Synthesis of tubuphenylalanines via ireland-claisen rearrangement

Article abstract of DOI:10.1021/jo301693d

The Ireland-Claisen rearrangement is the central step in the synthesis of tubuphenylalanine, a key building block of the highly antitumor-active tubulysins. The rearrangement of substituted β-amino acid allyl esters, in combination with subsequent decarboxylation and oxidative cleavage of the double bond, allows the highly stereoselective introduction of substituents into the α-position of the resulting σ-amino acids.

Full text of DOI:10.1021/jo301693d

Article
pubs.acs.org/joc
Synthesis of Tubuphenylalanines via Ireland−Claisen Rearrangement
Dominic Becker and Uli Kazmaier*
Institute for Organic Chemistry, Saarland University, Building C4.2, D-66123 Saarbruecken, Germany
S
* Supporting Information
ABSTRACT: The Ireland−Claisen rearrangement is the
central step in the synthesis of tubuphenylalanine, a key
building block of the highly antitumor-active tubulysins. The
rearrangement of substituted β-amino acid allyl esters, in
combination with subsequent decarboxylation and oxidative cleavage of the double bond, allows the highly stereoselective
introduction of substituents into the α-position of the resulting γ-amino acids.
various tumor cell lines.6 Its activity is only slightly lower
INTRODUCTION
■
compared to the more complex tubulysins,7 and it also shows a
In 2000, Hofle and Reichenbach reported the isolation of a new
̈
strong antiangiogenic effect.8
group of peptide secondary metabolites from myxobacteria
called tubulysins.1 From the bacteria Angiococcus disciformis An
d48 and Archangium gephyra nine different tubulysins (A−I)
were isolated (Figure 1), which show powerful inhibition of
In the meantime, a few syntheses of tubulysins them-
selves,9−11 as well as to their derivates are described in the
literature.12−17 SAR-studies clearly indicate, that the N,O-acetal
is not necessary for the high biological activity,9,18,19 but at least
a N-methyl group should be present for good activity.14,19 The
N-terminus is rather conserved, while the C-terminal Tup
allows a range of modifications.19 Therefore, this subunit seems
to be the ideal position not only to generate new derivatives but
also to introduce labels (photo affinity, fluorescence, etc.) for
biological studies.20
For this purpose a highly flexible stereoselective synthesis is
desirable, allowing not only modifications at the phenyl ring,
but also at the methyl substituent. During the syntheses of the
tubulysins and their derivatives, a few synthetic routes toward
tubuphenylalanine have been developed. While the stereogenic
center at the γ-position can easily be obtained from
phenylalanine, the stereoselective introduction of the α-methyl
group is synthetically the greater challenge. Some approaches
are based on more or less stereoselective hydrogenations of
unsaturated precursors, and subsequent separation of the
diastereomers.6,11,21,22 Menthol was found to be a suitable
auxiliary for the separation of α-epimeric tubuphenylalanine
derivatives.6,22,23 Alternatively, the α-methyl group can also be
introduced by ring-opening of chiral aziridines with deprotected
SAMP-hydrazones12 or by more or less diastereoselective
methylation of a phenylalanine-derived lactame.24 Two other
approaches generate the stereogenic center at the γ-position via
stereoselective addition, either toward an Evans auxiliary based
chiral hydrazine25 or a phenylacetaldimine generated from
chiral (R)-tert-butanesulfinamide.9 Another new synthesis
describes the synthesis of tubuphenylalanine starting from
(−)-citronellol, which allows the synthesis of tubuphenylala-
nine on a gram scale but in a rather long reaction sequence.26
Figure 1. Tubulysins and pretubulysin.
tubulin polymerization,2 leading to apoptosis.3,4 The mode of
action differs from that of other tubulin binders such as
paclitaxel or the epothilones, and the bioactivity is significantly
higher, with IC50 values in the low nanomolar or even
picomolar range toward various cancer cell lines.2
Compared to other tubulin binders, the structure is relatively
simple, consisting of N-methylpipecolic acid (Mep), isoleucine
(Ile), the unusual amino acid tubuvaline (Tuv), and a chain-
extended analogue of phenylalanine or tyrosine, called
tubuphenylalanine (Tup) or tubutyrosine (Tut). All tubulysins
contain an acetoxy group in the tubuvaline unit and differ in the
substitution pattern of the N,O-acetal, the unique structural
motive of these peptides. Recently, 23 “new tubulysins” have
been discovered from Angiococcus disciformis An d48 and
Cystobacter SBCb004, missing (in part) these tubuvaline
substituents.5 Probably, these new structures are biosynthetic
intermediates, and one of them, pretubulysin D (Figure 1) also
shows biological activity in the subnanomolar range toward
Special Issue: Robert Ireland Memorial Issue
Received: August 10, 2012
Published: October 4, 2012
© 2012 American Chemical Society
59
dx.doi.org/10.1021/jo301693d | J. Org. Chem. 2013, 78, 59−65

The Journal of Organic Chemistry
Article
salt was found to be unstable and the ester enolate decomposed
completely during warm up. Quite different was the situation if
ZnCl2 was added for chelation (Table 1, entry 2). In a clean
reaction, the rearrangement product was obtained with very
high diastereoselectivity but very moderate yield. No
decomposition was observed here, and starting material could
be recovered. A similar situation was observed with the titanium
enolate (Table 1, entry 3). Here the selectivity could even be
increased, but the reaction was incomplete. Obviously, the
chelates of the β-amino acid esters are less reactive compared to
the α-amino analogous, which generally undergo Claisen
rearrangement in the range of −20 °C to rt. While ester
enolates of α-amino acids can be heated overnight without
decomposition (an additional positive effect of chelate
formation), this behavior is not observed with β-amino acid
esters, indicating that these chelate complexes are less stable.
Therefore, we decided to apply the Ireland−Claisen rearrange-
ment to our system. Indeed, after heating the silylketene acetals
formed to 60 °C for 2 h, the desired rearrangement product
was obtained in very high yield, albeit with significant lower
selectivity, which is in perfect agreement with the results
described by Knight et al.39 For our purpose, the simple
diastereoselectivity of the rearrangement process does not play
a major role, since the carboxylic acid functionality is removed
in the next reaction step according to Scheme 1. Only the
chirality transfer from a chiral allyl alcohol should work
perfectly.
RESULTS AND DISCUSSION
■
Although a range of different approaches has been developed,
each protocol has some drawbacks, either concerning yield or
stereo- or chemoselectivity. Therefore, we decided to develop
an independent approach that would allow us to also vary the
α-position, taking advantage of the Claisen rearrangement.
Based on the pioneering work by Robert Ireland in Claisen
rearrangements,27−30 we developed a version, especially
suitable for α-amino acids, proceeding via chelated amino
acid ester enolates.31−34 Because of the fixed enolate geometry
in the chelate complex, the rearrangement proceeds with
excellent diastereoselectivity and chirality transfer, as far as
chiral allylic esters are applied.35,36 This approach was used for
the synthesis of highly functionalized amino acids37,38 but was
limited to α-amino acids. Our retrosynthetic plan toward
tubuphenylalanine and α-derivatives thereof is shown in
Scheme 1.
Scheme 1
To prove this option, we synthesized chiral allylic esters of N-
protected prolonged phenylalanine, easily obtained via Arndt−
Eistert homologation.40 One of the easiest ways to obtain the
requested chiral alcohols is given with the enzymatic kinetic
resolution of racemic alcohols, using Novozym 435, an
immobilized Candida antarctica lipase. According to Kazlaus-
kas,41 in racemic allylic alcohols of type 1 the (R)-configured
enantiomer is selectively acylated, while the (S)-isomers remain
untouched. In general, the ee’s of both products are excellent,
and it is no problem to separate them, e.g., by flash
chromatography. The only critical point of rather small alcohols
such as 3a is their high volatility (bp 120 °C), and therefore, the
isolated yield of the enantiomerically pure alcohol (S)-3a and
the acetate (R)-4a (similar boiling point) can be low.
Therefore, we decided to abstain from workup and to subject
the reaction mixture of the kinetic resolution directly to the
esterification with prolonged Boc-protected phenylalanine. To
get a high diastereoselectivity in the allylic ester, we allowed the
reaction mixture to proceed slightly >50% conversion, and
indeed, the requested allyl ester 5a was obtained in acceptable
yield and a high diastereomeric ratio (Table 2). To get access to
α-modified tubuphenylalanines, we also subjected the racemic
alcohols 3b and 3c to the same protocol, getting comparable
results.
The carboxylic acid A should be accessible via oxidative
cleavage of alkene B, which can be obtained from C by radical
decarboxylation. β-Amino acid C should be the product of a
Claisen rearrangement of allylic ester D, easily available from β-
amino acid E.
Based on our good results obtained with chelated ester
enolates, we tried to transfer this protocol to β-amino acid
esters. As a model reaction, we decided to investigate the
Claisen rearrangement of the crotyl ester of Boc-protected β-
alanine 1 (Table 1).39 According to Ireland, the simple
Table 1. Claisen Rearrangements of β-Alanine Crotyl Ester
entry
MXn
ZnCl2
T (°C)
yield (%)
ratio syn:anti
1
2
3
4
rt
rt
35
24
86
96:4
98:2
86:14
ClTi(Oi-Pr)3
rt
ClSiMe3
60
The allylic esters 5 obtained were subsequently subjected to
the Ireland−Claisen rearrangement, giving rise to the rearrange-
ment products 6 in consistently excellent yield. As in our
control experiment, the diastereoselectivities were also modest
in these cases, but as already mentioned, the configuration of
the carboxyl group is irrelevant because it is removed in the
next step. The carboxylic acids where subjected to a Barton
decarboxylation.42 It should be mentioned that the esterifica-
tion43 with 2-mercaptopyridine N-oxide should be carried out
in the absence of light to avoid decomposition of the rather
labile ester. The crude product was subjected to a BEt3-
initiatized radical reaction in the dark using t-BuSH as a
diastereoselectivity observed should provide important in-
formations on the enolate geometry. If a chelate complex is
formed, an excellent diastereoselectivity should be observed, as
usually found for α-amino acids.
The Claisen rearrangement was investigated in the presence
of several metal salts. For analytical purposes, the rearrange-
ment product was directly converted into the known methyl
ester 2.39
As expected, no rearrangement product was obtained in the
absence of a chelating metal salt (Table 1, entry 1). The lithium
60
dx.doi.org/10.1021/jo301693d | J. Org. Chem. 2013, 78, 59−65

The Journal of Organic Chemistry
Article
Table 2. Syntheses of Chiral Allyl Esters
Scheme 2
EXPERIMENTAL SECTION
■
General Remarks. Reactions with dry solvents were carried out in
oven-dried glassware (100 °C) under nitrogen. Solvents were dried as
follows: THF was distilled from LiAlH4, CH2Cl2 from CaH2, MeOH
from Mg, and toluene from Na. The products were purified by flash
chromatography on silica gel (0.063−0.2 mm). Mixtures of EtOAc and
hexanes were generally used as eluents. Analysis by TLC was carried
out on commercially precoated Polygram SIL-G/UV 254 plates.
Visualization was accomplished with UV light, KMnO4 solution, or
entry
3
R
5
yield (%)
dr
1
2
3
3a
3b
3c
Me
Et
5a
5b
5c
38
39
35
>97:3
>98:2
>99:1
TBDMSOCH2
1
ninhydrine. H NMR and 13C NMR spectra were obtained at room
temperature at 400 and 100 MHz, respectively. Chemical shifts are
expressed in ppm relative to internal solvent. Selected signals of minor
isomers are extracted from the NMR spectra of the isomeric mixtures.
The enantiomeric and diastereomeric ratios were determined by
HPLC using a chiral column (Reprosil 100 Chiral-NR 8 μm). Melting
points are uncorrected. High-resolution mass were recorded on a
quadrupole mass spectrometer.
hydrogen source.44 In all examples, good to very high yields
were obtained, indicating the reliability of this protocol.
In the next step, the double bond of 7 had to be subjected to
an oxidative cleavage to get access to the carboxylic acid. To
avoid γ-lactam ring formation, we first converted the Boc-
protected amide into a double protected amide 8. Subsequent
ozonolysis using a protocol developed by Marshall45 provided
the protected desired tubuphenylalanine derivatives 9 in good
yields and almost perfect diastereoselectivity (Table 3).
For analytical purposes and to determine the absolute
configuration of the new introduced α-substituent, we
subjected 9a to a N-deprotection giving rise to the hydro-
chloride of the tubuphenylalanine methyl ester 10a which was
described previously in the literature (Scheme 2).22 Our
analytical data were in accordance to the data reported. In
addition, deprotonation of 10a resulted in the formation of the
corresponding lactam 11a, which is also a known compound.15
(S,E)-Pent-3-en-2-yl (S)-3-(tert-butoxycarbonylamino)-4-
phenylbutanoate (5a). A mixture of racemic alcohol 3a (1.68 g,
19.5 mmol) in vinyl acetate (9 mL, 97.5 mmol) was shaken in the
presence of Novozym 435 (100 mg, 6 wt %) for 24 h at room
temperature. The enzyme was filtered off, and the resulting solution
was diluted with 70 mL of dry diethyl ether. (S)-3-(tert-
Butoxycarbonylamino)-4-phenylbutanoic acid (3.00 g 10.7 mmol),
DMAP (130 mg, 1.00 mmol), and DCC (2.43 g, 11.8 mmol) in dry
diethyl ether (30 mL) were added at 0 °C, and the mixture was
allowed to warm to room temperature overnight. The precipitate was
filtered off, and the organic layer was washed twice with 1 M KHSO4,
H2O, satd NaHCO3 solution and brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography (hexanes/
ethyl acetate 9:1) provided allylic ester 5a (258 mg, 0.741 mmol, 38%,
97% ds) as a colorless oil. Rf = 0.21 (hexanes/ethyl acetate 9:1). [α]20
D
= −24.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.29 (d, J =
6.5 Hz, 3 H), 1.40 (s, 9 H), 1.71 (ddd, J = 6.5, 1.7, 0.7 Hz, 3 H), 2.39
(dd, J = 15.8, 6.0 Hz, 1 H), 2.48 (dd, J = 15.8, 5.8 Hz, 1 H), 2.80 (dd, J
= 13.5, 7.5 Hz, 1 H), 2.89 (m, 1 H), 4.14 (m, 1 H), 5.03 (bs, 1 H),
5.34 (dq, J = 6.3, 6.3 Hz, 1 H), 5.49 (ddq, J = 15.3, 7.0, 1.5 Hz, 1 H),
5.74 (dqd, J = 15.3, 6.5, 1.0 Hz, 1 H), 7.16−7.24 (m, 3 H), 7.28 (m, 1
H). 13C NMR (100 MHz, CDCl3): δ 17.6, 20.2, 28.3, 37.9, 40.3, 48.9,
71.5, 79.2, 126.5, 128.4, 128.5, 129.4, 130.6, 137.8, 155.1, 170.9. HPLC
(hexane/i-PrOH 90:10, 0.5 mL/min): tR = 11.52 min (3%), tR = 12.39
min (97%). HRMS (CI) m/z: calcd for C20H30NO4 (M + H)+:
CONCLUSION
■
In conclusion, we have developed a straightforward protocol
toward tubuphenylalanine and derivatives thereof, based on an
Ireland−Claisen rearrangement. All reaction steps proceed with
high yield, and the desired products can be obtained with high
optical purity. This protocol should be general applicable to
various kinds of substituted tubuphenylalanine derivatives and
should also give access to the other stereoisomers by starting
from the enantiomeric allylic alcohols.
Table 3. Syntheses of Protected Tubuphenylalanines
5
6
yield (%)
dr
7
yield (%)
8
yield (%)
9
yield (%)
dr
5a
5b
5c
6a
6b
6c
93
91
93
2:1
2:1
1:1
7a
7b
7c
85
93
78
8a
8b
8c
88
83
86
9a
9b
9c
82
79
81
>97:3
>99:1
>98:2
61
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The Journal of Organic Chemistry
Article
348.2169, found 348.2186. Anal. Calcd for C20H29NO4 (347.45): C
69.14; H, 8.41; N, 4.03; found C 69.20; H, 8.25; N, 4.21.
4.54 (d, J = 8.0 Hz, 0.5 H), 5.46 (m, 2 H), 5.64 (d, J = 9.3 Hz, 0.5 H),
7.19−7.24 (m, 3 H), 7.28 (m, 2 H). Minor diastereomer (selected
signals): δ 0.99 (d, J = 6.5 Hz, 3 H), 1.26 (s, 4.5 H), 1.30 (s, 4.5 H),
1.63 (d, J = 6.3 Hz, 3 H), 2.92 (dd, J = 13.5, 5.8 Hz, 1 H), 3.95 (m, 1
H), 5.08 (m, 1 H). 13C NMR (100 MHz, CDCl3), major diastereomer:
δ 17.9, 19.3, 28.4, 37.2, 41.3, 51.3, 52.2, 79.0, 126.2, 126.4, 128.3,
129.5, 132.2, 137.9, 155.0, 179.8. Minor diastereomer (selected
signals): δ 27.8, 51.8. HRMS (CI): m/z calcd for C20H30NO4 (M +
H)+ 348.2169, found 348.2198. Anal. Calcd for C20H29NO4 (347.45):
C, 69.14; H, 8.41; N, 4.03. Found: C 69.01; H, 8.37; N, 3.90.
(S,E)-Hex-3-en-2-yl (S)-3-(tert-Butoxycarbonylamino)-4-phe-
nylbutanoate (5b). According to ester 5a, allylic ester 5b was
prepared from racemic alcohol 3b (200 mg, 2.00 mmol), vinyl acetate
(0.93 mL, 10.0 mmol), Novozym 435 (12 mg, 6 wt %), (S)-3-(tert-
butoxycarbonylamino)-4-phenylbutanoic acid (307 mg, 1.10 mmol),
DMAP (13.0 mg, 100 μmol), and DCC (248 mg, 1.20 mmol).
Purification by flash chromatography (hexanes/ethyl acetate 9:1)
resulted in the isolation of 5b (277 mg, 0.77 mmol, 39%, >98% ds) as
a colorless oil. Rf: 0.21 (hexanes/ethyl acetate 9:1). [α]20D = −25.8 (c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.99 (t, J = 7.5 Hz, 3 H),
1.29 (d, J = 6.3 Hz, 3 H), 1.40 (s, 9 H), 2.06 (qdd, J = 7.3, 7.3, 1.0 Hz,
2 H), 2.39 (dd, J = 15.6, 6.0 Hz, 1 H), 2.48 (dd, J = 15.6, 5.5 Hz, 1 H),
2.80 (dd, J = 13.3, 7.8 Hz, 1 H), 2.91 (dd, J = 13.1, 5.5 Hz, 1 H), 4.14
(bs, 1 H), 5.07 (d, J = 7.3 Hz), 5.36 (dq, J = 7.0, 7.0 Hz, 1 H), 5.46
(ddt, J = 15.3, 7.0, 1.8 Hz, 1 H), 5.78 (dtd, J = 15.3, 8.3, 0.75 Hz, 1 H),
7.17−7.23 (m, 3 H), 7.28 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ
13.2, 20.3, 25.1, 28.3, 37.9, 40.3, 48.9, 71.6, 79.3, 126.5, 128.3, 128.4,
129.4, 135.3, 137.8, 155.1, 170.9. HPLC (hexane/i-PrOH 95:5, 1 mL/
min): tR = 8.49 min (2%), tR = 9.61 min (98%). HRMS (CI): m/z
calcd for C21H32NO4 (M + H)+ 362.2326, found 362.2312. Anal.
Calcd for C21H31NO4 (361.48): C, 69.78; H, 8.64; N, 3.87. Found: C
69.84; H, 9.16; N, 4.31.
(3R,E)-2-[(S)-1-(tert-Butoxycarbonylamino)-2-phenylethyl]-3-
ethylhex-4-enoic Acid (6b). According to 6a, unsaturated acid 6b
was prepared from diisopropylamine (0.23 mL, 1.66 mmol), n-
butyllithium (1.00 mL, 1.60 mmol, 1.6 M in hexane), allylic ester 5b
(200 mg, 0.55 mmol) and TMSCl (0.21 mL, 1.66 mmol). Purification
by flash chromatography (hexanes/ethyl acetate 7:3) provided 6b (184
mg, 0.51 mmol, 91%, 67% ds) as a white solid; mp. 133−135 °C. Rf:
1
0.23 (hexanes/ethyl acetate 7:3). [α]20D= −23.5 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3), major diastereomer: δ 0.87 (bs, 3 H), 1.36
(s, 9 H), 1.40 (m, 1 H), 1.55 (m, 1 H), 1.69 (bs, 3 H), 2.28 (bs, 1 H),
2.80−2.85 (m, 2 H), 2.96 (m, 1 H), 4.02 (m, 1 H), 4.52 (d, J = 8.8 Hz,
1 H), 5.38 (m, 1 H), 5.45 (dq, J = 15.0, 6.0 Hz, 1 H), 7.19−7.22 (m, 3
H), 7.28 (m, 2 H). Minor diastereomer (selected signals): δ 1.24 (s, 9
H), 1.69 (bs, 3 H), 2.40 (bs, 1 H), 2.67 (m 2 H), 3.94 (m, 1 H). 13C
NMR (100 MHz, CDCl3), major diastereomer: δ 11.9, 18.0, 25.9, 28.3,
37.9, 44.2, 51.9, 52.7, 79.2, 16.3, 128.3, 128.3, 129.5, 30.7, 138.1, 155.0,
178.2. Minor diastereomer (selected signals): δ 11.9, 26.0, 28.0, 53.2,
53.8, 80.5, 128.0, 130.4. HRMS (CI) m/z calcd for C21H32NO4 (M +
H)+: 362.2326, found 362.2327. Anal. Calcd for C21H31NO4 (361.48):
C, 69.78; H, 8.64; N, 3.87. Found: C, 69.32; H, 8.57; N, 3.95.
(3R,E)-2-([(S)-1-(tert-Butoxycarbonylamino)-2-phenylethyl]-
3-(tert-butyldimethylsilyloxymethyl)hex-4-enoic Acid (6c). The
unsaturated acid 6c was prepared according to 6a from diisopropyl-
amine (0.82 mL, 5.80 mmol), n-butyllithium (3.50 mL, 5.60 mmol, 1.6
M in hexane), allylic ester 5c (924 mg, 1.93 mmol), and TMSCl (0.73
mL, 5.80 mmol). Purification by flash chromatography (hexanes/ethyl
acetate 8:2) gave rise to unsaturated acid 6c (854 mg, 1.79 mmol, 93%,
50% ds) as a white solid. Mp: 55−57 °C. Rf: 0.25 (hexanes/ethyl
acetate 8:2). [α]20D = −8.8 (c 1.0, CHCl3). Diastereomeric ratio 1:1.47
1H NMR (400 MHz, CDCl3), diastereomer I: δ 0.07 (s, 6 H), 0.88 (s,
(S,E)-5-(tert-Butyldimethylsilyloxy)pent-3-en-2-yl (S)-3-(tert-
Butoxycarbonylamino)-4-phenylbutanoate (5c). According to
ester 5a, allylic ester 5c was prepared from racemic alcohol 3c46 (1.51
g, 7.00 mmol), vinyl acetate (3.24 mL, 35.0 mmol), Novozym 435 (91
mg, 6 wt.%), (S)-3-(tert-butoxycarbonylamino)-4-phenylbutanoic
(1.07 g, 3.85 mmol), DMAP (43.0 mg, 350 μmol), and DCC (867
mg, 4.20 mmol). Purification by flash chromatography (hexanes/ethyl
acetate 9:1) gave rise to 5c (1.17 g, 2.45 mmol, 35%, >99% ds) as a
colorless oil. Rf: 0.18 (hexanes/ethyl acetate 9:1). [α]20 = −20.3 (c
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 6 H), 0.91 (s, 9
H), 1.31 (d, J = 6.5 Hz, 3 H), 1.40 (s, 9 H), 2.40 (dd, J = 15.8, 5.8 Hz,
1 H), 2.49 (dd, J = 15.8, 5.5 Hz, 1 H), 2.80 (dd, J = 13.3, 7.5 Hz, 1 H),
2.91 (dd, J = 12.8, 6.0 Hz, 1 H), 4.14 (m, 1 H), 4.18 (m, 2 H), 5.07 (d,
J = 7.3 Hz, 1 H), 5.42 (dqd, J = 6.5, 6.5, 0.5 Hz, 1 H), 5.71 (ddt, J =
15.6, 6.0, 1.5 Hz, 1 H), 5.80 (dtd, J = 15.3, 4.3, 0.75 Hz, 1 H), 7.18 (m,
2 H), 7.22 (m, 1 H), 7.28 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ
−5.3, 18.4, 20.2, 25.9, 28.3, 37.8, 40.3, 48.8, 62.8, 70.8, 79.2, 126.5,
128.5, 128.8, 129.4, 131.8, 137.8, 155.1, 170.9. HPLC (hexane/i-PrOH
95:5, 1 mL/min): tR = 8.43 min (1%), tR = 9.44 min (99%). HRMS
(CI): m/z calcd for C26H44NO5Si (M + H)+ 478.2983, found
478.2995. Anal. Calcd for C26H43NO5Si (477.71): C, 65.37; H, 9.07;
N, 2.93. Found: C, 65.11; H, 8.90; N, 2.82.
9 H), 1.34 (s, 9 H), 1.68 (d, J = 6.0 Hz, 3 H), 2.59−2.69(m, 2 H),
2.82−3.01 (m, 2 H), 3.63 (m, 2 H), 4.02 (bs, 1 H), 4.74 (d, J = 9.0 Hz,
1 H), 5.45−5.66 (m, 2 H), 7.18−7.21 (m, 3 H), 7.27 (m, 2 H).
Diastereomer II (selected signals): δ 0.01 (s, 6 H), 0.82 (s, 9 H), 1.40
(s, 9 H), 2.63 (m, 3 H). 13C NMR (100 MHz, CDCl3), diastereomer I:
δ −5.57, 18.1, 18.2, 25.8, 28.3, 38.2, 44.5, 49.4, 52.2, 66.2, 79.1, 126.3,
127.7, 128.3, 129.6, 129.8, 138.1, 155.1, 175.7. Diastereomer II
(selected signals): δ −5.49, 18.2. HRMS (CI): m/z calcd
C26H44NO5Si (M + H)+ 478.2983, found 478.2970. Anal. Calcd for
C26H43NO5Si (477.71): C, 65.37; H, 9.07; N, 2.93. Found: C, 64.81;
H, 8.28; N, 3.07.
(3R,E)-2-[(S)-1-(tert-Butoxycarbonylamino)-2-phenylethyl]-3-
methylhex-4-enoic Acid (6a). To a solution of freshly distilled
diisopropylamine (0.87 mL, 6.19 mmol) in abs THF (6 mL) in a dry
Schlenk tube was added n-butyllithium (3.75 mL, 6.00 mmol, 1.6 M in
hexane) at −30 °C under nitrogen. After 5 min at this temperature, the
mixture was allowed to warm to room temperature for 30 min and was
cooled to −78 °C again. In a second Schlenk tube allylic ester 5a (721
mg, 2.07 mmol) was dissolved in abs THF (6 mL) under nitrogen and
cooled to −78 °C. The base solution was slowly transferred to the
substrate solution at −78 °C via a transfer cannula. After 30 min,
TMSCl (0.78 mL, 6.17 mmol) was added, and stirring was continued
for 60 min at this temperature. The cooling bath was removed, and the
reaction mixture was warmed to room temperature and heated to 60
°C for 2 h. After being cooled to room temperature, the mixture was
diluted with diethyl ether and hydrolyzed with 1 M HCl. The organic
layer was further washed with 1 M HCl, H2O, satd NaHCO3 solution,
and brine, dried over Na2SO4, and concentrated in vacuo. Purification
by flash chromatography (hexanes/ethyl acetate 7:3) afforded
unsaturated acid 6a (668 mg, 1.92 mmol, 93%, 67% ds) as a white
tert-Butyl [(2R,4S,E)-4-Methyl-1-phenylhept-5-en-2-yl]-
carbamate (7a). To a solution of unsaturated acid 6a (299 mg,
861 μmol), 2-mercaptopyridine N-oxide (109 mg, 857 μmol), and
DMAP (11.0 mg, 90 μmol) in dry dichloromethane (4 mL) was added
DCC (204 mg, 989 μmol) in dichloromethane (2 mL) at 0 °C in the
dark. The mixture was allowed to warm to room temperature
overnight. The solvent was removed under reduced pressure, and the
residue was dissolved in ether. The organic layer was filtered, washed
with satd NaHCO3 solution and brine, dried over Na2SO4, and
concentrated in vacuo to yield the green-yellow Barton ester.
The crude product was taken up in dry THF (4 mL) and was
treated with t-BuSH (960 μL, 8.53 mmol) in the dark. At 0 °C, BEt3
(260 μL, 260 μmol, 1 M in hexane) was added under air, and the
mixture was stirred for 1.5 h before it was diluted with ether. The
organic layer was washed with 6 M HCl, H2O, satd NaHCO3, H2O,
and brine and dried over Na2SO4. Removal of the solvent under
reduced pressure and purification by flash chromatography (hexanes/
ethyl acetate 9:1) resulted in the isolation of 7a (222 mg, 732 μmol,
solid. Mp: 131−133 °C. Rf: 0.26 (hexanes/ethyl acetate 7:3). [α]20
=
D
1
33.6 (c 1.0, CHCl3). 1:1 mixture of rotamers. H NMR (400 MHz,
CDCl3), major diastereomer: δ 1.14 (d, J = 6.8 Hz, 3 H), 1.35 (s, 4.5
H), 1.42 (s, 4.5 H), 1.66 (bs, 3 H), 2.27 (dd, J = 10.2, 3.1 Hz, 0.5 H),
2.49−2.81 (m, 2.5 H), 2.98 (dd, J = 13.9, 3.6 Hz, 1 H), 4.05 (m, 1 H),
85%) as a colorless oil. Rf: 0.28 (hexanes/ethyl acetate 9:1). [α]20
=
D
62
dx.doi.org/10.1021/jo301693d | J. Org. Chem. 2013, 78, 59−65

The Journal of Organic Chemistry
Article
+10.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.94 (d, J = 6.8
Hz, 3 H), 1.27 (m, 1 H), 1.34 (m, 1 H), 1.40 (s, 9 H), 1.64 (dd, J =
6.3, 1.0 Hz, 3 H), 2.21 (m, 1 H), 2.76 (m, 2 H), 3.83 (m, 1 H), 4.28
(bs, 1 H), 5.18 (dd, J = 15.2, 8.0 Hz, 1 H), 5.38 (dqd, J = 15.3, 6.3, 0.7
Hz, 1 H), 7.15−7.22 (m, 3 H), 7.27 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ 17.9, 21.4, 28.4, 33.7, 41.5, 41.7, 49.8, 78.8, 124.2, 126.1,
128.2, 129.6, 136.1, 138.4, 155.7. HRMS (CI): m/z calcd C19H30NO2
(M + H)+ 304.2271, found 304.2293. Anal. Calcd for C19H29NO2
(303.44): C, 75.21; H, 9.63; N, 4.62. Found: C, 75.14; H, 9.33; N,
4.95.
Anal. Calcd for C24H37NO4 (403.27): C, 71.43; H, 9.24; N, 3.47.
Found: C, 71.53; H, 9.24; N, 3.67.
Di-tert-butyl [(2R,4S,E)-4-Ethyl-1-phenylhept-5-en-2-yl]-
iminodicarbonate (8b). The double-protected amine 8b was
prepared according to 8a from alkene 7b (328 mg, 1.03 mmol), n-
butyllithium (0.84 mL, 1.34 mmol, 1.6 M in hexane), and di-tert-butyl
dicarbonate (383 mg, 1.76 mmol). Purification by flash chromatog-
raphy (hexanes/ethyl acetate 95:5) gave rise to 8b (357 mg, 860 μmol,
83%) as a colorless oil. Rf: 0.19 (hexanes/ethyl acetate 95:5). [α]20
=
D
−59.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.4
Hz, 3 H), 1.24−1.44 (m, 3 H), 1.48 (s, 18 H), 1.70 (dd, J = 6.4, 1.6 Hz
3 H), 1.91 (m, 1 H), 2.07 (ddd, J = 14.0, 10.6, 3.3 Hz, 1 H), 2.87 (dd, J
= 13.3, 6.8 Hz, 1 H), 3.18 (dd, J = 13.3, 8.8 Hz, 1 H), 4.44 (m, 1 H),
5.10 (ddq, J = 15.0, 8.8, 1.5 Hz, 1 H), 5.41 (dq, J = 15.0, 6.3 Hz, 1 H),
7.21−7.26 (m, 3 H), 7.31 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ
11.8, 18.0, 27.9, 28.6, 37.8, 40.6, 41.7, 57.0, 81.5, 125.7, 126.0, 128.1,
129.5, 134.5, 139.2, 153.1. HRMS (CI): m/z calcd C25H40NO4 (M +
H)+ 418.2952, found 418.2951. Anal. Calcd for C25H39NO4 (403.27):
C, 71.81; H, 9.41; N, 3.35. Found: C, 72.01; H, 10.11; N, 3.72.
Di-tert-butyl [(2R,4S,E)-4-(tert-Butyldimethylsilyloxymethyl)-
1-phenylhept-5-en-2-yl]iminodicarbonate (8c). The double-
protected amine 8c was prepared according to 8a from alkene 7c
(49 mg, 113 μmol), n-butyllithium (92 μL, 147 μmol, 1.6 M in
hexane), and di-tert-butyl dicarbonate (62 mg, 284 μmol). Purification
by flash chromatography (hexanes/ethyl acetate 95:5) gave rise to 8c
tert-Butyl [(2R,4S,E)-4-Ethyl-1-phenylhept-5-en-2-yl]-
carbamate (7b). The alkene 7b was prepared according to 7a
from unsaturated acid 6b (100 mg, 277 μmol), N-mercaptopyridine N-
oxide (36 mg, 283 μmol), DMAP (3.0 mg, 25 μmol), DCC (66 mg,
320 μmol), t-BuSH (312 μL, 2.77 mmol), and BEt3 (83 μL, 83 μmol, 1
M in hexane). Purification by flash chromatography (hexanes/ethyl
acetate 9:1) provided 7b (81 mg, 255 μmol, 92%) as a colorless oil. Rf:
1
0.25 (hexanes/ethyl acetate 9:1). [α]20D = +1.2 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3): δ 0.80 (t, J = 7.3 Hz, 3 H), 1.15−1.33 (m, 4
H), 1.42 (s, 9 H), 1.66 (d, J = 6.0 Hz, 3 H), 1.94 (bs, 1 H), 2.72 (dd, J
= 13.3, 6.8 Hz 1 H), 2.80 (dd, J = 13.3, 5.3 Hz, 1 H), 3.81 (bs, 1 H),
4.30 (d, J = 8.0 Hz, 1 H), 5.02 (dd, J = 14.6, 9.5 Hz, 1 H), 5.38 (dq, J =
15.0, 6.5 Hz, 1 H), 7.16−7.22 (m, 3 H), 7.27 (m, 2 H). 13C NMR (100
MHz, CDCl3): δ 11.7, 17.9, 28.4, 29.7, 39.4, 41.3, 41.9, 49.7, 78.7,
125.9, 126.1, 128.1, 129.6, 134.5, 138.5, 155.1. HRMS (CI): m/z calcd
C20H32NO2 (M + H)+ 318.2428, found 318.2432. Anal. Calcd for
C20H31NO2 (317.47): C, 75.67; H, 9.84; N, 4.41. Found: C, 75.28; H,
9.81; N, 4.53.
tert-Butyl [(2R,4S,E)-4-(tert-Butyldimethylsilyloxymethyl)-1-
phenylhept-5-en-2-yl]carbamate (7c). The alkene 7c was
prepared according to 7a from unsaturated acid 6c (132 mg, 276
μmol), N-mercaptopyridine N-oxide (36 mg, 283 μmol), DMAP (3.0
mg, 25 μmol), DCC (66 mg, 320 μmol), t-BuSH (312 μL, 2.77
mmol), and BEt3 (83 μL, 83 μmol, 1 M in hexane). Purification by
flash chromatography (hexanes/ethyl acetate 9:1) provided 7c (94 mg,
217 μmol, 79%) as a colorless oil. Rf: 0.26 (hexanes/ethyl acetate 9:1).
[α]20D = +13.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ −0.01
(s, 3 H), −0.01 (s, 3 H), 0.86 (s, 9 H), 1.33 (m, 1 H), 1.41 (s, 9 H),
1.45 (m, 1 H), 1.63 (d, J = 6.3 Hz, 3 H), 2.23 (m, 1 H), 2.72 (dd, J =
13.5, 7.3 Hz, 1 H), 2.85 (dd, J = 13.3, 5.3 Hz, 1 H), 3.30 (m, 1 H),
3.47 (dd, J = 9.8, 5.5 Hz,1 H), 3.80 (m, 1 H), 4.44 (d, J = 8.3 Hz, 1 H),
5.10 (dd, J = 15.3, 8.5 Hz, 1 H), 5.42 (dq, J = 15.1, 6.5 Hz, 1 H), 7.15−
7.21 (m, 3 H), 7.27 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ −5.4,
−5.3, 18.1, 18.3, 25.9, 28.4, 35.4, 42.1, 42.3, 49.8, 67.0, 78.7, 126.1,
127.1, 128.1, 129.6, 131.5, 138.4, 155.7. HRMS (CI): m/z calcd
C25H44NO3Si (M + H)+ 434.3085, found 434.3118. Anal. Calcd for
C25H43NO3Si (433.69): C, 69.23; H, 9.99; N, 3.23. Found: C, 69.06;
H, 9.54; N, 3.58.
(52 mg, 97 μmol, 86%) as a colorless oil. Rf: 0.25 (hexanes/ethyl
1
acetate 95:5). [α]20 = −28.9 (c 1.0, CHCl3). H NMR (400 MHz,
D
CDCl3): δ −0.01 (s, 3 H), −0.01 (s, 3 H), 0.87 (s, 9 H), 1.35 (m, 1
H), 1.41 (s, 18 H), 1.63 (dd, J = 6.6, 1.5 Hz, 3 H), 2.21 (m, 1 H), 2.18
(m, 1 H), 2.82 (dd, J = 13.3, 6.8 Hz, 1 H), 3.13 (dd, J = 13.3, 8.8 Hz, 1
H), 3.44 (d, J = 6.0 Hz, 2 H), 4.37 (m, 1 H), 5.13 (ddq, J = 15.3, 8.8.
1.8 Hz, 1 H), 5.41 (dqd, J = 15.3, 6.5, 0.5 Hz, 1 H), 7.15−7.19 (m, 3
H), 7.23 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ −5.3, 18.1, 18.4,
25.9, 28.0, 34.2, 40.6, 42.1, 56.9, 67.4, 81.6, 126.0, 127.1, 128.1, 129.5,
131.8, 139.2, 153.1. HRMS (CI): m/z calcd C30H52NO5Si (M + H)+
534.3609, found 534.3622. Anal. Calcd for C30H51NO5Si (533.81): C,
67.50; H, 9.63; N, 2.62. Found: C, 67.87; H, 9.43; N, 2.60.
(2S,4R)-Methyl 4-[Bis(tert-butoxycarbonyl)amino]-2-methyl-
5-phenylpentanoate (9a). Through a solution of double-protected
amine 8a (207 mg, 513 μmol) and a NaOH solution (1.03 mL, 2.58
mmol, 2.5 M in dry MeOH) in dichloromethane (4 mL) was bubbled
ozone at −78 °C until the characteristic blue color and a yellow
precipitate appeared. The mixture was diluted with H2O (3.5 mL) and
ether (3.5 mL), warmed to room temperature, and extracted twice
with ether. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo. Purification by flash
chromatography (hexanes/ethyl acetate 9:1) gave rise to 9a (177
mg, 420 μmol, 82%, 97% ds) as a colorless oil. Rf: 0.25 (hexanes/ethyl
1
acetate 9:1). [α]20 = −30.1 (c 1.0, CHCl3). H NMR (400 MHz,
D
Di-tert-butyl [(2R,4S,E)-4-Methyl-1-phenylhept-5-en-2-yl]-
iminodicarbonate (8a). To a solution of alkene 7a (160 mg, 527
μmol) in dry THF (4 mL) was added n-butyllithium (430 μL, 688
μmol, 1.6 M in hexane) at −78 °C. After 30 min at this temperature,
di-tert-butyl dicarbonate (195 mg, 894 μmol) in THF (2 mL) was
added in one portion, and the reaction mixture was allowed to warm to
room temperature overnight before it was heated to 60 °C for 3 h. The
reaction mixture was hydrolyzed with satd NH4Cl solution and
extracted with ethyl acetate. The combined organic layers were washed
with 1 M HCl and brine, dried over Na2SO4, and concentrated in
vacuo. Purification by flash chromatography (hexanes/ethyl acetate
95:5) provided 8a (187 mg, 463 μmol, 88%) as a colorless oil. Rf: 0.30
(hexanes/ethyl acetate 95:5). [α]20D = −50.1 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 0.95 (d, J = 6.8 Hz, 3 H), 1.38 (m, 1 H), 1.41
(s, 18 H), 1.62 (dd, J = 6.3, 1.3 Hz, 3 H), 1.92 (ddd, J = 14.1, 10.0, 4.0
Hz, 1 H), 2.13 (m, 1 H), 2.79 (dd, J = 13.4, 6.7 Hz,1 H), 3.11 (dd, J =
13.3, 8.8 Hz, 1 H), 4.38 (m, 1 H), 5.19 (ddq, J = 15.1, 6.5, 1.5 Hz, 1
H), 5.36 (dqd, J = 15.1, 6.3, 0.8 Hz, 1 H), 7.14−7.19 (m, 3 H), 7.24
(m, 2 H). 13C NMR (100 MHz, CDCl3): δ 17.9, 21.4, 27.9, 34.1, 39.9,
40.5, 57.2, 81.6, 123.9, 126.0, 128.1, 129.5, 136.1, 139.2, 153.2. HRMS
(CI): m/z calcd C24H38NO4 (M + H)+ 404.2795, found 404.2783.
CDCl3): δ 1.17 (d, J = 7.3 Hz, 3 H), 1.39 (s, 18 H), 1.95 (ddd, J =
14.3, 9.8, 5.0 Hz, 1 H), 2.02 (ddd, J = 14.3, 10.0, 4.5 Hz, 1 H), 2.51
(m, 1 H), 2.82 (dd, J = 13.5, 6.3 Hz,1 H), 3.14 (dd, J = 13.5, 9.5 Hz, 1
H), 3.64 (s, 3 H), 4.45 (m, 1 H), 7.14−7.19 (m, 3 H), 7.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ 18.3, 27.9, 36.4, 36.6, 39.9, 51.6, 57.1,
81.8, 126.2, 128.2, 129.4, 138.7, 153.1, 176.6. HPLC (hexane/i-PrOH
9:1, 0.5 mL/min): tR = 10.89 min (97%), tR = 12.87 min (3%). HRMS
(CI): m/z calcd C23H36NO6 (M + H)+ 422.2537, found 422.2548.
Anal. Calcd for C23H35NO6 (421.24): C, 65.53; H, 8.37; N, 3.32.
Found: C, 65.14; H, 8.40; N, 3.42.
(2S,4R)-Methyl 4-[Bis(tert-butoxycarbonyl)amino]-2-ethyl-5-
phenylpentanoate (9b). Ester 9b was prepared according to 9a
from double-protected amine 8b (63.1 mg, 151 μmol) and NaOH
solution (0.3 mL, 0.75 mmol, 2.5 M in dry MeOH) in dichloro-
methane (1.2 mL). Purification by flash chromatography (hexanes/
ethyl acetate 9:1) provided 9b (52 mg, 119 μmol, 79%, 99% ds) as a
colorless oil. Rf: 0.26 (hexanes/ethyl acetate 9:1). [α]20 = −35.3 (c
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.4 Hz, 3 H),
1.39 (s, 18 H), 1.51−1.54 (m, 1 H), 1.58−1.65 (m, 1 H), 1.89 (ddd, J
= 15.0, 10.8, 4.3 Hz, 1 H), 2.09 (ddd, J = 14.3, 11.0, 3.5 Hz, 1 H), 2.36
(m, 1 H), 2.81 (dd, J = 13.6, 5.8 Hz, 1 H), 3.15 (dd, J = 13.6, 9.5 Hz, 1
63
dx.doi.org/10.1021/jo301693d | J. Org. Chem. 2013, 78, 59−65

The Journal of Organic Chemistry
Article
H), 3.64 (s, 3 H), 4.41 (m, 1 H), 7.13−7.18 (m, 3 H), 7.23 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ 11.7, 26.3, 27.9, 34.2, 40.0, 43.7, 51.4,
57.1, 81.8, 126.1, 128.2, 129.4, 137.7, 153.1, 176.1. HPLC (hexane/i-
PrOH 9:1, 0.5 mL/min): tR = 15.83 min (99%), tR = 17.67 min (1%).
HRMS (CI): m/z calcd C24H38NO6 (M + H)+ 436. 2694, found
436.2727. Anal. Calcd for C24H37NO6 (435.55): C, 66.18; H, 8.56; N,
3.22. Found: C 65.56; H, 8.76; N, 3.59.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (FOR 1406). D.B. is thankful for a fellowship from the
(2R,4R)-Methyl 4-[Bis(tert-butoxycarbonyl)amino]-2-(tert-
butyldimethylsilyloxymethyl)-5-phenylpentanoate (9c). Ester
9c was prepared according to 9a from double protected amine 8c
(72.0 mg, 135 μmol) and NaOH solution (0.27 mL, 0.68 mmol, 2.5 M
in dry MeOH) in dichloromethane (1.1 mL). Purification by flash
chromatography (hexanes/ethyl acetate 9:1) provided 9c (60 mg, 109
μmol, 81%, 98% ds) as a colorless oil. Rf: 0.32 (hexanes/ethyl acetate
9:1). [α]20D = −32.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ
−0.01 (s, 3 H), −0.01 (s, 3 H), 0.85 (s, 9 H), 1.39 (s, 18 H), 1.92
(ddd, J = 14.6, 10.5, 4.3 Hz, 1 H), 2.10 (ddd, J = 14.6, 11.4, 3.8 Hz, 1
H), 2.64 (m, 1 H), 2.81 (dd, J = 13.5, 5.8 Hz, 1 H), 3.16 (dd, J = 13.4,
9.7 Hz, 1 H), 6.64 (s, 3 H), 3.71 (m, 2 H), 4.44 (m, 1 H), 7.14−7.18
(m, 3 H), 7.23 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ −5.5, 18.2,
25.7, 27.9, 31.4, 40.0, 45.6, 51.5, 56.9, 65.0, 81.8, 126.2, 128.2, 129.4,
138.6, 153.0, 174.4. HPLC (hexane/i-PrOH 95:5 to 9:1 in 20 min, 0.5
mL/min): tR = 13.40 min (98%), tR = 19.33 min (2%). HRMS (CI):
m/z calcd C29H50NO7Si (M + H)+ 552.3351, found 552.3315. Anal.
Calcd for C29H49NO7Si (551.79): C, 63.12; H, 8.95; N, 2.54. Found:
C, 62.59; H, 9.20; N, 2.82.
Landesgraduiertenforderung Saarland.
̈
DEDICATION
■
Dedicated to the memory of Robert E. Ireland.
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drochloride (10a).6,22 A HCl solution (1.05 mL, 4.20 mmol, 4 M in
dioxane) was added to ester 9a (177 mg 420 μmol) at 0 °C under
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obtained as a white solid: mp 136−138 °C; [α]20 = +11.4 (c 1.0,
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D
CHCl3) [+11.2 (c 1.0, MeOH)].6 1H NMR (400 MHz, CDCl3): δ
−1.15 (d, J = 6.8 Hz, 3 H), 1.80 (ddd, J = 13.3, 9.0, 3.8 Hz, 1 H), 1.99
(ddd, J = 14.3, 10.5, 3.3 Hz, 1 H), 2.93 (dd, J = 14.0, 9.3 Hz, 1 H), 2.97
(m, 1 H), 3.29 (dd, J = 13.7, 5.4 Hz, 1 H), 3.61 (s, 3 H), 3.64 (m, 1
H), 7.24−7.28(m, 3 H), 7.32 (m, 2 H), 8.55 (bs, 3 H). 13C NMR (100
MHz, CDCl3): δ 17.7, 35.9, 36.0, 39.8, 51.9, 52.2, 127.3, 128.9, 129.3,
135.4, 175.7. HRMS (CI): m/z calcd C13H20NO2 (M − Cl)+
222.1489, found 222.1496. Anal. Calcd for C13H20ClNO2 (257.76):
C, 60.58; H, 7.82; N, 5.43. Found: C, 60.29; H, 7.48; N, 5.16.
(3S,5R)-5-Benzyl-3-methylpyrrolidin-2-one (11a).15 To a
solution of 10a (31.0 mg, 120 μmol) in MeOH (1 mL) was added
a solution of NaHCO3 (30.0 mg, 257 μmol) in H2O (1 mL), and the
mixture was stirred for 4 h at room temperature and 12 h at 70 °C.
The solvent was removed in vacuo, and the residue was extracted with
ethyl acetate. The combined organic layers were washed with H2O and
brine, dried over Na2SO4, and concentrated to dryness to yield the
lactam 21 (22.3 mg, 118 μmol, 98%) as a white solid. Rf: 0.14
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* Supporting Information
Copies of NMR data of all new compounds 5−9 and HPLC
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