Synthesis of single-enantiomer 6-hydroxy-7-phenyl-1,4-oxazepan-5-ones

Article abstract of DOI:10.1055/s-2005-872122

An efficient two-step preparation of (6R,7R)-6-hydroxy-7-phenyl-1,4- oxazepan-5-ones (1) starting from aminoethanols and (2R,3S)-3-phenyloxirane-2- carboxylic ethyl ester or potassium salt has been described. The most efficient catalyst identified for the

Full text of DOI:10.1055/s-2005-872122

PAPER
2549
Synthesis of Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
S
ingle-Enantiom
h
r
-
7-phen
i
yl-1,4-o
s
xazepan-
t
5-onesopher W. Becker, Bruce T. Dembofsky, James E. Hall, Robert T. Jacobs, Don E. Pivonka, Cyrus J. Ohnmacht*
Department of Medicinal Chemistry, AstraZeneca Pharmaceuticals LP, PO Box 15437, Wilmington, DE 19850-5437, USA
Fax +1(302)8864989; E-mail: cyrus.ohnmacht@astrazeneca.com
Received 18 January 2005; revised 2 May 2005
A report1 on the cyclization of the racemic cis-epoxide (5,
cis-racemate, Scheme 1) with MgI2 to yield racemic
trans-2-phenyltetrahydrofuran-3-ol (7, trans-racemate)
led us to speculate whether a similar transformation would
Abstract: An efficient two-step preparation of (6R,7R)-6-hydroxy-
7-phenyl-1,4-oxazepan-5-ones (1) starting from aminoethanols and
(2R,3S)-3-phenyloxirane-2-carboxylic ethyl ester or potassium salt
has been described. The most efficient catalyst identified for the
ring closure of the resulting intermediate epoxyamides was be possible with epoxyamide 8. We anticipated that as
with 5 and other similar alcohols, esters, and aldehydes,2
the epoxyamide 8 would exhibit chelation-controlled ep-
Sc(OTf)3. By choice of appropriate chiral starting substituted ami-
noethanol and 3-phenyloxirane-2-carboxylic derivatives, the proce-
dure allows facile synthesis of other single enantiomer 6-hydroxy-
oxide opening with MgI2 to yield the iodohydrin 9. A 7-
7-phenyl-1,4-oxazepan-5-ones.
exo-tet displacement of the iodide would theoretically
control the oxazepine versus pyran issue.
Key words: heterocycles, ring closure, epoxides, scandium,
magnesium
In order to rapidly test this approach we examined the re-
action of N-(2-hydroxy-2-phenylethyl)-N-methyl-3-phe-
nyloxirane-2-carboxamide (11df, Scheme 2) with MgI2
We wished to develop a synthesis of (6R,7R)-6-hydroxy-
7-phenyl-1,4-oxazepan-5-one (1) (Figure 1) that would
under the conditions employed by Karikomi.1 A 43%
yield of a 1:1 mixture of the 6-hydroxy-4-methyl-2,7-
diphenyl-1,4-oxazepan-5-ones 1f and 2d was obtained.
allow facile access for mono-, di- and tri-substitution at
R1, R2, R3, R4 and R5.
The relative stereochemistry of the substituents of the
product was determined by a NMR NOE study. The ma-
terial used in the study was prepared in 46% yield by the
method of Huang3 from commercial ethyl phenylglyci-
1
date (90% trans by H NMR) and DL-a-(methylamino-
methyl)benzylalcohol. NMR spectral analysis of 11df
confirmed that the material consisted only of trans-ep-
oxyamide. We did not further examine the diastereomeric
balance of 11df. Diastereomeric enrichment in the prepa-
ration of 11df would compromise a rigorous mechanistic
Figure 1 6-Hydroxy-7-phenyl-1,4-oxazepan-5-one diastereomers
1–4. See Table 2 for the letter assignment of R1–R5 combinations pre-
pared in this paper.
Scheme 1
Scheme 2 Reagents and conditions: a) Ethyl 3-phenyloxirane-2-carboxylate, MeOH, cat. NaOMe, –20 °C; b) 10 mol% MgI2, refluxing THF.
SYNTHESIS 2005, No. 15, pp 2549–2561
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Advanced online publication: 04.08.2005
DOI: 10.1055/s-2005-872122; Art ID: M00505SS
© Georg Thieme Verlag Stuttgart · New York

2550
C. W. Becker et al.
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analysis of the results of the ring closure. However, it is alcohol moiety on the epoxide. A direct epoxide opening
distinctly clear that trans-epoxide, such as 11df, should would be a 7-endo-tet ring closure. While 5-endo-tet ring
yield 6-hydroxy-7-phenyl-1,4-oxazepan-5-ones with cis- and 6-endo-tet ring closures are disfavored4 7-endo-tet
6-hydroxy and 7-phenyl groups if the speculated double ring closures are allowed and can even be facile under
inversion mechanism of Scheme 1 (starting with cis-ep- conditions of chelation control,5 a condition, in this case,
oxide; yielding trans products) is operational. At that possibly provided by the magnesium ion. The uncertainty
point in time, we felt that we were unable to distinguish around the diastereomeric purity of 11df prevented accu-
between two of the most likely alternative mechanisms, a rately deducing why only the two cis oriented 2,7-diphe-
carbonium ion intermediate or a concerted attack of the nyl derivatives 1f and 2d were obtained.
Table 1 Synthesis of Racemic trans-Epoxyamides
Mixture
11a
R1
R2
R3
H
H
H
H
H
R4
H
R5
Method
Yield (%)
H
H
H
B
A
B
A
A
A
A
27
84
40
46
59
69
60
11b
H
H
H
Me
H
11ce
11df
11h
C6H5 or (H)a
C6H5 or (H)a
H
H or (C6H5)a
H or (C6H5)a
H
H
H
Me
Me
Me
Me
Ph
11i
R1R4 = -(CH2)4-, R2,R3 = H
R2R3 = -(CH2)4-, R1,R4 = H
11j
a Mono-phenyl racemate
Table 2 Initial Scope-Determining Reactions with MgI2
Epoxyamide
11ab
R1
R2
R3
H
H
H
H
R4
H
R5
Oxazepanone (yield)a
No cyclized products
1b/2b (1:1) (50%)
No cyclized products
1he (9%), 2he(30%)
1i (0%), 2i (34%)
H
H
H
11bc
H
H
H
Me
H
11cec
C6H5 or (H)d
H
H or (C6H5)d
H
H
11hc
C6H5
Me
Me
Me
11ib
R1R4 = -(CH2)4-, R2 = R3 = H
R2R3 = -(CH2)4-, R1 = R4 = H
11jb
1jf (33%), 2jf (5%)
a Isolated yields.
b Reaction conditions: 20 mol% MgI2 in THF, overnight reflux.
c Reaction conditions: 10 mol% MgI2 in THF, overnight reflux.
d Mono phenyl racemate.
e Separated by flash column chromatography (hexanes–Et2O, 2:1).
f Separated as e, then crystallization from Et2O.
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Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2551
As 1f has the desired stereochemistry of 1, the utility of while the other trans-cyclohexyl derivative 11j gave the
this ring closure reaction in the context of our program desired fused cyclohexyl 1j in 33% yield.
was first investigated using additional racemic trans-ep-
In order to: 1) expedite preparation of our targeted ox-
oxyamides (Tables 1 and 2). As in the synthesis of 11df
azepanones 1, 2) elucidate some mechanistic features of
we employed the method of Huang3 (General Method A)
the ring closure and 3) examine the influence of possible
steric factors in the ring closure we decided to use only op-
tically pure starting epoxides in further syntheses.
to prepare the N-methyl substituted epoxyamides and an
adaptation of the method of Baldas and Porter6 (General
Method B) to prepare the secondary amides. The dia-
stereomeric makeup of 11ce, 11h–j was determined to be
1:1 (NMR or NMR and HPLC analysis).
The enantiomerically pure starting epoxyamides
(Table 3) used in further studies were all prepared by a
EDCI, HOBt coupling of the enantiomerically pure potas-
There are several intriguing observations that can be made
sium 3-phenyloxirane-2-carboxylate (Table 4) with the
concerning the cyclization results presented in Table 2.
appropriate (chiral) amine.
The secondary amides 11a or 11ce did not yield ring
Our initial study using enantiomerically pure starting ep-
closed products. Our working hypothesis was that amide
oxyamide was to be a repeat of the ring closure of 11j
N-substitution is necessary to ‘pre-organize’ the ring clo-
(Table 2) using a single diastereomer 12j (Scheme 3).
sure (Z amide versus E amide). In support of the hypothe-
However as we purified 12j by reversed phase chromatog-
raphy we discovered that a solution of purified 12j in 90%
MeCN–water containing 0.1% TFA on standing over-
night at room temperature gave a 90% yield (HPLC) of 1j.
sis, the 1H NMR spectra of the N-methyl amides all show
two conformations (twinned resonances) while the NH
amides show only a single set of resonances that can be as-
signed to the E conformation. The R1–R4 unsubstituted
11b underwent facile ring closure to a 1:1 mixture of 1b
and 2b. The use of chiral epoxide in the synthesis of 11b
would be expected to allow the synthesis of either pure 1b
or 2b. As with 11df and 11b the ring closure of the ep-
oxyamide 11h gave a mixture of 1h and 2h, however the
undesired diastereomer 2h predominated in a 3.3:1 ratio.
The cyclohexyl derivative 11i gave only the undesired 2i
Scheme 3 Reagents and conditions: a) 90% MeCN–H2O, 0.1%
TFA 16 h, 90%.
Table 3 Synthesis of Single-Enantiomer Epoxyamides
Epoxyamide Starting Epoxide R1
R2
H
R3
H
H
H
H
H
H
H
H
R4
H
R5
R8
H
R9
Ph
Ph
Ph
H
Yield (%)
12a
12b
12f
13f
14f
15f
12h
13h
12i
16
16
16
17
18
19
16
17
16
16
H
H
H
H
H
H
H
H
H
2R,3S
2R,3S
2R,3S
2S,3R
2R,3R
2S,3S
2R,3S
2S,3R
2R,3S
2R,3S
44
68
85
63
59
96
45
74
60
69
H
H
Me
Me
Me
Me
Me
Me
Me
H
Ph
Ph
Ph
Ph
H
H
H
H
Ph
Ph
H
H
H
H
Ph
Ph
H
Ph
Ph
H
H
Ph
H
R1R4 = (CH2)4 R2,R3 = H, R5 = Me
R2R3 = (CH2)4 R1,R4 = H, R5 = Me
Ph
Ph
12j
H
a EDCI, HOBt, NMM, CH2Cl2 (General method C) 0 °C → r.t.
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Table 4 Potassium 3-Phenyloxirane-2-carboxylates
The results of a study on the ring closure of the four (S)-
2¢-phenyl epoxyamides 12f, 13f, 14f and 15f are presented
in Table 5. TFA, as well as Sc(OTf)3, a reagent we had
found to be very useful in a synthesis of 3-hydroxy-2-phe-
nyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-ones7 were also
employed as ring closure catalysts.
R8
H
R9
Ph
H
R8
Ph
H
R9
H
MgI2 conditions were successful only with the 2R,3S-
trans-epoxyamide 12f (Table 5). This result as well as the
yield of 1f are consistent with that predicted from
Scheme 2 with the assumption that 11df consisted of a 1:1
diastereomeric mixture of 12f and 13d. Acid catalyst was
facile with the two 2R-epoxyamides (12f and 14f) but re-
quired longer reaction times and gave lower yields with
the two 2S-epoxyamides (13f and 15f). Sc(OTf)3 was ef-
ficient with all enantiomers but the relative sluggishness
of the 2S,3S-cis-epoxyamide 15f is evident.
16
18
17
19
Ph
Ph
To exemplify a ring closure with a substituent in the 3-po-
sition, we chose epoxyamides 12h and 13h (Table 6) con-
taining the 3¢-phenyl (S)-conformation and trans
configurations on the epoxide ring.
Table 5 Ring Closure of the (S)-2¢-Phenyl Epoxyamides
Starting
Reagent, yield,a reaction timeb
Epoxyamide
Oxazepinone
1f 2S,6R,7R
2f 2S,6S,7S
3f 2S,6R,7S
4f 2S,6S,7R
MgI2 (Method D)
87%, 3 h
TFA (Method E)
84%, 3 h
Sc(OTf)3 (Method F)
97%, 10 min
12f 2R,3S
13f 2S,3R
14f 2R,3R
15f 2S,3S
0%, 40 h
50%, 48 h
89%, 60 min
0%, 40 h
90%, 1 h
73%, 60 min
0%, 40 h
56%, 240 h
75%, 18 hb
a Typical reaction conditions: MgI2: 10 mol% MgI2 in THF under N2 at reflux, TFA: 10 mol% TFA in MeCN (0.4% TFA–MeCN by volume)
at r.t., Sc(OTf)3: 10 mol% Sc(OTf)3 in MeCN at r.t.
b Estimated (HPLC) 60% at 45 min.
Table 6 Ring Closure of Epoxyamides with a Substituent in the 3-Position
Reagent, yielda
Starting Epoxyamide
12h. 3¢R,2R,3S
Oxazepanone
1h 3R,6R,7R
2h 3R,6S,7S
MgI2b (Method D)
TFAc (Method E)
Sc(OTf)3d (Method F)
35%
10%
68%
76%
85%
13h. 3¢R,2S,3R
29%e
a Isolated yield.
b MgI2 (10 mol%) in THF under nitrogen at reflux overnight
c TFA (10 mol%) in MeCN (0.4% TFA–MeCN) at r.t. 24 h
d Sc(OTf)3 (10 mol%) in MeCN at r.t., 10 min.
e Yield determined by HPLC; addition of an additional 20 mol% MgI2 and 2 h additional reflux gave 85% isolated yield.
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Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2553
Cyclization of 12h was sluggish compared to 13h. While
the overnight MgI2 reaction of both 12h and 13h appear
equivalent, 12h did not proceed further with additional
catalyst. Unidentified iodinated and elimination products
predominated. With TFA, elimination products predomi-
nated with 12h.
In an effort to resolve some of the questions generated by
our initial scope-finding ring closure reactions (Table 2)
and to selectively prepare derivatives with the proper ste-
reochemistry for our program we undertook the series of
reactions shown in Table 7.
As is illustrated in Table 7, we were able to obtain the de-
sired pure enantiomers 1a, 1b and 1i employing scandium
triflate as the catalyst. Consistent with our scope deter-
mining reactions of Table 2 only 1b was prepared suc-
cessfully with MgI2 catalyst. TFA was also only
successful in the synthesis of 1b.
Figure 2 Raman intensity vs. time profiles for reaction of 12f
(green line) with TFA to yield 1f (blue line).
The TFA (4.5 mol%) catalyzed ring closure of 0.093 M
12f in MeCN, was followed by Raman spectroscopy
(Figure 2). The disappearance of starting material was fol-
lowed using the very strong epoxide band at 1238 cm–1.
The appearance of product was followed by using the
band at 1198 cm–1. The aromatic band at 1011.3–972.6
cm–1 was used as an internal standard to account for dif-
ferences in spectrometer alignment, temperature effects,
etc. The starting material and product band intensity pro-
files are covariant within the time resolution of the Raman
experiment. There is no evidence of a two-step reaction in
which the starting material was first complexed by the
acid and then later reacted to effect ring closure.
NMR Studies. Structural Assignment as Oxazapinones
Structural assignment of 1f and 2d (Scheme 2) serves to
exemplify NMR studies carried out to establish structures.
The 300 MHz 1H NMR spectrum of the mixture is shown
in Figure 3. An oxazepanone versus morpholinone ring
was confirmed based on a 2D HMBC spectrum optimized
for two and three-bond carbon–proton couplings [delays
set for J(C,H) = 10 Hz]. In this spectrum (Figure 4), the pro-
ton attached to C7 (oxazepanone) had two long-range
coupling correlations to carbons 8 and 9 in the phenyl A
ring. Only in the seven-membered oxazepanone ring is
this proton within three bonds of the two carbons. In the
morpholinone, H7 is four bonds from carbon 9 and a cou-
pling correlation would not be expected in this experi-
ment.
A similar experiment carried out with 0.7 mol% scandium
triflate was complete in about 30 minutes. A 4.5 mol%
scandium triflate reaction was virtually instantaneous.
Table 7 Preparation of Pure Enantiomers 1a, 1b and 1i Using Scandium Triflate as the Catalyst
Starting
Reagent yielda
b
Epoxyamide
Oxazepanone
R1
H
R2
H
R3
H
R4
H
R5
MgI2
0%
TFAb
Sc(OTf)3
29%c
12a
1a
1b
1i
H
0%
12b
H
H
H
H
CH3
CH3
56%
0%
50%
traced
82%
12i
R1–R4 = -(CH2)4-, R2 = R3 = H
61%e
a Isolated yield.
b See Table 3 for reaction conditions.
c Sc(OTf)3 (10 mol%), MeCN, 24 h at r.t.
d Presence by HPLC.
e Sc(OTf)3 (10 mol%), MeCN, 1 h at r.t. Real-time Raman spectroscopy analysis of epoxide reactivity.
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2554
C. W. Becker et al.
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Figure 3 1H NMR spectrum (300 MHz) of the mixture of 1f and 2d.
Figure 5 A portion of the contour plot of the NOESY spectrum of
1f and 2d mixture in CDCl3.
and the ethane protons. That data is consistent with an E
amide conformation (12a-E, Figure 7).
In the N-methyl amides (12b exemplifies the NMR data),
1
the H spectra consisted of two sets of resonances that
could be assigned to each conformer (Figure 8). The tem-
perature was lowered to –10 °C for acquisition of the
NMR spectra for the N-methyl amides because there was
better resolution of the resonances for the two conformers
at the lower temperature. As shown in Figure 9, the N-
methyl group of the E conformer displayed NOE to the
Figure 4 A portion of the contour plot of the HMBC spectrum of 1f
and 2d mixture in CDCl3.
The protons attached to C6 and C7 (H6 and H7) are in a
trans configuration as based on a 2D NOESY experiment
(Figure 5), which showed NOE’s between H6 and the A
phenyl ring ortho protons H9. This would only be expect-
ed if H6 and the A phenyl ring were in a cis configuration
relative to each other, which necessitates H6 and H7 being
trans to one another. There was very little NOE observed
between H6 and H7, which indicated that they are on op-
posite sides of the ring. The coupling constant between H6
and H7 was measured to be 9.1 Hz. This value also sup-
ports a trans configuration.
Figure 6 1H NMR spectrum (400 MHz) of 12a in CDCl3 at 27 °C.
NMR Studies: Study of Epoxy Amide E/Z Conformations
The epoxyamides of Table 3 were used in this study. As
the secondary amide 12a exists in solution as one con-
former, there was a single set of resonances for all protons
in the sample (Figure 6). A 2D NOESY spectrum shows
NOEs between the NH proton and the protons of the ep-
oxy ring whereas there is no NOE to the epoxy protons
Figure 7 A portion of the contour plot of the NOESY spectrum of
12a-E in CDCl3 at 27 °C.
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Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2555
aminium (2R,3S)-3-phenyloxirane-2-carboxylate9 (28.54 g, 0.10
mol), EtOH (65 mL) and H2O (15 mL) was added a warm (35 °C)
solution of KOH (6.7 g, 0.12 mol) in EtOH (50 mL). After stirring
for 20 min at ambient temperature, Et2O (200 mL) was added, stir-
ring was continued for an additional 10 min, the white solid collect-
ed by filtration and washed with Et2O. The yield of dried white solid
was 17.9 g (89%); [a]D25 –145.7 (c = 1.1, H2O).
epoxy ring H3 proton 2. For the Z conformer, there was
NOE observed between ethane H6 and the epoxy ring.
Quite similar and consistent results were observed for the
other N-methyl amides. Thus, the NOE data could be used
to assign the E and Z resonances in each spectrum for each
compound in the series.
1H NMR (300 MHz, DMSO-d6): d = 7.34–7.22 (m, 5 H), 3.67 (d,
J = 1.7 Hz, 1 H), 2.98 (d, J = 1.7 Hz, 1 H).
Potassium (2S,3R)-3-Phenyloxirane-2-carboxylate (17)
Using the procedure described for 16 except using (1R)-1-phenyle-
thanaminium (2S,3R)-3-phenyloxirane-2-carboxylate9 (5.24 g,
0.184 mol), returned the title compound (2.2 g, 60%) as a white
solid; [a]D25 +143.5 (c = 1.47, H2O).
1H NMR (300 MHz, DMSO-d6): d = 7.35–7.22 (m, 5 H), 3.68 (d,
J = 2 Hz, 1 H), 2.99 (d, J = 2 Hz, 1 H).
Potassium (2R,3R)-3-Phenyloxirane-2-carboxylate (18)
Using a procedure similar to that described for 16 except using ethyl
(2R,3R)-3-phenyloxirane-2-carboxylate10 (0.934 g, 4.9 mmol)
returned the title compound (0.793 g, 80%) as a white solid;
[a]D25 –6 (c = 1.05, H2O).
Figure 8 1H NMR (400 MHz) spectrum of 12b in CDCl3 at –10 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.49–7.46 (m, 2 H), 7.26–7.19
(m, 3 H), 3.84 (d, J = 5 Hz, 1 H), 3.32 (d, J = 5 Hz, 1 H).
Potassium (2S,3S)-3-Phenyloxirane-2-carboxylate (19)
Using a procedure similar to that described for 16 except using ethyl
(2S,3S)-3-phenyloxirane-2-carboxylate10 (0.753 g, 3.9 mmol) re-
turned the title compound (0.635 g, 80%) as a white solid; [a]D25 +6
(c = 1.05, H2O).
1H NMR (300 MHz, DMSO-d6): d = 7.49–7.46 (m, 2 H), 7.26–7.20
(m, 3 H), 3.84 (d, J = 5 Hz, 1 H), 3.32 (d, J = 5 Hz, 1 H).
(1S,2S)-2-(Methylamino)cyclohexanol (20)
Oil.
[a]D23 +73.3 (c = 0.9, H2O); Lit.11 [a]D20 +86.3 (c = 5, H2O), Lit.12
[a]D20 +92.5 (c = 5, H2O).
(1R,2R)-2-(Methylamino)cyclohexanol (21)
Oil; bp 85–95 °C (kugelrohr bulb temperature)/2 torr; [a]D24 –84.1
Figure 9 A portion of the contour plot of the NOESY spectrum of
12b in CDCl3 at –10 °C.
20
20
(c = 5, H2O); Lit.11 [a]D –84.4 (c = 5, H2O), Lit.12 [a]D –91.5
(c = 5, H2O).
Compounds 20 and 21 were obtained via resolution of (1RS,2RS)-
2-(methylamino)cyclohexanol13 employing (+)-di-para-toluoyltar-
taric acid13 and (–)-di-para-toluoyltartaric acid, respectively. [Note
that the stereochemistry of the enantiomers are misdrawn in ref.13]
In conclusion, we have developed a facile method of prep-
aration of single enantiomer 6-hydroxy-7-phenyl-1,4-ox-
azepan-5-ones. The method was largely exemplified with
6R,7R-enantiomers required for our program but can
readily be applied to other single enantiomers. We exam-
ined three catalysts in the ring closure of the intermediate
epoxyamides and in all cases where a comparison was
carried out Sc(OTf)3 was superior to MgI2 or TFA. These
results raise interesting questions about the stereochemi-
cal and electronic factors that influence the selectivities
evidenced by our synthetic results. Additional studies
would be required to fully elucidate the mechanistic de-
tails of the ring closure reaction.
(2R)-2-(Methylamino)-2-phenylethanol (22)
To a stirred cooled (0 °C) mixture of LiAlH4 (6.11 g, 40 mmol) and
THF (100 mL) under a N2 atmosphere was added dropwise a solu-
tion of (2R)-[(ethoxycarbonyl)amino](phenyl)acetic acid14 {mp
143–145°, [a]D25 –154.4 (c = 1.036, MeOH); Lit.15 [a]D20 –158 (c =
1, MeOH)} (8.93 g, 40 mmol) keeping the temperature between 0–
5 °C. The mixture was stirred at ambient temperature for 15 min and
then stirred at reflux overnight. The mixture was cooled in an ice
bath and 15% NaOH solution (20 mL) was added cautiously drop-
wise. When approximately half had been added the reaction became
a gel-like mass. THF (200 mL) was added, the mixture was swirled
and the 15% NaOH addition was completed. After stirring for 1 h
the solid was filtered off and the filter cake washed well with
EtOAc. The solvent was the removed from the filtrate to yield a
clear oil which was placed under vacuum where it solidified, (5.91
Potassium (2R,3S)-3-Phenyloxirane-2-carboxylate (16)
This material was prepared essentially by a method reported by
Harada8 for the preparation of potassium (2,3-trans)-3-phenylox-
irane-2-carboxylate. To a stirred mixture of (1S)-1-phenylethan-
24
g, 98%); mp 53–56 °C (Lit.16 62 °C); [a]D –84.5 (c = 1.018,
EtOH); Lit.17 [a]D20 –79.6 (c = 1.0, EtOH).
Synthesis 2005, No. 15, 2549–2561 © Thieme Stuttgart · New York

2556
C. W. Becker et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.27–7.38 (m, 5 H), 3.70–3.75 (m,
1 H), 3.63–3.67 (m, 1 H), 3.52–3.58 (m, 1 H), 2.35 (s, 3 H), 1.8 (br
s, 2 H, exchangeable). NMR analysis using the chiral shift reagent
TBPTA18 gave an ee of > 99%.
N-(2-Hydroxyethyl)-N-methyl-(2,3-trans)-3-phenyloxirane-2-
carboxamide (11b)
To a solution of ethyl 3-phenyloxirane-2-carboxylate (10.0 g, 52.0
mmol) in MeOH (20 mL) at –20 °C was added 2-(methylamino)eth-
anol (4.6 g, 62.0 mmol) followed by catalytic NaOMe (25%, 20
drops). The reaction was then set in a freezer (ca –20 °C) for 10 d,
diluted with 10% HCl (10 drops), H2O (100 mL), extracted with
CH2Cl2 (2 ×), and the organic layers combined, dried, filtered and
evaporated to afford the title compound (9.7 g, 84%).
1H NMR (300 MHz, CDCl3): d = 7.44–7.31 (m, 5 H), 4.08 (s, 1 H),
3.87–3.79 (m, 2.6 H), 3.67–3.69 (m, 2.4 H), 3.19 (s, 1.7 H), 3.04 (s,
1.3 H), 2.82 (br s, 0.4 H), 2.70 (br s, 0.6 H).
(1S)-2-(Methylamino)-1-phenylethanol (23)
A
stirred mixture of (1RS)-2-(methylamino)-1-phenylethanol
(31.24 g, 206.6 mmol) and acetone (250 mL) was heated to near re-
flux to dissolve all the solid and a solution of dibenzoyl-D-tartaric
acid (18.51 g, 51.7 mmol) in acetone (100 mL) was added in one
portion. After a few minutes a precipitate appeared. The mixture
was stirred for 2 h at ambient temperature, the solid collected by fil-
tration, washed with acetone (100 mL) and Et2O (100 mL) and dried
in vacuo at 35 °C to yield bis[(2S)-2-hydroxy-N-methyl-2-phenyl-
ethanaminium]dibenzoyl-D-tartrate as a white solid (30.71 g, 90%);
mp 162–163 °C; [a]D24 +100.0 (c = 1.035, H2O).
1H NMR (300 MHz, DMSO-d6): d = 7.96 (d, J = 7.0 Hz, 4 H), 7.58–
7.63 (t, 2 H), 7.45–7.50 (t, 4 H), 7.22–7.34, (m, 10 H), 5.63 (s, 2 H),
4.79 (dd, J = 9.7, 3.1 Hz, 2 H), 2.92 (dd, J = 3.3, 12.5 Hz, 2 H), 2.75–
2.82 (m, 2 H), 2.44 (s, 6 H), plus 6 exchangeable protons.
MS (APCI): m/z = 222 [M + H].
(23-trans)-N-[(1R)-2-Hydroxy-1-phenylethyl]-N-methyl-3-phe-
nyloxirane-2-carboxamide (11h)
Using a procedure similar to that described for 11df except using
(2R)-2-(methylamino)-2-phenylethanol (22, 12.6 g, 83.4 mmol), a
reaction time of 96 h, concentration of the reaction mixture and col-
umn chromatography (2% MeOH–CHCl3) yielded pure 11h (12.2
g, 59%).
1H NMR (300 MHz, CDCl3): d = 7.16–7.39 (m, 10 H), 5.81 (q, J =
7.4 Hz, 0.6 H), 5.31 (q, J = 8.1 Hz, 0.4 H), 4.12–4.22 (m, 3 H), 3.99
(d, J = 1.3 Hz, 0.2 H), 3.83 (d, J = 1.4 Hz, 0.2 H), 3.72 (d, J = 1.5
Hz, 0.3 H), 3.70 (d, J = 1.3 Hz, 0.3 H), 2.92 (s, 0.6 H), 2.87 (s, 0.6
H), 2.82 (s, 0.8 H), 2.80 (s, 0.8 H), 2.46–2.58 (m, 0.6 H).
Anal. Calcd for C36H40N2O10 (660.73): C, 65.44; H, 6.10; N, 4.24.
Found: C, 65.15; H, 5.97; N, 4.16.
A sample of the salt, freed as described below, gave title compound;
24
24
[a]D +41.0 (c = 1.024, EtOH); Lit.19 [a]D +40.41 (c = 1.89,
EtOH). NMR analysis using the chiral shift reagent TBPTA18 gave
an ee of 92.6%.
A portion (15.63 g) of the above salt was dissolved in refluxing 95%
EtOH (250 mL) and treated warm with sufficient Et2O to bring the
volume of the solution to 400 mL. After standing in a freezer for 2
h, the solid was collected, washed with Et2O and dried in vacuo at
35 °C to return 12.52 g (80% recovery) of purified bis[(2S)-2-hy-
droxy-N-methyl-2-phenylethanaminium] dibenzoyl-D-tartrate; mp
172–173 °C; [a]D25 +103.3 (c = 1.045, H2O).
MS (APCI): m/z = 298 [M + H].
(2,3-trans)-N-[(1S,2S)-2-Hydroxycyclohexyl]-N-methyl-3-phe-
nyloxirane-2-carboxamide (11j)
Using a procedure similar to that described for 11h except using
(1S,2S)-2-(methylamino)cyclohexanol (20, 3.00 g, 21.1 mmol) and
a reaction time of 6 d gave pure title compound 11j (3.5 g, 60%).
1H NMR (300 MHz, CDCl3): d = 7.29–7.41 (m, 5 H), 3.48–4.35 (m,
4 H), 3.04 (s, 0.8 H), 3.01 (s, 0.8 H), 2.92 (s, 1.4 H), 1.90–2.36 (m,
2 H), 1.47–1.93 (m, 3 H), 1.18–1.61 (m, 4 H).
To a mixture of the purified bis[(2S)-2-hydroxy-N-methyl-2-phe-
nylethanaminium] dibenzoyl-D-tartrate (12.5 g, 18.9 mmol) and
H2O (125 mL) in a separatory funnel were added 28% ammonium
hydroxide (12.5 mL, 90 mmol) and EtOAc (75 mL) and the mixture
was shaken until no solid remained. The aqueous phase was extract-
ed with EtOAc (5 × 75 mL) and the combined EtOAc extracts were
stripped in vacuo. The residual oil was treated with Et2O and a small
amount of Celite, swirled and filtered. The solvent was removed
and the colorless oil placed under high vacuum where it solidified.
The yield of the white solid title compound was 5.7 g [100% from
the salt, 72% overall from starting racemic 2-(methylamino)-1-phe-
nylethanol]; mp 45–47 °C (Lit.19 39–40 °C, Lit20,21 43–45 °C);
[a]D23 +42.0 (c = 1.012, EtOH).
MS (APCI): m/z = 276 [M + H].
(2,3-trans)-N-[(1R,2R)-2-Hydroxycyclohexyl]-N-methyl-3-phe-
nyloxirane-2-carboxamide (11i)
Using a procedure similar to that described in 11h except using
(1R,2R)-2-(methylamino)cyclohexanol (21, 4.3 g, 33.3 mmol) and
a reaction time of 14 d yielded the pure title compound 11i (5.7 g,
69%).
1H NMR (300 MHz, CDCl3): d = 7.28–7.44 (m, 5 H), 4.25–4.37 (m,
0.5 H), 4.13 (d, J = 2.0 Hz, 0.2 H), 4.07 (m, 0.6 H), 3.82 (d, J = 2.0
Hz, 0.2 H), 3.47–3.68 (m, 2.5 H), 3.04 (s, 0.75 H), 3.01 (s, 0.75 H),
2.92 (s, 1.5 H), 2.39 (d, J = 5.0 Hz, 0.2 H), 2.06–2.19 (m, 1.3 H),
1.96 (d, J = 7.0 Hz, 0.5 H), 1.56–1.78 (m, 3 H), 1.27–1.56 (m, 4 H).
1H NMR (300 MHz, CDCl3): d = 7.25–7.38 (m, 5 H), 4.73 (dd, J =
4.0, 8.8 Hz, 1 H), 2.82 (dd, J = 4.0, 11.8 Hz, 1 H), 2.72 (dd, J = 8.8,
11.8 Hz, 1 H), 2.46 (s, 3 H), 2.40 (br s, 2 H, exchangeable). NMR
analysis using the chiral shift reagent TBPTA18 gave an ee of >99%.
MS (APCI): m/z = 276 [M + H].
Preparation of Epoxyamides by the Method of Huang;3 General
Method A
N-(2-Hydroxy-2-phenylethyl)-N-methyl-(2,3-trans)-3-phenyl-
Preparation of Epoxyamides by the Method of Baldas and Por-
ter;6 General Method B
N-(2-Hydroxyethyl)-(2,3-trans)-3-phenyloxirane-2-carbox-
amide (11a)
To a stirred solution of ethanolamine (3.10 g, 5.1 mmol), MeOH (15
mL) and H2O (9 mL), under N2, was added a solution of ethyl-3-
phenyloxirane-2-carboxylate (10.0 g, 5.2 mmol) in MeOH (10 mL)
and the mixture was stirred at ambient temperature overnight. The
solvent was removed in vacuo and the residue was chromato-
graphed on silica gel (2% MeOH–CH2Cl2) to yield the solidified
impure material (4.50 g, 43%). A second chromatography on silica
gel (20% and 40% Et2O–CH2Cl2 followed by 5% MeOH–CH2Cl2)
and trituration of combined purer fractions (TLC: silica gel, 10%
oxirane-2-carboxamide (11df)
To a solution of ethyl 3-phenyloxirane-2-carboxylate (5.0 g, 26.0
mmol) in MeOH (10 mL) at –20 °C was added 2-(methylamino)-1-
phenylethanol (4.29 g, 28.4 mmol) followed by catalytic NaOMe
(25%, 10 drops). The reaction was placed in a freezer (ca –20 °C)
for 2 d, filtered and washed with cold MeOH to afford the title mix-
ture as a white solid (3.3 g, 46%).
1H NMR (300 MHz, CDCl3): d = 7.40–7.28 (m, 10 H), 5.08–4.88
(m, 0.9 H), 4.08–4.04 (m, 0.8 H), 3.85–3.44 (m, 3.3 H), 3.07, 3.06
(s, 2 H), 2.98 (s, 1 H).
Synthesis 2005, No. 15, 2549–2561 © Thieme Stuttgart · New York

PAPER
Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2557
MeOH–CHCl3) with Et2O–hexanes, yielded the title epoxyamide as
a white solid (2.78 g, 27%); mp 92–94 °C.
4.04 (d, J = 1.8 Hz, 0.33 H), 3.81–3.46 (m, 3.67 H), 3.07 (s, 3 H),
2.67 (d, J = 3.9 Hz, 0.33 H).
1H NMR (300 MHz, CDCl3): d = 7.39–7.35 (m, 3 H), 7.30–7.25 (m,
2 H), 6.65 (br s, 1 H, exchangeable), 3.91 (d, J = 2.0 Hz, 1 H), 3.80–
3.75 (m, 2 H), 3.55 (d, J = 2.0 Hz, 1 H), 3.57–3.40 (m, 2 H), 2.28 (s,
1 H, exchangeable).
Anal. Calcd for C18H19NO3·0.2 H2O (300.96): C, 71.84; H, 6.50; N,
4.65. Found: C, 71.83; H, 6.31; N, 4.83.
(2R,3R)-N-[(2S)-2-Hydroxy-2-phenylethyl]-N-methyl-3-
phenyloxirane-2-carboxamide (14f)
Using a procedure similar to that described for 12f except using po-
MS (APCI): m/z = 208 [M + H].
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.72; H, 6.36; N, 6.76.
tassium (2R,3R)-3-phenyloxirane-2-carboxylate (18, 460 mg, 2.4
23
mmol) gave the pure 14f (420 mg, 59%); [a]D +18.66 (c = 1.34,
EtOH).
N-(2-Hydroxy-2-phenylethyl)-(2,3-trans)-3-phenyloxirane-2-
carboxamide (11ce)
Using a procedure similar to that described for 11a except using ra-
cemic 2-amino-1-phenylethanol (21.6 g, 15.7 mmol) and ethyl 3-
phenyloxirane-2-carboxylate (30.8 g, 16.0 mmol) in MeOH (60
mL)–H2O (30 mL) gave the white title compound (17.95 g, 40%);
mp 137–141 °C.
1H NMR (300 MHz, CDCl3): d = 7.45–7.03 (m, 10 H), 4.81–4.79
(m, 0.2 H), 4.71–4.62 (m, 0.8 H), 4.32 (d, J = 4.4 Hz, 0.8 H), 4.19
(d, J = 4.4 Hz, 0.2 H), 3.93 (d, J = 4.4 Hz, 0.8 H), 3.85–3.42 (m, 1.2
H), 3.02 (dd, J = 14.1, 7.2 Hz, 1 H), 2.85 (d, J = 4.4 Hz, 0.8 H), 2.75
(s, 0.6 H), 2.74 (s, 2.4 H), 2.04–2.02 (m, 0.2 H).
MS (APCI): m/z = 298 [M + H].
1H NMR (300 MHz, CDCl3): d = 7.42–7.30 (m, 8 H), 7.25–7.23 (m,
2 H), 6.60 (br m, 1 H), 4.92–4.87 (m, 1 H), 3.81 (d, J = 1.8 Hz, 0.5
H), 3.78 (d, J = 1.8 Hz, 0.5 H), 3.77–3.68 (m, 1 H), 3.52 (d, J = 1.8
Hz, 1 H), 3.47–3.38 (m, 1 H), 2.80 (br s, 1 H).
Anal. Calcd for C18H19N2O3·(0.1 C4H8O2) (306.17): C, 72.18; H,
6.52; N, 4.58. Found: C, 72.15; H, 6.47; N, 4.67.
(2S,3S)-N-[(2S)-2-Hydroxy-2-phenylethyl]-N-methyl-3-phenyl-
oxirane-2-carboxamide (15f)
MS APCI, m/z = 266 [M + H – H2O].
Using a procedure similar to that described for 12f except using po-
tassium (2S,3S)-3-phenyloxirane-2-carboxylate (19, 390 mg, 2.0
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
71.74; H, 6.02; N, 4.81.
20
mmol) yielded the pure 15f (580 mg, 96%); mp 118–119 °C; [a]D
–88.7 (c = 1.16, EtOH).
Preparation of Epoxyamides by Carbodiimide Coupling;
General Method C
(2R,3S)-N-[(2S)-2-Hydroxy-2-phenylethyl]-N-methyl-3-phenyl-
1H NMR (300 MHz, CDCl3): d = 7.40–7.14 (m, 10 H), 4.88–4.84
(m, 0.25 H), 4.63–4.58 (m, 0.75 H), 4.30 (d, J = 4.4 Hz, 0.75 H),
4.24 (d, J = 4.4 Hz, 0.25 H), 4.06 (d, J = 4.4 Hz, 0.25 H), 3.92 (d,
J = 4.4 Hz, 0.75 H), 3.72–3.44 (m, 1 H), 3.26 (d, J = 4.0 Hz, 0.5 H),
3.21 (d, J = 4.0 Hz, 0.5 H), 3.14 (d, J = 3.6 Hz, 0.75 H), 2.85 (s, 3
H), 2.47 (d, J = 3.4 Hz, 0.25 H).
oxirane-2-carboxamide (12f)
To a stirred cooled (ice-bath) solution of (1S)-2-(methylamino)-1-
phenylethanol (23, 800 mg, 5.3 mmol) in CH2Cl2 (25 mL) was add-
ed successively potassium (2R,3S)-3-phenyloxirane-2-carboxylate
(16, 711 mg, 3.65 mmol), HOBt (1.2 g, 7.8 mmol), 1-(3-dimeth-
ylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.3
mmol) and N-methylmorpholine (581 mL, 5.3 mmol). After 1.5 h
the ice bath was removed and the reaction stirred at ambient temper-
ature. After 2.5 h the volume was reduced to ca. 10 mL and the res-
idue partitioned between H2O (25 mL) and EtOAc (50 mL). The
organic layer was washed successively with 0.5 N HCl (2 × 50 mL),
H2O (2 × 50 mL), sat. NaHCO3 (25 mL), brine (25 mL), dried
(Na2SO4), filtered and the solvent was removed to yield the crude
title compound (1.1 g). Trituration with Et2O (25 mL) returned pure
12f (590 mg). Material obtained by evaporation of the filtrate sol-
vent was purified by chromatography (eluent: 50% EtOAc–hex-
anes) to give an addition 340 mg of pure title compound (85% total
yield). The 340 mg was recrystallized from Et2O (10 mL) to afford
the analytically pure title compound (224 mg); mp 99.5–102.5 °C;
[a]D23 –26.9 (c = 1.08, EtOH).
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19N2O3 (297.35): C, 72.71; H, 6.44; N, 4.71.
Found: C, 72.54; H, 6.38; N, 4.75.
(2R,3S)-N-[(1S,2S)-2-Hydroxycyclohexyl]-N-methyl-3-phenyl-
oxirane-2-carboxamide (12j)
Using a procedure similar to that described for 12f except using
(1S,2S)-2-(methylamino)cyclohexanol (20, 1.8 g, 13.9 mmol)
yielded the title compound 12j (2.35 g, 81%). Recrystallization
from toluene returned analytically pure 12j (1.4 g, 60% recovery);
mp 119–121 °C; [a]D23 –99.1 (c = 1.07, MeCN).
1H NMR (300 MHz, CDCl3): d = 7.31–7.38 (m, 5 H), 4.30 (m, 0.5
H), 4.13 (d, J = 1.9 Hz, 0.5 H), 4.08 (d, J = 1.8 Hz, 0.5 H), 3.69 (d,
J = 1.9 Hz, 0.5 H), 3.51–3.68 (m, 2 H), 3.04 (s, 1.5 H), 2.92 (s, 1.5
H), 2.26 (s, 0.5 H, exchangeable), 2.13 (m, 0.5 H, exchangeable),
1.67–2.00 (m, 4 H), 1.23–1.49 (m, 4 H).
1H NMR (300 MHz, CDCl3): d = 7.43–7.28 (m, 10 H), 5.06 (m, 0.6
H), 4.98–4.91 (m, 0.4 H), 4.08 (d, J = 1.7 Hz, 1 H), 3.85–3.57 (m, 4
H), 3.06 (s, 1.2 H), 2.98 (s, 1.8 H).
MS (APCI); m/z = 276 [M + H].
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
69.52; H, 7.70; N, 5.18
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19N2O3 (297.37): C, 72.71; H, 6.44; N, 4.71.
Found: C, 72.40; H, 6.42; N, 4.74.
(2R,3S)-N-[(1R)-2-Hydroxy-1-phenylethyl]-N-methyl-3-
phenyloxirane-2-carboxamide (12h)
Using a procedure similar to that described for 12f except using
(2R)-2-(methylamino)-2-phenylethanol (22, 2.26 g, 15.0 mmol) and
a 20 h reaction time gave the pure title compound 12h (1.34 g,
45%); [a]D23 –212.6 (c = 1.03, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.40–7.16 (m, 10 H), 5.83 (dd,
J = 9.3, 5.1 Hz, 0.6 H), 5.31 (t, J = 7.0 Hz, 0.4 H), 4.23– 4.08 (m, 3
H), 3.97 (d, J = 1.7 Hz, 0.4 H), 3.69 (d, J = 1.7 Hz, 0.6 H), 2.87 (s,
1.8 H), 2.82 (s, 1.2 H), 2.48 (t, J = 5.5 Hz, 0.4 H), 2.36 (dd, J = 7.3,
4.4 Hz, 0.6 H).
(2S,3R)-N-[(2S)-2-Hydroxy-2-phenylethyl]-N-methyl-3-phenyl-
oxirane-2-carboxamide (13f)
Using a procedure similar to that described for 12f except using po-
tassium (2S,3R)-3-phenyloxirane-2-carboxylate (17, 610 mg, 3.2
mmol) yielded 13f (600 mg, 63%); [a]D23 +104.6 (c = 1.09, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.43–7.22 (m, 10 H), 5.07–5.02
(m, 0.67 H), 4.94–4.88 (m, 0.33 H), 4.08 (d, J = 1.8 Hz, 0.67 H),
Synthesis 2005, No. 15, 2549–2561 © Thieme Stuttgart · New York

2558
C. W. Becker et al.
PAPER
HRMS: m/z [M + H] calcd for C18H20NO3: 298.1443; found:
298.1432.
mmol) and the aqueous workup described for 12f followed by col-
umn chromatography of the resulting oil on silica gel (eluent:
CHCl3, then 2% MeOH in CHCl3) gave the impure title compound
(2.11 g). Further purification by column chromatography on silica
gel [eluent: hexanes–CH2Cl2 (1:1), CH2Cl2 and 5%, 10% and 20%
EtOAc–CH2Cl2] returned the title compound (0.93 g, 18%) as a hy-
groscopic tacky solidified white foam; [a]D –14.9 (c = 1.01,
EtOH).
1H NMR (300 MHz, CDCl3): d = 7.4–7.33 (m, 5 H), 4.36–4.27 (m,
0.55 H), 4.08 (m, 1 H), 3.83 (d, 0.45 H), 3.73–3.48 (m, 2 H), 3.01
(s, 1.65 H), 2.92 (s, 1.35 H), 2.47 (d, 0.45 H, exchangeable), 2.17–
2.12 (m, 1.55 H, 0.55 H exchangeable), 1.79–1.22 (m, 7 H).
(2S,3R)-N-[(1R)-2-Hydroxy-1-phenylethyl]-N-methyl-3-
phenyloxirane-2-carboxamide (13h)
Using a procedure similar to that described for 12f except using
(2R)-2-(methylamino)-2-phenylethanol (22, 1.24 g, 8.19 mmol),
potassium (2S,3R)-3-phenyloxirane-2-carboxylate (17, 1.05 g, 5.46
mmol) and a 5 h reaction time gave the pure title compound 13h
(1.20 g, 74%); [a]D23 –43.0 (c = 1.0, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.39–7.26 (m, 10 H), 5.81–5.77
(m, 0.6 H), 5.35–5.30 (m, 0.4 H), 4.20–4.09 (m, 3 H), 3.82 (d, J =
1.4 Hz, 0.4 H), 3.72 (d, J = 1.4 Hz, 0.6 H), 2.92 (s, 1.8 H), 2.80 (s,
1.2 H), 2.44 (t, J = 5.9 Hz, 0.6 H), 2.27 (t, J = 5.8 Hz, 0.4 H).
23
Anal. Calcd for C16H21NO3·0.1 H2O (277.15): C, 69.34; H, 7.71; N,
5.05. Found: C, 69.34; H, 7.76; N, 4.85.
HRMS: m/z [M + H] calcd for C18H20NO3: 298.1443; found:
298.1439.
MgI2 Ring Closures; General Method D
(2S,6R,7R)- and (2R,6S,7S)-6-Hydroxy-4-methyl-2,7-diphenyl-
1,4-oxazepan-5-one (1:1 mixture of 1f and 2d)
(2R,3S)-N-(2-Hydroxyethyl)-3-phenyloxirane-2-carboxamide
(12a)
To a stirred, cooled (ice-bath) mixture of potassium (2R,3S)-3-phe-
nyloxirane-2-carboxylate (16, 1.01 g, 5.0 mmol) and CH2Cl2 (40
mL) were added successively HOBt (1.67 g, 12.5 mmol), 1-(3-di-
methylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.63 g,
8.5 mmol) and N-methylmorpholine (0.86 g, 8.5 mmol) and the
mixture was stirred for 10 min. Aminoethanol (0.52 g, 8.5 mmol)
was added, the bath was removed and the mixture was stirred at am-
bient temperature overnight. The reaction mixture containing a
white precipitate was added to a 1.5 inch diameter column contain-
ing 50 g of silica gel and the column was eluted with 2% MeOH–
CH2Cl2. Fractions containing the desired material (TLC, silica gel:
2% MeOH–CH2Cl2) were combined, the solvent was removed in
vacuo and the residual gum was triturated with toluene. The collect-
ed white solid was recrystallized from hot toluene (15 mL) to yield
the title compound as colorless needles (0.45 g, 44%); mp 102–104
°C; [a]D23 –140.2 (c = 1.035, EtOH).
Figure 10 Numbering of 1f:2d for 13C NMR spectra.
To a stirred solution of (2,3-trans)-N-(2-hydroxy-2-phenylethyl)-N-
methyl-3-phenyloxirane-2-carboxamide (11df, 2.1 g, 7.6 mmol) in
anhyd THF (300 mL) was added 10 mol% of MgI2 (215 mg, 0.76
mmol, 98% purity) and the mixture was heated at reflux over a
weekend, cooled, and evaporated to an orange oil. Column chroma-
tography (1% MeOH–CH2Cl2) afforded the title mixture of 1f and
2d (900 mg, 43%; Figure 10).
1H NMR (300 MHz, CDCl3): d = 7.29–7.46 (m, 10 H), 4.70 (d, J =
8.7 Hz, 1 H), 4.57 (dd, J = 9.1, 4.1 Hz, 1 H), 4.47 (d, J = 9.1 Hz, 1
H), 4.31 (d, J = 4.1 Hz, 1 H), 4.07 (dd, J = 15.9, 9.1 Hz, 1 H) 3.33
(d, J = 15.9 Hz, 1 H), 3.26 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.40–7.35 (m, 3 H), 7.30–7.26 (m,
2 H), 6.64 (br s, 1 H), 3.91 (d, J = 1.9 Hz, 1 H), 3.79–3.76 (m, 2 H),
3.55 (d, J = 1.9 Hz, 1 H), 3.57–3.42 (m, 2 H), 2.25 (br s, 1 H).
MS (APCI): m/z = 208 [M + H].
Anal. Calcd for C11H13NO3·0.1 H2O (209.03): C, 63.216; H, 6.37;
N, 6.70. Found: C, 63.24; H, 6.28; N, 6.76.
13C NMR (75.5 MHz, CDCl3): d = 174.61 (C5), 139.43 (C8), 139.39
(C12), 128.69 (C10), 128.25 (C15), 128.14 (C14), 128.11 (C11),
127.64 (C9), 125.81 (C13), 82.07 (C7), 81.19 (C2), 73.94 (C6),
59.59 (C3), 37.45 (C16).
(2R,3S)-N-(2-Hydroxyethyl)-N-methyl-3-phenyloxirane-2-car-
boxamide (12b)
Using a procedure similar to that described for 12a except using po-
tassium (2R,3S)-3-phenyloxirane-2-carboxylate (16, 0.58 g, 2.9
mmol), 2-(methylamino)ethanol (0.32 g, 4.3 mmol) and the aque-
ous workup described for 12f gave the pure 12b (191 mg). The H2O
layer was re-extracted with EtOAc (3 ×) to yield an additional 312
mg of less-pure product. Column chromatography (eluent: 0–3%
MeOH–CH2Cl2) returned the title compound (245 mg). Total yield
was 436 mg (68%).
1H NMR (300 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 4.09 (d, J =
1.9 Hz, 0.8 H), 3.89–3.76 (m, 2.5 H), 3.71–3.54 (m, 2.6 H), 3.20 (s,
1.7 H), 3.05 (s, 1.3 H), 2.57 (br s, 0.6 H), 2.19 (br s, 0.4 H).
MS (APCI): m/z = 298 [M + Na].
(6R,7R)- and (6S,7S)-6-Hydroxy-4-methyl-7-phenyl-1,4-ox-
azepan-5-one (1:1 mixture of 1b and 2b)
To a stirred solution of (2,3-trans)-N-(2-hydroxyethyl)-N-methyl-
3-phenyloxirane-2-carboxamide (11b, 5.4 g, 24.4 mmol) in anhyd
THF (300 mL) was added 10 mol% of MgI2 (670 mg, 2.44 mmol,
98% purity) and the mixture was heated to reflux overnight, cooled,
and evaporated to a crude orange oil. Column chromatography (1%
MeOH–CH2Cl2) returned the title mixture (2.7 g, 50%).
1H NMR (300 MHz, CDCl3): d = 7.38–7.29 (m, 5 H), 4.49–4.44 (q,
1 H), 4.30 (d, J = 4 Hz, 1 H), 4.23 (d, J = 9 Hz, 1 H), 4.14–3.97 (m,
2 H), 3.70–3.63 (q, 1 H), 3.27–3.21 (q, 1 H), 3.19 (s, 3 H).
MS (APCI): m/z = 222 [M + H].
HRMS: m/z [M + H] calcd for C12H16NO3: 222.1130; found:
222.1129.
MS (APCI): m/z = 222 [M + H].
(2R,3S)-N-[(1R,2R)-2-Hydroxycyclohexyl]-N-methyl-3-phenyl-
oxirane-2-carboxamide (12i)
Using a procedure similar to that described for 12a except using po-
tassium (2R,3S)-3-phenyloxirane-2-carboxylate (16, 3.13 g, 24.2
mmol), (1R,2R)-2-(methylamino)cyclohexanol (21, 3.13 g, 24.2
(6R,7R)-6-Hydroxy-4-methyl-7-phenyl-1,4-oxazepan-5-one
(1b)
Anhydrous MgI2 (26 mg, 0.095 mmol) was added in one portion to
a stirred solution of (2R,3S)-N-(2-hydroxyethyl)-N-methyl-3-phe-
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Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2559
nyloxirane-2-carboxamide (12b, 105 mg, 0.47 mmol) in anhyd THF
(25 mL) and the mixture was stirred at reflux overnight. The reac-
tion was cooled, partitioned between EtOAc (50 mL) and sat. aq
NH4Cl (25 mL) and stirred for 15 min. The layers were separated
and the organic layer was washed with brine, dried over Na2SO4, fil-
tered and concentrated under reduced pressure to a crude oil. Chro-
matography [eluent: 1% MeOH–CH2Cl2] returned the pure product
(59 mg, 56% yield), which was identical to 1b obtained by Method
F; [a]D20 +35.4 (c = 0.96, EtOH).
Sc(OTf)3 Ring Closures; General Method F
(6R,7R)-6-Hydroxy-7-phenyl-1,4-oxazepan-5-one (1a)
To a stirred solution of (2R,3S)-N-(2-hydroxyethyl)-3-phenylox-
irane-2-carboxamide (12a, 0.2072 g, 1.0 mmol) in MeCN (5 mL)
was added scandium triflate (0.0492 g, 0.10 mmol) and the mixture
was stirred at ambient temperature for 24 h. The solvent was re-
moved in vacuo and the residue added to a silica gel column with
CH2Cl2. Elution with CH2Cl2 returned the crude title compound
(0.0755 g, 36%). The material was dissolved in refluxing toluene (5
mL), treated hot with hexanes (2 mL), scratched with a spatula to
initiate crystal formation and allowed to stand at ambient tempera-
ture overnight. Filtration returned the white title compound (0.0595
g, 29%); mp 150–152 °C; [a]D23 +32.3 (c = 1.02, EtOH).
MS (APCI): m/z = 222 [M + H].
The MgI2 preparation of compounds 1f, 1h, and 2h in Tables 5
and 6 was carried out using the procedure described for 1b and all
compounds were identical to material prepared using method F.
1H NMR (300 MHz, CDCl3): d = 7.39–7.32 (m, 5 H), 6.39 (br s, 1
H), 4.44 (dd, J = 3.7, 9.2 MHz, 1 H), 4.27 (d, J = 9.1 MHz, 1 H),
4.19–4.13 (q, 1 H), 4.02 (d, exchangeable, J = 3.7 MHz, 1 H), 3.81–
3.62 (m, 2 H) 3.31–3.23 (m, 1 H).
TFA Ring Closures; General Method E
(2R,3S)-N-[(1S,2S)-2-Hydroxycyclohexyl]-N-methyl-3-phenyl-
oxirane-2-carboxamide (1j, Scheme 3)
To an ice cooled suspension of potassium (2R,3S)-3-phenyloxirane-
2-carboxylate (16, 220 mg, 1.1 mmol) in CH2Cl2 (15 mL) were add-
ed successively (1S,2S)-2-(methylamino)cyclohexanol (20, 281
mg, 2.2 mmol), HOBt (281 mg, 2.0 mmol), 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (271 mg, 1.4 mmol)
and N-methylmorpholine (153 mL, 1.4 mmol) and the mixture was
stirred for 15 min. The ice bath was removed and the mixture was
stirred at r.t. overnight. The reaction volume was reduced to ca 5
mL, partitioned between EtOAc (75 mL) and 5% citric acid (30
mL), washed with 5% citric acid, H2O, sat. NaHCO3, brine, dried
over Na2SO4, filtered, concentrated under reduced pressure to give
slightly impure 12j (300 mg).
MS (APCI): m/z = 208 [M + H].
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.54; H, 6.16; N, 6.69.
(6R,7R)-6-Hydroxy-4-methyl-7-phenyl-1,4-oxazepan-5-one
(1b)
To a cooled (ice-bath) solution of (2R,3S)-N-(2-hydroxyethyl)-N-
methyl-3-phenyloxirane-2-carboxamide (12b, 81 mg, 0.366 mmol)
in MeCN (2 mL) was added scandium triflate (18 mg, 0.037 mmol)
in one portion. After 5 min no starting material remained. The mix-
ture was concentrated under reduced pressure and purified by col-
umn chromatography (eluent: 1% MeOH–CHCl3) to give the title
compound (67 mg, 82%). A sample (61 mg) was triturated with
Et2O, filtered and vacuum dried at r.t. overnight to give the analyti-
cally pure 1b (22 mg); mp 70–73 °C; [a]D23 +35.6 (c = 1.18, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 4.47 (d, J =
9.1 Hz, 1 H), 4.31 (s, 1 H), 4.23 (d, J = 9.1 Hz, 1 H), 4.14–3.98 (m,
2 H), 3.68 (d, J = 13.0 Hz, 0.5 H), 3.65 (d, J = 13.0 Hz, 0.5 H), 3.27
(d, J = 4.1 Hz, 0.5 H), 3.22 (d, J = 4.1 Hz, 0.5 H), 3.20 (s, 3 H).
A 150 mg sample of this material was purified by reverse phase
chromatography (C18 column eluting with 15–90% MeCN–H2O–
0.1%TFA over 20 min). The purest fractions, as determined by the
chromatographic trace, were combined and allowed to stand in the
MeCN–H2O–0.1% TFA eluent (estimated as ca 90% MeCN) over-
night. Over this time period the eluted compound 12j was converted
to nearly pure ring-closed oxazepinone 1j. The volume was reduced
under reduced pressure, the residue made basic with sat. NaHCO3,
extracted into CH2Cl2, the organic layer washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure to
yield 1j (100 mg, 67%) which was identical spectrographically to
material prepared by Method F.
MS (APCI): m/z = 222 [M + H].
Anal. Calcd for C12H15NO3 (221.26): C, 65.15; H, 6.83; N, 6.33.
Found: C, 64.74; H, 6.68; N, 6.36.
(3R,6R,7R)-6-Hydroxy-4-methyl-3,7-diphenyl-1,4-oxazepan-5-
one (1h)
Using a procedure similar to that described for 1b except using
(2R,3S)-N-[(1R)-2-hydroxy-1-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (12h, 170 mg, 0.57 mmol) yielded the pure ti-
tle compound 1h (130 mg, 76%); mp 136–137 °C; [a]D23 +29.0 (c =
1.07, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.47–7.20 (m, 10 H), 4.74 (dd,
J = 13.7, 4.7 Hz, 1 H), 4.59 (d, J = 4.4 Hz, 1 H), 4.34–4.28 (m, 2 H),
4.17–4.09 (m, 2 H), 3.39 (s, 3 H).
The remaining 150 mg of 12j was purified as above and monitored
for conversion to 1j. Immediately after chromatography was com-
plete the ratio of isolated material was 9:1 (12j/1j). After 7 h the ra-
tio was 1:3 (12j/1j) with small amounts of elimination products.
After 20 h conversion to 1j was ca 90%.
(6R,7R)-6-Hydroxy-4-methyl-7-phenyl-1,4-oxazepan-5-one
(1b)
To a stirred cooled (ice-bath) solution of (2R,3S)-N-(2-hydroxyeth-
yl)-N-methyl-3-phenyloxirane-2-carboxamide (12b, 90 mg, 0.41
mmol) in MeCN (2 mL) was added TFA (3.3 mL, 0.041 mmol), the
ice bath was removed and the mixture was stirred at ambient tem-
perature for 40 h. Purification by reverse phase chromatography
(Rainin–Dynamax 60 Å C-18 21 × 250 mm column, 20–95%
MeCN–H2O over 20 min), combination of the proper fractions and
freeze drying returned 45 mg (50% yield) of ca 95% pure product.
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19N2O3·0.25 H2O (301.86): C, 71.62; H, 6.51;
N, 4.64. Found: C, 71.87; H, 6.26; N, 4.72.
(2R,3R,5aS,9aS)-3-Hydroxy-5-methyl-2-phenyloctahydro-1,5-
benzoxazepin-4(5H)-one (1j)
Using a procedure similar to that described for 1b except using
(2R,3S)-N-[(1S,2S)-2-hydroxycyclohexyl]-N-methyl-3-phenylox-
irane-2-carboxamide (12j, 208 mg, 0.756 mmol) yielded the pure ti-
tle compound 1j (191 mg, 92%); mp 200–201 °C; [a]D23 –37.1 (c =
1.51, MeCN).
20
The material was analytically identical to 1b from Method F; [a]D
+34.4 (c = 0.90, EtOH).
The TFA preparation of compounds 1f, 2f, 3f, 4f, 1h, and 2h in
Tables 5 and 6 was carried out using the procedure described for 1b
and all compounds were identical to material prepared using meth-
od F.
1H NMR (300 MHz, CDCl3): d = 7.26–7.38 (m, 5 H), 4.55 (d, J =
8.7 Hz, 1 H), 4.32 (d, J = 8.8 Hz, 1 H), 4.29 (br s, 1 H), 3.69–3.77
Synthesis 2005, No. 15, 2549–2561 © Thieme Stuttgart · New York

2560
C. W. Becker et al.
PAPER
23
(m, 1 H), 3.42–3.50 (m, 1 H), 3.16 (s, 3 H), 2.06–2.15 (m, 2 H),
1.82–1.87 (m, 1 H), 1.60–1.75 (m, 2 H), 1.17–1.53 (m, 3 H).
tle compound 3f (95 mg, 73%); mp 126–128 °C; [a]D –39.5 (c =
0.78, EtOH).
MS (APCI): m/z = 276 [M + H].
1H NMR (300 MHz, CDCl3): d = 7.46–7.28 (m, 10 H), 5.41 (d, J =
4.1 Hz, 1 H), 4.98 (t, J = 3.6 Hz, 1 H), 4.62 (d, J = 9.0 Hz, 1 H), 4.38
(d, J = 3.1 Hz, 1 H), 3.99 (dd, J = 15.7, 9.1 Hz, 1 H), 3.24 (d, J =
15.7 Hz, 1 H), 3.10 (s, 3 H).
Anal. Calcd for C16H21NO3 (275.35): C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.49; H, 7.46; N, 4.95.
(2R,3R,5aR,9aR)-3-Hydroxy-5-methyl-2-phenyloctahydro-1,5-
benzoxazepin-4(5H)-one (1i)
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19NO3·0.35 H2O (303.66): C, 71.20; H, 6.54;
N, 4.61. Found: C, 71.13; H, 6.42; N, 4.63.
To a stirred solution of (2R,3S)-N-[(1R,2R)-2-hydroxycyclohexyl]-
N-methyl-3-phenyloxirane-2-carboxamide (12i, 0.2754 g, 1.0
mmol) in MeCN (5 mL) was added scandium triflate (0.0492 g,
0.10 mmol) and the mixture was stirred at ambient temperature for
1 h. The solvent was removed in vacuo and the residue in CHCl3
was added to a silica gel column. Elution with CHCl3 returned the
title compound as a white solid (0.1998 g, 73%); mp 143–154 °C.
Recrystallization from toluene–hexanes (1:2, 25 mL) returned the
(2S,6S,7R)-6-Hydroxy-4-methyl-2,7-diphenyl-1,4-oxazepan-5-
one (4f)
Using a procedure similar to that described for 1b except using
(2S,3S)-N-[(2S)-2-hydroxy-2-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (15f, 100 mg, 0.34 mmol) and a 18 h reaction
time yielded the pure title compound 4f (75 mg, 75%) as a non-crys-
talline solid; mp 53–58 °C; [a]D23 +24.9 (c = 0.72, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.45–7.30 (m, 10 H), 5.02 (d, J =
4.1 Hz, 1 H), 4.86–4.79 (m, 2 H), 3.97 (d, J = 15.7 Hz, 1 H), 3.68
(d, J = 14.9 Hz, 1 H), 3.11 (br s, 1 H), 3.11 (s, 3 H).
23
white title compound (0.1692 g, 61%); mp 157–159 °C; [a]D
–29.6 (c = 1.015, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.56 (d, J = 7.1 Hz, 2 H), 7.41–
7.29 (m, 3 H), 4.84 (d, J = 10 Hz, 1 H), 4.63 (d, J = 10 Hz, 1 H), 4.60
(br s, 1 H, exchangeable), 3.94–3.86 (m, 1 H), 3.12–3.04 (m, 1 H),
3.08 (s, 3 H), 2.23–2.17 (m, 1 H), 2.01–1.96 (m, 1 H), 1.79–1.73 (m,
2 H), 1.46–1.24 (m, 4 H).
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19NO3·0.1 H2O (300.965): C, 71.84; H, 6.50;
N, 4.65. Found: C, 71.73; H, 6.32; N, 4.64.
MS (APCI): m/z = 276 [M + H].
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
69.58; H, 7.62; N, 5.05.
(3R,6S,7S)-6-Hydroxy-4-methyl-3,7-diphenyl-1,4-oxazepan-5-
one (2h)
Using a procedure similar to that described for 1b except using
(2S,3R)-N-[(1R)-2-hydroxy-1-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (13h, 175 mg, 0.59 mmol) yielded the pure ti-
tle compound 2h (149 mg, 85%); mp 129–132 °C ; [a]D23 +9.4 (c =
1.06, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.46–7.30 (m, 8 H), 7.26–7.22 (m,
2 H), 5.05 (dd, J = 8.6, 1.0 Hz, 1 H), 4.81 (d, J = 8.9 Hz, 1 H), 4.50
(br s, 1 H), 4.47 (d, J = 8.9 Hz, 1 H), 4.29 (dd, J = 12.6, 1.5 Hz, 1
H), 4.08 (dd, J = 12.6, 8.6 Hz, 1 H), 2.74 (s, 3 H).
(2S,6R,7R)-6-Hydroxy-4-methyl-2,7-diphenyl-1,4-oxazepan-5-
one (1f)
Using a procedure similar to that described for 1b except using
(2R,3S)-N-[(2S)-2-hydroxy-2-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (12f, 103 mg, 0.347 mmol) yielded the pure ti-
tle compound 1f (100 mg, 97%). An analytical sample was obtained
23
by recrystallization from Et2O–hexanes; mp 120–121 °C; [a]D
+52.5 (c = 0.97, EtOH).
1H NMR (300 MHz, CDCl3): d = 7.46–7.27 (m, 10 H), 4.70 (d, J =
8.8 Hz, 1 H), 4.58 (dd, J = 9.1, 4.1 Hz, 1 H), 4.47 (d, J = 9.1 Hz, 1
H), 4.32 (d, J = 4.1 Hz, 1 H), 4.07 (dd, J = 15.9, 8.8 Hz, 1 H), 3.30
(d, 1 H), 3.25 (s, 3 H).
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19NO3·0.1 H2O (299.16): C, 72.27; H, 6.47; N,
4.68. Found: C, 72.10; H, 6.40; N, 5.00.
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19N2O3·0.15 H2O (300.06): C, 72.05; H, 6.48;
N, 4.67. Found: C, 71.87; H, 6.26; N, 4.72.
References
(1) Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T.
Tetrahedron Lett. 2002, 43, 1495.
(2) Righi, G.; Pescatore, G.; Bonadies, F.; Bonini, C.
Tetrahedron 2001, 57, 5649.
(3) Huang, D.-F.; Huang, L. Tetrahedron 1990, 46, 3135.
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Tetrahedron 1990, 46, 2611.
(2S,6S,7S)-6-Hydroxy-4-methyl-2,7-diphenyl-1,4-oxazepan-5-
one (2f)
Using a procedure similar to that described for 1b except using
(2S,3R)-N-[(2S)-2-hydroxy-2-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (13f, 89 mg, 0.30 mmol) yielded the pure title
compound 2f (80 mg, 89%). An analytical sample was prepared by
recrystallization from Et2O; mp 129–130 °C; [a]D23 +65.7 (c = 0.78,
EtOH).
1H NMR (300 MHz, CDCl3): d = 7.53–7.28 (m, 10 H), 4.89–4.82
(m, 3 H), 4.32 (d, J = 4.4 Hz, 1 H), 4.05 (dd, J = 4.4, 15.8 Hz, 1 H),
3.50 (dd, J = 2.2, 15.8 Hz, 1 H), 2.98 (s, 3 H).
MS (APCI): m/z = 298 [M + H].
Anal. Calcd for C18H19NO3 (297.35): C, 72.71; H, 6.44; N, 4.71.
Found: C, 72.39; H, 6.47; N, 4.73.
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(2S,6R,7S)-6-Hydroxy-4-methyl-2,7-diphenyl-1,4-oxazepan-5-
one (3f)
Using a procedure similar to that described for 1b except using
(2R,3R)-N-[(2S)-2-hydroxy-2-phenylethyl]-N-methyl-3-phenylox-
irane-2-carboxamide (14f, 131 mg, 0.44 mmol) yielded the pure ti-
(13) Lu, X.; Xu, Z.; Tang, G. Org. Process Res. Dev. 2001, 5,
184.
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Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones
2561
(14) Bodurow, C. C.; Boyer, B. D.; Brennan, J.; Bunnell, C. A.;
Burks, J. E.; Carr, M. A.; Doecke, C. W.; Eckrich, T. M.;
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Synthesis 2005, No. 15, 2549–2561 © Thieme Stuttgart · New York