields: (a) (1) MsCl, Et3N, CH2Cl2, 0 8C; (2) PhSH, NaOMe, THF/MeOH, rt; (3) m-CPBA, CH2Cl2, 0 8C–rt (73%
over three steps). (b) (1) (i) n-BuLi, THF, K78 8C; (ii) 6$DIBAL$OMe; (2) Na(Hg), Na2HPO4, MeOH, 0 8C; (3) HF, ACN, rt (33% over three steps, E/Z
88:12). (c) (1) (i) PhLi, THF, K60 8C; (ii) 6, K60 to K41 8C; (iii) PhLi; (iv) MeOH; (v) t-BuOK K41 8C–rt; (2) TBAF, THF, rt (61% over two steps, E/Z
87:13). (d) Ac2O, DMAP, Et3N, rt (94%). (e) (CF3CO)2O, Et3N, CH2Cl2, rt (81%). (f) (1) Dess–Martin periodinane, ACN/CH2Cl2, 0 8C–rt; (2) PDC, MeOH,
DMF, rt (40% over two steps).
Table 2. Reaction conditionsa and results of epoxidation of alkenes 8a–e with m-CPBA and CF3CO3H
R
R
R
O
O
peracid
+
(±)-8a-e
9a-e (syn)
10a-e (anti )
(relative stereochemistry indicated)
Entry
Substrate
R
Ratio 9:10 (syn/anti)b
Isolated yield (%)
Reaction time (h)
m-CPBA CF3CO3H
m-CPBA
CF3CO3H
m-CPBA
CF3CO3H
1
2
3
4
5
(G)-8a
(G)-8b
(G)-8c
(G)-8d
(G)-8e
CH2OH
71:29
60:40
63:37
67:33
76:24d
72:28
69:31
64:36
79:21
66:33e
93
82
82c
86
80
74
68
88c
80
79
2
5
15
24
29
0.5
2
5
4
0.5
CH2OAc
CH2OCOCF3
COOMe
NHBoc
a Reactions with m-CPBA were performed at room temperature and reactions with CF3CO3H at 0 8C.
b Determined by HPLC and NMR of the crude reaction product.
c The yields refer to the crude product.
d Data taken from Ref. 5c.
e The reaction was run at K78 8C since the anti isomer was unstable at 0 8C.
aldehyde (oxidation with PCC gave substantial decompo-
sition of the product), which was reacted with PDC and
methanol18 to form the unstable b,g-unsaturated ester 8d.
Formation of the corresponding carboxylic acid had to be
avoided since it was found to decompose immediately by
decarboxylation.
We observed that the epoxidations of 8b–d using
trifluoroperacetic acid were more syn-stereoselective
than when using m-CPBA (Table 2, entries 2–4),
which is in accord with an earlier report.10 However,
the syn-directing effect of the allylic carbamate group in
8e was significantly decreased in the trifluoroperacetic
acid epoxidation (Table 2, entry 5). No significant
difference in stereoselectivity between the peracid in
epoxidation of alcohol 8a was found (Table 2, entry 1).
These results again suggest that the two peracids have
different preferences of coordination to different
functional groups. Apparently, trifluoroperacetic acid
coordinates more favourably to the methyl ester than
to the allylic carbamate, alcohol, and acetate moieties.
In contrast, m-CPBA coordinates better to the allylic
carbamate than to the alcohol or ester functions. This is
in line with the results found in our previous study of
epoxidations of derivatives of 1f in which the functional
groups direct the peracid to different faces of the
alkene.9
2.2.2. Epoxidation of the alkenes 10a–e. The alkenes 8a–e
were reacted with trifluoroperacetic acid and m-CPBA to
give diastereomeric mixtures of epoxides 9a–e (syn) and
10a–e (anti). The results are listed in Table 2. The
stereochemical assignment of epoxides 9 and 10 was
based on NMR-data. Consistent chemical shift differences
between signals of the epoxide isomers observed in earlier
studies5b,c was used also in the assignments of 9 and 10.
Diagnostic NMR spectral data of epoxide 9a–b and 10a–b
are given in Table 3 and NMR data used for identification of
epoxides 9d and 10d are given in Table 4. Epoxides 9c and
10c were identified by chemical correlation with 9a and 10a
via methanolysis.

3604
D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
1
Table 3. Selected H and 13C NMR shifts (in ppm) for assignment of the
DR
L
relative stereochemistry of epoxides 9a, 10a, 9b and 10ba,b
S
DR
S = small
L= large
DR= directing group
S
Compound Rel. stereochem.
H-1
H-4
C-1
C-7
L
2f
3f
2g
3g
9a
10a
syn
anti
syn
anti
syn
anti
3.67
3.46
3.67
3.54
3.71
3.45
2.63
2.98
2.56
3.07
2.56
2.96
63.06
62.43
63.50
62.66
64.11
62.50
32.94
34.92
34.22
35.34
31.73
34.69
staggered model
H-eclipsed model
R
R
O
O
O
O
O
R
H
NRR'
O
H
H
O
O
2j
3j
2k
3k
9b
10b
syn
anti
syn
anti
syn
anti
4.11
3.90
4.12
3.95
4.15
3.97
2.48
2.85
2.72
2.77
2.45
2.85
64.49
63.56
64.78
63.83
64.82
63.78
34.52
34.92
34.81
35.13
34.89
34.99
H
H
O
O
H
NCOOR
H
O
H
O
R
R
R
A
B
C
a Data for compounds 2f,g,j,k and 3f,g,j,k are from Ref. 5b and c.
b See Scheme 2 for atom numbering. For compounds 2f, g,j,k and 3f,g,j,k
this implies the corresponding atoms.
Figure 2. Top: proposed transition state models for epoxidation of alkenes
by peracids. Bottom: different modes of hydrogen bonding interactions of
peracids with allylic functional groups.
nitrogen atom also gives a strong syn direction (C, Fig. 2).8d
Analogously, de Sousa et al. found evidence that homo-
allylic silyl ethers are moderate syn-directors by reverse
hydrogen bonding.23 A similar observation has been made
by us when alkene 11 was treated with trifluoroperacetic
acid.9 The trifluoroacetylated carbamate is a hydrogen bond
acceptor, and the directing carbonyl group appears to be
more basic than that of the trifluoroacetate, resulting in
epoxide products with a threo/erythro ratio of 81:19. Hence,
reverse hydrogen bonding may well explain the directing
effects of the acetate and methyl ester functions in the
present study.
1
Table 4. Selected H NMR shifts (in ppm) for assignment of the relative
stereochemistry of epoxides 9d and 10da,b
Compound
Rel. stereochem.
H-5
9a
10a
9b
10b
9d
10d
9e
syn
anti
syn
anti
syn
anti
syn
anti
1.63–1.76
1.78–1.99
1.60–1.71
1.77–1.89
1.63–1.72
1.82–1.90
1.67–1.75
1.68–1.83
10e
a Data for compounds 9e and 10e are from Ref. 5c
b See Scheme 2 for atom numbering.
Obviously, there are several factors that control the face
selectivity in peracid epoxidation of acyclic alkenes with
directing groups, of which the most important are; (i) the
conformational preferences in the transition state, (ii) the
directing effect, which is due to hydrogen bonding between
the coordinating functionality and the peracid. The steric
preferences in the transition state have been a matter of
discussion. Extensive theoretical work on 1,2 asymmetric
induction19 and empirical studies on epoxidation of cyclic
allylic alcohols8c,20 support a staggered model (Fig. 2), but a
model where the hydrogen is eclipsed with the double bond
(Fig. 2) has also been used, and possibly there are different
transition states depending on the substitution pattern of the
alkene.6c,21 The interpretation of our results is not affected
by choice of model. Regarding the directing effect, the
hydrogen bond donor–acceptor capability of the reactants,
and the distance between the alkene and the coordinating
group should influence the stereoselectivity.
Boc
OCOCF3
N
COCF3
11
The acidity of the peracid should influence the direction of
the hydrogen bonding; the more acidic the peracid the
stronger the hydrogen bond donating capability. Thus,
trifluoroperacetic acid (pKaZ3.7) is more prone to
coordinate to different functional groups through hydrogen
bond donation than m-CPBA (pKaZ7.57). This hypothesis
is supported by the current study in that the acetate function
in 8b directs trifluoroperacetic acid more strongly than
m-CPBA to the syn face of the alkene (Table 2), and that the
acetate is a better hydrogen bond acceptor than the
trifluoroacetate of 8c, for which no significant difference
between the peracids was found.
The mode of hydrogen bonding between the peracid and the
coordinating group can influence the stereoselectivity in the
peracid epoxidations. For allylic alcohols it is believed that
the face selectivity is due to hydrogen bonding from OH to
O-3 in the peracid (A, Fig. 2).22 Similarly, allylic
carbamates can direct the peracid via hydrogen bonding
from NH to O-3 in the peracid (B, Fig. 2).5b,8d However,
there is also evidence for a directing effect via reverse
hydrogen bonding, that is, the peracid is donating a
hydrogen bond to the carbonyl oxygen of the carbamate
3. Conclusions
Suitable reaction conditions for efficient synthesis of b,g-
unsaturated esters using the E-selective Schlosser reaction
were identified. Careful monitoring of the temperature and
the use of phenyllithium as the base allowed the production
of E-alkenes in high yield and high E/Z-selectivity. The
peracid epoxidation of the synthesised E-alkene dipeptido-
mimetics was highly stereoselective, and the formation of
the threo-isomers was favoured in most reactions. The
results strongly suggest a powerful directing effect from the
ˇ
group. This was proposed by Kocovsky and Stary who
showed that an allylic carbamate group with a disubstituted
´
´

D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
3605
carbamate function, which is difficult to overcome by
changing the peracid or the reaction conditions. However,
the second functional group also exhibited strong directing
effects. Employing trifluoroperacetic acid as the epoxidation
reagent we obtained a reversed stereoselectivity in the
epoxidation of two vinylic dipeptide isosteres (1b and 1j).
This change in stereodirection probably emanates from a
stronger coordination of the peracid to the ester function
than to the carbamate moiety. The ester functionality in 1b
and 1j would direct the epoxidation to the erythro face of the
alkene. This change of directing properties is supposed to be
due to differences in peracid acidity and thereby differences
in hydrogen bond donating capacity.
was removed in vacuo. The crude products were purified by
column chromatography as described earlier.5b,c
4.2.2. Epoxidation with m-CPBA (method B). m-CPBA
(1.5 equiv) was added to a solution of the substrate (0.2 M)
in CH2Cl2. After stirring at room temperature for the
reaction time specified in Table 1, the reaction was worked
up as described above for method A.
4.2.3. Epoxidation with trifluoroperacetic acid (method
C). Trifluoroacetic acid anhydride (4 equiv) was added to a
solution of urea–hydrogen peroxide (15 equiv, 3 M) and
Na2HPO4 (10 equiv) in CH2Cl2. After stirring at 0 8C for
30 min, substrate was added. Stirring was continued (see
Table 1 for reactiontimes)atthe sametemperatureafter which
the reaction was quenched immediately by addition of satd aq
NaHCO3 and the phases were separated. The organic phase
was further washed with satd aq Na2S2O3, 1 M aq HCl and
brine. The organic layers were dried (MgSO4), filtered and the
solvent was removed. The crude products were purified by
column chromatography as described earlier.5b,c
4. Experimental
4.1. General methods
Melting points were determined with a Tomas–Hoover
apparatus and are uncorrected. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter at ambient
4.3. Data for the oxazolidinones (4). (4S,5R)-4-Benzyl-5-
[(1S)-hydroxy-(2R)-methoxycarbonyl-3-phenylpropyl]-
1,3-oxazolidin-2-one (4a) and (4S,5S)-4-benzyl-5-[(1R)-
hydroxy-(2R)-methoxycarbonyl-3-phenylpropyl]-1,3-
oxazolidin-2-one (4b)
1
temperature. H and 13C NMR spectra were recorded on a
JEOL JNM-EX270 spectrometer at 270 and 68 MHz,
respectively, or a JEOL Eclipse 400 spectrometer at 400
and 100 MHz, respectively, in CDCl3. Chemical shifts are
reported in ppm with the solvent residual peak as internal
standard (CHCl3 dH 7.26, CDCl3 dC 77.0). 2D COSY,
HMQC and HMBC NMR spectroscopy was used to validate
structural assignment of the signals. Analytical thin-layer
chromatography was performed on Merck silica gel, grade
60 F254 and the spots were visualised by UV light (254 nm)
and treatment with 5% phosphomolybdic acid in ethanol
and heating. Flash chromatography was performed on
The compounds were isolated from the trifluoroperacetic
acid-mediated epoxidation reaction of 1b after chromato-
graphy using ether/pentane 1:3 as eluent (see method C).
4.3.1. Compound 4a. Mp 115–117 8C; [a]2D0 K46.3 (c 0.50,
CHCl3); H NMR (270 MHz) d 7.35–7.16 (m, 10H), 4.94
1
(bs, 1H), 4.11 (dd, 1H, JZ8.5, 4.6 Hz), 3.98 (dt, 1H, JZ9.3,
4.8 Hz), 3.66 (s, 3H), 3.58 (m, 2H), 3.15–2.94 (m, 4H), 2.74
(t, 1H, JZ13.6 Hz); 13C NMR (68 MHz) d 175.8, 157.4,
137.4, 136.1, 129.1 (2C), 129.0 (4C, s), 128.7 (2C), 127.3,
126.9, 81.3, 71.8, 57.0, 52.1, 46.8, 42.3, 35.4; IR (KBr)
3343, 1748 cmK1. Anal. Calcd for C21H23NO5: C, 68.28; H,
6.28; N, 3.79. Found: C, 68.28; H, 6.17; N, 3.87.
˚
Merck silica gel SI-60 A. For analytical HPLC a Hitachi
system (L-4000 UV detector at 254 nm and L-6200 pump
with flow rate 1.5 mL/min) fitted with a LiChroCART 4!
250 mm 5 mm LiChrospher Si 60 column was used. Infrared
spectra were recorded on a Perkin-Elmer 298 or 16PC FT-
IR spectrometer and only the major peaks are listed.
Elemental analyses were conducted by MikroKemi AB,
Uppsala, Sweden. High-resolution mass analysis was
4.3.2. Compound 4b. Mp 188–190 8C. [a]2D0 K40.5 (c 0.74,
CHCl3); H NMR (270 MHz) d 7.38–7.18 (m, 10H), 4.92
¨
performed by Stenhagen analyslab AB, Molndal, Sweden.
1
The synthesis of the olefins 1a–l, data for epoxides 2a–l and
3a–l, and the analysis procedure of isomeric ratios of
epoxides using NMR-spectroscopy and HPLC are described
in Ref. 5b and 5c The synthesis and the epoxidation of
olefin 8e are described in Ref. 5c, and the preparation of
aldehyde 6 in Ref. 5b. Phosphonium salt 7 was prepared
according to literature procedures.15
(bs, 1H), 4.64 (dd, 1H, JZ10.1, 7.3 Hz), 4.35 (dd, 1H, JZ
10.0, 2.2 Hz), 4.07 (ddd, 1H, JZ12.0, 7.2, 3.2 Hz), 3.65 (bs,
1H), 3.52 (s, 3H), 3.33–3.08 (m, 4H), 2.64 (t, 1H, JZ
13.0 Hz); 13C NMR (68 MHz) d 176.1, 157.6, 138.1,
136.7, 129.1 (4C), 129.0 (2C), 128.5 (2C), 127.2, 126.6,
76.7, 68.0, 56.3, 51.9, 48.4, 35.9, 31.2; IR (KBr) 3373,
1744 cmK1. Anal. Calcd for C21H23NO5!0.5H2O: C,
66.65; H, 6.39; N, 3.70. Found: C, 66.74; H, 6.31; N,
3.59. The stereochemistry of this compound was established
by X-ray crystallography.13
4.2. General procedures for epoxidation reactions
4.2.1. Epoxidation with MMPP (method A). MMPP
(2 equiv) was added to a solution of the substrate (0.13 M)
and trioctylmethylammonium chloride (0.05 equiv) in a
two-phase system consisting of CHCl3 and H2O (1:1). After
stirring at room temperature for the reaction time specified
in Table 1, the mixture was poured into satd aq Na2S2O3 and
the phases were separated. The organic phase was further
washed with 1 M aq HCl, satd aq NaHCO3 and brine. The
organic layer was dried (MgSO4), filtered and the solvent
4.4. Synthesis of the alkenes 8a–d
4.4.1. Phenyl-(3-phenylpropyl)sulfone (5). 3-Phenylpro-
panol (15.0 g, 110 mmol) and Et3N (6.0 mL, 330 mmol)
were dissolved in CH2Cl2 (450 mL). Methanesulfonyl
chloride (21.5 g, 275 mmol) was added drop wise at 0 8C.
After 2 h H2O was added and the mixture was extracted
three times with CH2Cl2. The combined organic phases

3606
D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
were dried (MgSO4) and concentrated in vacuo without
heating to afford a crude oil, which was used in next step
without further purification.
The crude product (500 mg, 1.31 mmol) was dissolved in
acetonitrile (40 mL) containing 2% HF (2 mL of a 40%
aqueous HF solution) at room temperature. After 1 h H2O
was added and the mixture was extracted with CH2Cl2. The
organic phase was dried (MgSO4) and concentrated to
afford 470 mg of a crude oil. The E/Z ratio was 88:12
according to GC and NMR (33% combined yield over two
steps). The isomers were separated by repeated column
chromatography (CH2Cl2/MeOH/hexane 4:1:25) to afford
8a as a colourless oil: HPLC (0.5% EtOH in hexane), tR
Thiophenol (73.0 mL, 716 mmol) was added to a solution of
NaOCH3 (38.65 g, 716 mmol) in THF/MeOH (5:1,
300 mL). The mixture was stirred for 30 min at room
temperature and the mesylate from the previous step was
added as an oil. The reaction mixture was stirred at room
temperature overnight. The day after, satd aq NaHCO3 was
added and the organic solvent was evaporated. The mixture
was partitioned between H2O and ether, and the aqueous
phase was extracted three times with ether. The combined
ether layers were dried (MgSO4) and concentrated to afford
a yellow-brown oil. Purification by column chromatography
(petroleum ether) gave phenyl-(3-phenylpropyl)sulfide
(24.37 g, 97% over two steps): 1H NMR data were in
agreement with those reported;24 13C NMR (68 MHz) d
141.2, 136.5, 129.0 (2C), 128.8 (2C), 128.4 (2C), 128.3
(2C), 125.9, 125.7, 34.6, 32.8, 30.5.
1
13.2 min; H NMR (270 MHz) d 7.30–7.11 (m, 10H), 5.48
(app dt, 10H, JZ6.6, 15.4 Hz), 5.21 (ddt, 1H, JZ1.1, 8.1,
15.4 Hz), 3.51 (ddd, 1H, JZ4.7, 8.1, 10.7 Hz), 3.33 (ddd,
1H, JZ4.3, 7.7, 10.7 Hz), 2.74–2.51 (m, 4H), 2.50–2.40 (m,
1H), 2.38–2.26 (m, 2H), 1.22 (app ddd, 1H, JZ1.1, 4.3,
8.1 Hz); 13C NMR (68 MHz) d 141.6, 139.8, 132.8, 131.3,
129.1 (2C), 128.4 (2C), 128.3 (2C), 128.2 (2C), 125.9,
125.8, 65.0, 47.1, 37.7, 35.7, 34.3; IR (neat) 3370, 3020,
2920, 1600, 1490, 1450 cmK1. Anal. Calcd for C19H22O: C,
85.7; H, 8.3. Found: C, 85.6; H, 8.5.
By Schlosser olefination with 7. Phosphonium salt 7 (1.19 g,
2.58 mmol) was suspended by magnetic stirring in dry THF
(5 mL) under N2. The vessel was cooled to K60 8C and
phenyllithium (2.0 M in dibutyl ether, 1.36 mL, 2.72 mmol)
was added. The reaction was allowed to warm to room
temperature and was stirred for 30 min during which an
orange colour solution developed. The reaction was again
cooled to K60 8C and a solution of 6 (0.72 g, 2.59 mmol) in
THF (2 mL) was added drop wise at which the colour faded.
The reaction was allowed to warm to K41 8C and was left
with stirring for 30 min. Another equivalent of phenyl-
lithium was added to yield a dark violet solution which was
stirred for 30 min. Addition of MeOH (0.105 mL,
2.29 mmol) gave a slight yellow solution, which was stirred
for 30 min at K41 8C. t-BuOK (0.29 g, 2.59 mmol) was
added in one portion and the reaction was stirred for 30 min
and was then allowed to reach room temperature. The
reaction was quenched by addition of diethyl ether (15 mL)
and satd aq NH4Cl (25 mL). The mixture was stirred briefly
and the phases were separated. The aqueous phase was
extracted with diethyl ether (25 mL) and the combined
organic phases were washed with H2O and brine, dried
over MgSO4 and evaporated. The product, 2-benzyl-1-
[(tert-butyldimethylsilyl)oxy]-6-phenyl-3-hexene (mixture
of E/Z-isomers), was purified by column chromatography
as described above.
The sulfide (1.50 g, 6.57 mmol) was dissolved in CH2Cl2
(75 mL) and m-CPBA (5.18 g, 21.0 mmol) was added at
0 8C. The mixture was allowed to reach room temperature
while stirring overnight. The reaction was quenched by slow
addition of aq NaOH (10%, 25 mL) saturated with NaHSO3.
After filtration and dilution, the aqueous phase was
extracted four times with CH2Cl2. The combined organic
layers were extracted once with 1 M NaOH, dried (MgSO4)
and concentrated. The crude product was recrystallised
(CH2Cl2/hexane) to afford sulfone 5 (1.24 g, 72%). 1H
NMR data and melting point were in agreement with those
reported;25 13C NMR (68 MHz) d 139.7, 138.9, 133.6 (2C),
129.2 (2C), 128.5 (2C), 128.3 (2C), 127.9, 126.3, 55.3,
33.9, 24.1.
4.4.2. 2-Benzyl-6-phenyl-(E)-3-hexen-1-ol (8a). By Julia
olefination with 5. Sulfone 5 (0.64 g, 2.46 mmol) was
dissolved in dry THF (20 mL) under N2 atmosphere. The
solution was cooled to K78 8C and n-butyllithium (1.6 M in
hexane, 1.84 mL, 2.95 mmol) was added. The solution was
stirred for 30 min at K78 8C. In a separate flask, aldehyde 6
(1.03 g, 3.69 mmol) was treated with DIBAL-methoxide
(1.16 M, 3.18 mL) at K78 8C in THF (10 mL). The solution
of the activated aldehyde was added immediately to the
solution of the sulfone anion, and the mixture was stirred for
30 min at K78 8C. The reaction was quenched by addition
of satd aq NH4Cl and allowed to reach room temperature.
After removal of THF by evaporation, the mixture was
extracted five times with CH2Cl2. The organic phase was
dried (MgSO4) and concentrated to afford a colourless oil.
The crude product was dissolved in THF (4 mL) and TBAF
(1 M in THF, 6.9 mL, 6.9 mmol) was added and the
resulting mixture was stirred for 26 h. The mixture was
diluted with diethyl ether (60 mL) and washed with 10% aq
citric acid solution (60 mL), satd aq NaHCO3 (60 mL) and
brine (60 mL), dried over MgSO4, filtered and evaporated.
The crude product was purified by gradient column
chromatography (EtOAc/hexanes 1:20–1:10) to yield the
title compound with an E/Z-ratio of 87:13 (0.42 g, 61%
combined yield over two steps). The E/Z-isomers were
separated as indicated above.
The crude oil was dissolved in MeOH (75 mL) and
Na2HPO4 (3.49 g, 24.6 mmol) and 6% Na(Hg) (9.43 g)
were added at 0 8C. After 4 h, H2O and 1 M HCl were added
and the insoluble material was filtered off. MeOH was
removed by evaporation and the mixture was extracted with
CH2Cl2 four times. The organic phase was dried (MgSO4)
and concentrated. Purification by column chromatography
(ether/petroleum ether 1:19) gave an E/Z mixture
of 2-benzyl-1-[(tert-butyldimethylsilyl)oxy]-6-phenyl-3-
hexene.
4.4.3. 2-Benzyl-6-phenyl-(E)-3-hexenylacetate (8b).
Alcohol 8a (50 mg, 0.188 mmol) and Et3N 131 mL,
0.938 mmol) were dissolved in CH2Cl2 (5 mL). Acetic

D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
3607
anhydride (89 mL, 0.938 mmol) and a catalytic amount of
DMAP were added. The reaction was stirred at room
temperature overnight. The mixture was extracted with 1 M
HCl and satd aq NaHCO3. The organic phase was dried
(MgSO4), filtered and concentrated. Purification of the
crude oil by column chromatography (ether/pentane 1:12)
afforded the title compound (54.6 mg, 94%): HPLC (10%
EtOAc in hexane), tR 4.6 min, 1H NMR (270 MHz) d 7.29–
7.09 (m, 10H), 5.42 (app dt, 1H, JZ6.4, 15.4 Hz), 5.28 (app
dd, 1H, JZ7.5, 15.4 Hz), 4.02–3.91 (m, 2H), 2.78–2.51 (m,
5H), 2.31–2.23 (m, 2H), 2.02 (s, 3H); 13C NMR (68 MHz) d
171.0, 141.7, 139.4, 131.7, 130.3, 129.2 (2C), 128.4 (2C),
128.2 (4C), 126.0, 125.7, 66.8, 43.3, 38.2, 35.8, 34.3, 20.9;
IR (neat) 3020, 2930, 1740, 1490, 1450, 1240 cmK1. Anal.
Calcd for C21H24O2: C, 81.8; H, 7.8. Found: C, 81.7; H, 7.9.
The crude aldehyde (approx 0.36 mmol) was dissolved in
dry DMF (2 mL) under a N2 atmosphere and MeOH
(106 mL, 2.6 mmol) was added. The mixture was stirred for
10 min and subsequently PDC (0.982 g, 2.20 mmol) was
added. The reaction was quenched after 19 h by adding the
reaction solution in small portions to a vigorously stirred
mixture of H2O (25 mL) and diethyl ether (75 mL). The
resulting suspension was filtered through Celite and the
filtrate was washed with H2O. The aqueous layer was
washed extracted twice with ether and the combined organic
phases were washed with brine, dried over MgSO4, filtered
and evaporated. Purification of the unstable product was
done by rapid chromatography on a short column (EtOAc/
hexanes 1:100) to yield the title compound (49 mg, 40%
over two steps, repeated attempts gave comparable yields).
1H NMR (400 MHz) 7.30–7.09 (m, 10H), 5.52–5.48 (m,
2H), 3.63 (s, 3H), 3.31–3.23 (m, 1H), 3.06 (dd, 1H, JZ7.7,
13.6 Hz), 2.79 (dd, 1H, JZ7.3, 13.6 Hz), 2.63 (dt, 2H, JZ
3.3, 7.7 Hz), 2.33–2.27 (m, 2H); 13C NMR (100 MHz)
174.2, 141.6, 138.8, 133.0, 129.0 (2C), 128.4 (2C), 128.2
(4C), 127.6, 126.3, 125.8, 51.7, 51.0, 38.8, 35.5, 34.2; IR
(neat) 3027, 2928, 1735, 1449, 1160 cmK1; HRMS (FAB)
calcd for C20H23O2 (MHC) 295.170, found 295.167.
4.4.4. 2-Benzyl-6-phenyl-(E)-3-hexenyltrifluoroacetate
(8c). Alcohol 8a (150 mg, 0.563 mmol) and Et3N (235 mL,
1.69 mmol) were dissolved in CH2Cl2 (10 mL) and
trifluoroacetic anhydride (86 mL, 0.619 mmol) was added.
The reaction was stirred at room temperature. More Et3N
and trifluoroacetic anhydride were added twice since there
was starting material left after 2 and 4 h, respectively. After
5 h, the reaction mixture was extracted with 1 M aqueous
HCl and saturated aqueous NaHCO3. The organic phase was
dried (MgSO4) and concentrated. Purification of the crude
oil by column chromatography (ether/pentane 1:4) afforded
the title compound (166 mg, 81%) as a colourless oil: HPLC
4.5. Epoxidation of the alkenes 8a–d
Epoxidations were performed as described above (method B
and C). Data on isomeric ratios, yields and reaction times
are given in Table 2.
1
(2% EtOAc in hexane), tR 4.8 min; H NMR (270 MHz) d
7.31–7.08 (m, 10H), 5.49 (dt, 1H, JZ6.5, 15.4 Hz), 5.32–
5.23 (m, 1H), 4.26–4.15 (m, 2H), 2.74–2.58 (m, 5H), 2.33–
4.5.1. (2R*,3S*,4R*)-2-Benzyl-3,4-epoxy-6-phenyl-hexan-
1-ol (9a) and (2R*,3R*,4S*)-2-benzyl-3,4-epoxy-6-phenyl-
hexan-1-ol (10a). Purification by column chromatography
(CH2Cl2/MeOH/hexane 4:1:12) afforded 9a and 10a.
2.25 (m, 2H); 13C NMR (68 MHz) d 157.4 (q, JCCF
Z
42 Hz), 141.6, 138.5, 133.0, 129.1, 128.9 (2C), 128.4 (4C),
128.2 (2C), 126.4, 125.8, 114.5 (q, JCFZ285 Hz), 69.8,
43.1, 37.7, 35.6, 34.3; IR (neat) 3020, 2930, 1780, 1490,
1450, 1220, 1160 cmK1. Anal. Calcd for C21H21F3O2: C,
69.60; H, 5.84. Found: C, 69.57; H, 5.90.
Compound 9a. HPLC (3% EtOH in hexane), tR 9.9 min; 1H
NMR (270 MHz) d 7.32–7.09 (m, 10H), 3.75–3.68 (m, 2H),
2.82 (dd, 1H, JZ6.8, 13.7 Hz), 2.70 (dd, 1H, JZ2.4,
7.7 Hz), 2.66–2.43 (m, 4H), 2.07 (br s, 1H), 1.76–1.63 (m,
3H); 13C NMR (68 MHz) d 141.1, 139.2, 129.1 (2C), 128.9
(2C), 128.4 (2C), 128.2 (2C), 126.3, 126.0, 64.1, 60.9, 57.8,
45.0, 34.9, 33.5, 31.7; IR (neat) 3440, 3020, 2920, 1600,
1490, 1450 cmK1. Anal. Calcd for C19H22O2!0.1H2O: C,
80.3; H, 7.8. Found: C, 80.3; H, 8.0.
4.4.5. Methyl 2-benzyl-6-phenyl-(E)-3-hexenoate (8d).
Alcohol 8a (110 mg, 0.413 mmol) was dissolved in
CH2Cl2 (1.5 mL) and acetonitrile (2 mL) under a N2
atmosphere and cooled to 0 8C. Dess–Martin periodinane
(15 wt% solution in CH2Cl2, 1.46 g solution,
0.516 mmol) was added drop wise to the stirred solution.
The reaction was stirred for 30 min at 0 8C and another
3 h at rt. The solvent volume was reduced to half by
rotary evaporation without heating, and the remaining
solution was cooled to 0 8C, and cold satd aq Na2S2O3
solution was added and stirring was continued for
20 min. The mixture was extracted three times with
diethyl ether, and the combined organic layers were
washed with cold satd aq NaHCO3, dried over MgSO4,
filtered and evaporated. The product was purified by
rapid chromatography on a short column (EtOAc/hexanes
1:20) to yield the unstable compound E-2-benzyl-6-
phenyl-3-hexenal as a crude oil (95 mg), which was
Compound 10a. HPLC (3% EtOH in hexane, tR 8.6 min; 1H
NMR (270 MHz) d 7.33–7.15 (m, 10H), 3.53–3.37 (m, 2H),
2.96 (app dt, 1H, JZ2.3, 5.8 Hz), 2.88–2.69 (m, 4H), 2.61
(dd, 1H, JZ8.6, 13.7 Hz), 1.99–1.78 (m, 3H), 1.67–1.63 (m,
1H); 13C NMR (68 MHz) d 141.1, 139.0, 129.0 (2C), 128.5
(2C), 128.4 (2C), 128.3 (2C), 126.2, 126.1, 62.5, 61.1, 56.9,
43.9, 34.7, 33.6, 32.1; IR (neat) 3440, 3020, 2920, 1600,
1490, 1450 cmK1. Anal. Calcd for C19H22O2: C, 80.8; H,
7.9. Found: C, 80.7; H, 7.7.
4.5.2. (2R*,3S*,4R*)-2-Benzyl-3,4-epoxy-6-phenyl-hexa-
nyl acetate (9b) and (2R*,3R*,4S*)-2-benzyl-3,4-epoxy-6-
phenyl-hexanyl acetate (10b). Purification by column
chromatography (diethyl ether/pentane 1:9) afforded 9b
and 10b.
1
used immediately in the next step. H NMR (400 MHz) d
9.57 (d, 1H, JZ1.8 Hz), 7.32–7.10 (m, 10H), 5.61–5.54
(m, 1H), 5.32 (dd, 1H, JZ8.4, 15.8 Hz), 3.25 (q, 1H,
JZ7.4 Hz), 3.11 (dd, 1H, JZ6.2, 13.9 Hz), 2.74 (dd,
1H, JZ7.7, 13.9 Hz), 2.68–2.62 (m, 2H), 2.38–2.32
(m, 2H).
Compound 9b. HPLC (10% EtOAc in hexane), tR 18.1 min;
1H NMR (270 MHz) d 7.32–7.10 (m, 10H), 4.22–4.09

3608
D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
(m, 2H), 2.77 (dd, 1H, JZ6.5, 13.5 Hz), 2.68–2.64 (m, 1H),
2.61–2.48 (m, 3H), 2.47–2.43 (m, 1H), 2.09 (s, 3H), 1.86–
1.73 (m, 1H), 1.71–1.60 (m, 2H); 13C NMR (68 MHz) d
171.0, 141.1, 138.8, 128.9 (2C), 128.5 (2C), 128.4 (2C),
128.2 (2C), 126.4, 126.0, 64.8, 59.2, 58.0, 42.9, 34.9, 33.5,
31.8, 20.9; IR (neat) 3020, 2930, 1740, 1490, 1450,
1240 cmK1. Anal. Calcd for C21H24O3: C, 77.8; H, 7.5.
Found: C, 77.6; H, 7.6.
Supplementary data
NMR spectral assignments of characterised compounds. 1H
and 13C NMR spectra of 8d and 10d. Experimental details,
selected details of the final structure refinement and crystal
data of 4b.
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2006.01.095
Compound 10b. HPLC (10% EtOAc in hexane), tR
12.7 min; 1H NMR (270 MHz) d 7.32–7.15 (m, 10H),
4.00–3.94 (m, 2H), 2.93 (dd, 1H, JZ5.0, 13.7 Hz), 2.85
(app dt, 1H, JZ2.3, 5.8 Hz), 2.83–2.63 (m, 4H), 2.01 (s,
3H), 1.89–1.77 (m, 3H); 13C NMR (68 MHz) d 170.8, 141.0,
138.4, 129.1 (2C), 128.5 (4C), 128.3 (2C), 126.4, 126.0,
63.8, 59.9, 58.0, 42.5, 35.0, 33.8, 32.1, 20.8; IR (neat) 3020,
2930, 1740, 1490, 1450, 1240 cmK1. Anal. Calcd for
C21H24O3: C, 77.8; H, 7.5. Found: C, 77.7; H, 7.5.
References and notes
¨
1. For general reviews, see: (a) Hoft, E. Top. Curr. Chem. 1993,
164, 63–77. (b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem.
Rev. 1993, 93, 1307–1370. (c) Bonini, C.; Righi, G.
Tetrahedron 2002, 58, 4981–5021.
2. Several mechanistic studies have been performed; see, for
example (a) Bartlett, P. D. Rec. Chem. Prog. 1957, 18, 111. (b)
Hanzlik, R. P.; Shearer, G. O. J. Am. Chem. Soc. 1975, 97,
5231–5233. (c) Angelis, Y. S.; Orfanopoulos, M. J. Org.
Chem. 1997, 62, 6083–6085.
4.5.3. (2R*,3S*,4R*)-2-Benzyl-3,4-epoxy-6-phenyl-hexa-
nyl trifluoroacetate (9c) and (2R*,3R*,4S*)-2-benzyl-3,4-
epoxy-6-phenyl-hexanyl trifluoroacetate (10c). The epox-
ides 9c and 10c were not isolated, instead the crude mixture
was treated with K2CO3 in MeOH to produce a mixture with
unchanged ratio of the corresponding alcohol epoxides 9a
and 10a.
3. (a) Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N.
J. Am. Chem. Soc. 1997, 119, 3385–3386 and references
therein. (b) Okovytyy, S.; Gorb, L.; Leszczynski, J. Tetra-
hedron Lett. 2002, 43, 4215–4219.
4.5.4. Methyl (2R*,3S*,4R*)-2-benzyl-3,4-epoxy-6-phe-
nyl-hexanoate (9d) and methyl (2R*,3R*,4S*)-2-benzyl-
3,4-epoxy-6-phenyl-hexanoate (10d). Purification by
gradient column chromatography (EtOAc/hexanes 1:33–
1:20) afforded 9d and 10d.
4. Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem.
Rev. 2005, 105, 1603–1662.
5. (a) Li, Y. L.; Luthman, K.; Hacksell, U. Tetrahedron Lett.
1992, 33, 4487–4490. (b) Jenmalm, A.; Berts, W.; Li, Y. L.;
Luthman, K.; Csoregh, I.; Hacksell, U. J. Org. Chem. 1994, 59,
1139–1148. (c) Jenmalm, A.; Berts, W.; Luthman, K.;
Csoregh, I.; Hacksell, U. J. Org. Chem. 1995, 60,
1026–1032.
Compound 9d. HPLC (5% EtOH in hexane), 1.5 mL/min, tR
14.4 min; H NMR (400 MHz) d 7.31–7.08 (m, 10H), 3.71
1
(s, 3H), 3.06 (dd, 1H, JZ7.0, 13.9 Hz), 2.94 (dd, 1H, JZ
2.2, 8.4 Hz), 2.80 (dd, 1H, JZ8.8, 13.9 Hz), 2.67–2.58 (m,
1H), 2.56–2.48 (m, 1H), 2.48–2.41 (m, 2H), 1.72–1.63 (m,
2H); 13C NMR (100 MHz) d 173.2, 141.0, 138.0, 128.8
(2C), 128.6 (2C), 128.4 (2C), 128.2 (2C), 126.7, 126.0, 58.5,
58.1, 52.0, 50.3, 35.3, 33.3, 31.7; IR (neat) 3027, 2949,
1732, 1604, 1495, 1454, 1200, 1165. Anal. Calcd for
C20H22O3: C, 77.4; H, 7.1. Found: C, 77.5; H, 7.3.
6. For other examples of cooperative coordination of m-CPBA,
see: (a) Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979,
4347–4350. (b) Kogen, H.; Nishi, T. J. Chem. Soc., Chem.
Commun. 1987, 311–312. (c) Clayden, J.; Collington, E. W.;
Egert, E.; Mcelroy, A. B.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1994, 2801–2810.
7. For directing effects of allylic amides and carbamates, see: (a)
Hasegawa, A.; Sable, H. Z. J. Org. Chem. 1966, 31,
¨
4154–4161. (b) Backvall, J.-E.; Oshima, K.; Palermo, R. E.;
Compound 10d. HPLC (5% EtOAc in hexane), 1.5 mL/min,
tR 8.4 min; 1H NMR (400 MHz) d 7.34–7.20 (m, 10H), 3.61
(s, 3H), 3.06 (app d, 2H, JZ7.0 Hz), 2.94–2.89 (m, 2H),
2.82–2.68 (m, 2H), 2.53 (app q, 1H, JZ7.3 Hz), 1.89–1.84
(m, 2H); 13C NMR (100 MHz) d 172.4, 141.0, 138.0, 128.9
(2C), 128.4 (4C), 128.3 (2C), 126.6, 126.0, 58.4, 57.9, 51.8,
50.2, 35.7, 33.5, 32.1; IR (neat) 3027, 2949, 1738, 1604,
1496, 1454, 1201, 1164 cmK1; HRMS (FAB) calcd for
C20H23O3 (MHC) 311.165, found 311.167
Sharpless, K. B. J. Org. Chem. 1979, 44, 1953–1957. (c)
Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1984, 25,
1587–1590. (d) Shaw, K. J.; Luly, J. R.; Rapoport, H.
J. Org. Chem. 1985, 50, 4515–4523. (e) Hauser, F. M.;
Ellenberger, S. R.; Glusker, J. P.; Smart, C. J.; Carrell, H. L.
J. Org. Chem. 1986, 51, 50–57. (f) Luly, J. R.; Dellaria, J. F.;
Plattner, J.; Soderqvist, J. L.; Yi, N. J. Org. Chem. 1987, 52,
1487–1492. (g) Roush, W. R.; Straub, J. A.; Brown, R. J.
J. Org. Chem. 1987, 52, 5127–5136. (h) Hori, K.; Ohfune, Y.
J. Org. Chem. 1988, 53, 3886–3888. (i) Rotella, D. P.
Tetrahedron Lett. 1989, 30, 1913–1916. (j) Campbell,
M. M.; Floyd, A. J.; Lewis, T.; Mahon, M. F.; Ogilvie, R. J.
Tetrahedron Lett. 1989, 30, 1993–1996. (k) Pettersson, H.;
Acknowledgements
¨
Gogoll, A.; Backvall, J.-E. J. Org. Chem. 1992, 57,
Financial support was obtained from the Knut and Alice
Wallenberg Foundation and the Swedish Research Council.
The authors thank Professor Uli Hacksell for his interest in
this work and for valuable discussions.
6025–6031. (l) Romeo, S.; Rich, D. H. Tetrahedron Lett.
1993, 34, 7187–7190. (m) Albeck, A.; Persky, R. J. Org.
Chem. 1994, 59, 653–657. (n) Perlman, N.; Livneh, M.;
Albeck, A. Tetrahedron 2000, 56, 1505–1516. (o) O’Brien, P.;

D. Wiktelius et al. / Tetrahedron 62 (2006) 3600–3609
3609
Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden,
M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5,
4955–4957.
14. Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833–4836.
15. Wylie, P. L.; Prowse, K. S.; Belill, M. A. J. Org. Chem. 1983,
48, 4022–4025.
8. For directing effects of carbonyl groups on epoxidations with
m-CPBA, see: (a) Paryzek, Z. J. Chem. Soc., Perkin Trans. 1
16. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157.
17. Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem. Eur.
J. 2003, 9, 570–574.
ˇ
1978, 329–336. (b) Kocovsky, P. Tetrahedron Lett. 1988, 29,
´
2475–2478. (c) Mohamadi, F.; Spees, M. M. Tetrahedron Lett.
18. O’Connor, B.; Just, G. Tetrahedron Lett. 1987, 28, 3235–3236.
19. Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223.
20. (a) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem.
Soc. B 1970, 1374–1381. (b) Narula, A. S. Tetrahedron Lett.
1983, 24, 5421–5424.
ˇ
´
´
1989, 30, 1309–1310. (d) Kocovsky, P.; Stary, I. J. Org. Chem.
1990, 55, 3236–3243. (e) Armstrong, A.; Barsanti, P. A.;
Clarke, P. A.; Wood, A. J. Chem. Soc., Perkin Trans. 1 1996,
1373–1380.
9. Jenmalm Jensen, A.; Luthman, K. Tetrahedron Lett. 1998, 39,
3213–3214.
21. (a) Chautemps, P.; Pierre, J. L. Tetrahedron 1976, 32,
549–557. (b) Kishi, Y. Aldrichim. Acta 1980, 13, 23–30. (c)
Fleming, I. J. Chem. Soc., Perkin Trans. 1 1992, 3363–3369.
22. Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979, 12,
63–74.
10. Fehr, C. Angew. Chem., Int. Ed. 1998, 37, 2407–2409.
11. Heaney, H. Top. Curr. Chem. 1993, 164, 1–19.
12. Similar byproducts have been observed by others, see Ref. 3g
and 3l.
23. (a) de Sousa, S. E.; Kee, A.; O’Brien, P.; Watson, S. T.
Tetrahedron Lett. 1999, 40, 387–390. (b) de Sousa, S. E.;
O’Brien, P.; Pilgram, C. D.; Roder, D.; Towers, T. D.
Tetrahedron Lett. 1999, 40, 391–392.
13. Crystallographic data for 4b have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 267293. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: C44 1223 336033 or
deposit@ccdc.cam.ac.uk].
24. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978, 43,
1064–1071.
25. Julia, M.; Uguen, D. Bull. Soc. Chim. Fr. 1976, 513–518.