Studies on a new access to z-ethylenic pseudodipeptides based on ring-closing metathesis: Obtention and reductive cleavage of N-arylsulfonyl dihydropyridones

Article abstract of DOI:10.1055/s-0029-1217328

In the reaction with tert-butyloxycarbonyl anhydride (Boc₂O), N-(o-vinylacetyloxy)benzenesulfonyl allylic amines 4a-c undergo concomitant O to N acyl migration to give N-(o-vinylacetyloxy)-N-(o-tert-butoxycarbonyloxy) benzenesulfonyl allylic am

Full text of DOI:10.1055/s-0029-1217328

1614
LETTER
Studies on a New Access to Z-Ethylenic Pseudodipeptides Based on
Ring-Closing Metathesis: Obtention and Reductive Cleavage of
N-Arylsulfonyl Dihydropyridones
New
Access to
u-Ethylenic c
iptides
B
e
a
sed on Ring-C
l
V
osing
M
etathesis andromme, Olivier N’Guyen Van Buu, François Guibé, Sophie Bezzenine-Lafollée
Institut de Chimie Moléculaire et des Matériaux d’Orsay, Laboratoire de Catalyse Moléculaire, UMR 8075, Bât 420, Université Paris-Sud,
91405 Orsay, France
Fax +33(1)69154680; E-mail: sbezzenine@icmo.u-psud.fr
Received 3 February 2009
tides based on olefin metathesis.4 The key step of our
Abstract: In the reaction with tert-butyloxycarbonyl anhydride
method5 (Scheme 1) is ring-closing metathesis (RCM) of
enantiopure diethylenic amides of general formula 1 bear-
ing an auxiliary group, namely the o,p-dimethoxybenzyl
(Boc2O), N-(o-vinylacetyloxy)benzenesulfonyl allylic amines 4a–c
undergo concomitant O to N acyl migration to give N-(o-vinyl-
acetyloxy)-N-(o-tert-butoxycarbonyloxy)benzenesulfonyl allylic
amines 16a–c. In the presence of Grubbs’ second-generation cata- group (Dmb), on the nitrogen atom. By this method, enan-
lyst, 16a–c are converted into N-arylsulfonyl-3,6-dihydropyridones
17a–c. The Boc group was removed from 17b and the resulting 18
was reductively cleaved with LiAlH4 to the ring-opened N-arylsul-
fonylamino alcohol 20 and with DIBAL to the ring-opened N-aryl-
sulfonylamino aldehyde 21 that are close N-protected precursors of
the Z-ethylenic pseudopeptidic analogue of L-Phe-Gly.
tiopure Z-ethylenic analogues of L-Phe-L-Phe, L-Phe-D-
Phe, L-Phe-L-Val and L-Phe-D-Val have been prepared.2
However, owing to the strength of the amide bond, the
conversion of 3,6-dihydropyridones 2 into pseudodipep-
tides 3 required rather harsh conditions resulting in limi-
tations in the scope of this method.2 Moreover, we found
that further conversion of 3 into N-protected derivatives
was difficult due to the proximity of the free carboxyl and
amino groups.
Key words: acyl migration, dihydropyridone, N-arylsulfonyl, ring
opening, diolefin RCM, pseudopeptides, Z-ethylenic
Z-Ethylenic pseudopeptides are conformationally locked
isosteres of peptides with a cis amide bond and as such are
pseudopeptidic entities of particular interest.1,2 In addi-
tion, some further diastereoselective manipulation of the
double bond such as epoxidation, aziridination and dihy-
droxylation are liable to lead to other reactive and poten-
tially biologically interesting pseudopeptidic analogues.
However, if we exclude Etskorn’s recent work1 on Z-al-
kene Xaa-cis-Pro mimics, few synthetic methods have
been proposed for the obtention of YZ(CH=CH) dipep-
tides in enantiomerically pure form. Tourwé and co-
workers3 have introduced and repeatedly used (o-ami-
nomethyl)phenylacetic acid and a-benzyl-(o-aminometh-
yl)phenylacetic acid as cis amide bond surrogates of Gly-
cis-Gly and Gly-cis-Phe.
R1
R1
R1
Grubbs
catalyst
Cl– +H3N
HOOC
DmbN
O
DmbN
O
R2
R2
R2
1
2
3
Scheme 1
To circumvent these difficulties, we sought to perform the
metathetic cyclization on substrates in which the acyl and
amino moieties are linked through an appropriate bifunc-
tional fragment. The linker chosen was 2-hydroxyben-
zenesulfonic acid. In other words (Scheme 2), we hoped
that upon RCM diolefinic N-o-(vinylacetyloxy)benzene-
sulfonyl allylic amines of general formula 4 would yield
For some years, we have been involved in devising a new
methodology for the synthesis of Z-ethylenic pseudopep-
R1
R1
R1
O2
O2
S
O2
S
N
S
metathesis
?
Nu
?
N
H
N
H
O
H
O
OH
O
O
O
Nu
R2
R2
R2
4a R1 = R2 = H
5
6
b R1 = Bn (S); R2 = H
c R1 = Ph (R+S); R2 = H
Scheme 2
SYNLETT 2009, No. 10, pp 1614–1618
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217328; Art ID: D04009ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Access to Z-Ethylenic Pseudodipeptides Based on Ring-Closing Metathesis
1615
macrocyclic compounds 5. Then nucleophilic attack on would be more amenable to ring opening than their corre-
the activated ester function should lead to the desired Z- sponding N-Dmb analogues (i.e., 2). Indeed, N-acyl-
ethylenic pseudopeptidic entities 6 having their terminal sulfonylamines in general may be cleaved under basic
amino group protected as a sulfonamide. Ragnarsson et conditions to the corresponding carboxylic acids or may
al.6 have shown that N-sulfonylamino acids are easily undergo reductive cleavage to alcohols by reaction with
converted into N-Boc derivatives by reaction with hydrides.8
(Boc)2O followed by reductive cleavage (Mg/MeOH) of
the sulfonyl group.
We planned to convert, by reaction with an oxophilic elec-
trophile reagent, various diethylenic N-(o-vinylacetyl-
Unexpectedly, RCM on 4a (10 mol% of Grubbs’ first- oxy)benzenesulfonyl allylic amines 4 into O-masked
generation catalyst, benzene, r.t.) was found to lead, in N-(vinylacetyl)-N-(o-hydroxy)benzenesulfonyl
allylic
low conversion (25%) and in low yield (20%), to dihydro- amines 8 which would in turn would be converted by
pyridine 7 to the exclusion of macrocycle 5. We therefore RCM into dihydropyridones 9 (Scheme 4). Removal of
surmised (Scheme 3) that the reactive species in the meta- the oxophilic fragment (if necessary) and cleavage of the
thetic reaction was the isomeric entity 4¢ resulting from dihydropyridone ring would complete the access to the
intramolecular O to N migration of the acyl moiety and desired Z-ethylenic pseudopeptidic derivatives. At this
present in minor amounts.7
point it should be specified that in our previous work9
many unsuccessful attempts were made towards direct N-
acylation of N-allyl benzenesulfonylamines with vinyl-
acetyl chloride. In all cases except when the allyl amino
group bore no substituents, the reactions proceeded poorly
and/or extensive reconjugation of the double bond of the
vinylacetyl moiety was observed. The electrophilically in-
duced O to N migration of the vinylacetyl group within 4
thus appeared to be the only access to compounds 8.
OH
O2S
Grubbs I (10 mol%)
N
4a
(20%)
O
7
Sulfonamides 4 were synthesized starting from the bis-O-
trimethylsilyl derivative 10 of 2-hydroxybenzenesulfonic
acid (Scheme 5). 2-Hydroxybenzenesulfonic acid is not
commercially available and so 10 was synthesized on
multigram scale in three steps from 2-chlorophenol ac-
cording to the literature procedure10 and then converted
into benzoyl ester 11 (PhCOCl, 1 equiv, neat, 95 °C for 3
h, then 105 °C for 3 h). The ester 11 was reacted with
freshly distilled thionyl chloride to give (o-benzoyl-
oxy)benzenesulfonyl chloride 12.11 Compound 12 was
converted into allylic sulfonylamines 13 by reaction first
with one equivalent of the desired allylic amine [allyl-
amine itself, enantiopure (S)-a-benzylallylamine, racemic
O2
S
N
O
OH
4'
Scheme 3
Thus and at first sight, the issue of the ring-closing met-
athesis on 5 seemed to bring us back to the dihydropyri-
done problem that we wanted to avoid! However due to
the electronegativity of the arylsulfonyl group, we specu-
lated that N-arylsulfonyldihydropyridones such as 7
R1
R1
O2
S
O2
S
N
N
E
1) – E
metathesis
6
4
O
O
OE
2) cleavage
OE
R2
R2
8
9
Scheme 4
SO2Cl
SO3SiMe3
OCOPh
SO3SiMe3
SOCl2
PhCOCl
R1
OCOPh
OSiMe3
10
11
12
R1
H2N
1)
2)
SO2NH
DIPEA
NH2
12
(excess)
OH
13a–c
Scheme 5
Synlett 2009, No. 10, 1614–1618 © Thieme Stuttgart · New York

1616
L. Vandromme et al.
LETTER
a-phenylallylamine] in the presence of DIPEA and subse-
quently with an excess of allylamine in order to remove
the benzoyl group.12 In that way, compounds 13a,b,c were
obtained in 97%, 62% and 75% yields, respectively.
O2
Grubbs
catalysts
O2
S
TESOTf
2,6-lutidine
S
N
N
4a
O
O
OSiEt3
OSiEt3
9
15
Unexpectedly, introduction of the vinylacetyl group onto
allylic sulfonamides 13 proved to be somewhat tricky.
When 13a was reacted with vinylacetyl chloride in the
presence of a tertiary amine such as triethylamine or
DIPEA, the desired vinylacetic ester was sometimes ob-
Amberlyst 15, MeOH
Scheme 7
tained but in some other runs (ca. one over two) and under Our next choice as the acyl migration inducing agent was
apparently similar reaction conditions the major or even tert-butyloxycarbonyl anhydride (Boc)2O (Scheme 8).
exclusive product was the corresponding crotonic ester re-
sulting from migration of the double bond from the b,g to
Compounds 4a,b,c were reacted with (Boc)2O in the pres-
ence of a catalytic amount of DMAP (0.05 equiv) to give
the a,b position of the acyl moiety. This difficulty could
finally be overcome by carrying out the acylation reaction
on the tributyltin salts of 13 under apolar, weakly basic
and nonprotic conditions (Scheme 6).13 Compounds
4a,b,c were obtained in 90%, 69% and 76% yields, re-
spectively.
the O-Boc, N-vinylacetyl compound 16a,b,c16 in 95%,
79% and 71%, yields respectively. The ring-closing met-
athesis on 16a,b,c took place successfully, leading to N-
arylsulfonyl dihydropyridones 17a,b,c in 71%, 70% and
68% yields, respectively.17 Boc removal and ring-opening
steps were studied on dihydropyridone 17b. Compound
17b was heated at 100 °C for three hours in dioxane–3 M
aqueous HCl to give the free phenolic derivative 18 in
70% yield. We first attempted the ring opening of 18 in
the presence of a nucleophile reasoning that this process
would be nucleophilically assisted by the neighboring
phenolic group (through transient formation, by intra-
molecular N→O acyl transfer, of a macrocyclic activated
ester as represented in 5). Exposure of 18 to benzylamine
(r.t., MeCN) did not give the expected product, but was
found to give 5,6-dihydropyridone 19 resulting from re-
conjugation of the double bond with the carbonyl group
(Scheme 9).
R1
O
NaHCO3, H2O
Bu3SnCl
SO2NH
Cl
13a–c
4a–c
hexane, 60 °C
OSnBu3
14a–c
Scheme 6
Migration induced by CH2N2, albeit successful in the case
of compound 4,7 did not appear to give consistent results
over a range of compounds (i.e. with substituted allylami-
no groups). Furthermore methyl phenoxides require harsh
conditions for their cleavage.14 Trimethylsilyl phenoxides
are too labile to allow purification by chromatography on
silica. We finally considered the triethylsilyl group as a
possible electrophilic fragment. The N-(o-vinylacetyl-
oxy)benzenesulfonyl allylic amine 4a was reacted with
triethylsilyl triflate in CH2Cl2 in the presence of 2,6-luti-
dine (THF, 0 °C to r.t., 2 h) to give the expected N-acyl O-
silylated derivative 15 in 72% yield after chromatogra-
phy.15 To our disappointment and for unknown reasons,
we were unable to achieve ring-closing metathesis of 15
in benzene even at 80 °C irrespective of the catalyst (first
or second generation). Apparently, immediate poisoning
of the catalyst takes place. In the meantime, we observed
that upon cleavage of the triethylsilyl group of 15 (Am-
berlyst 15, MeOH) 4a was immediately and quantitatively
(98% yield) reformed (Scheme 7), thus confirming the
strong preference for the O- over the N-acyl form.
Bn
Bn
O2
S
O2
S
N
N
PhCH2NH2
(quant)
O
O
OH
OH
18
19
Scheme 9
From this result, it was clear that cleavage of the pyridone
ring using potentially protic conditions that favor migra-
tion of the double bond would be quite hopeless. The re-
ductive cleavage of acyclic acylsulfonamide with LiAlH4
is well documented.8 We therefore turned to reducing
agents to achieve ring opening. Gratifyingly, treatment of
18 with one equivalent of LiAlH4 gave the expected ring-
opened allylic alcohol 20 in 74% yield (Scheme 10).18
Compound 18 was also reacted with two equivalents of
R1
R1
R1
O2
S
O2
S
Grubbs
catalysts
N
N
(Boc)2O
4a–c
O
O
OBoc
DMAP (cat.)
OBoc
Scheme 8
Synlett 2009, No. 10, 1614–1618 © Thieme Stuttgart · New York

LETTER
New Access to Z-Ethylenic Pseudodipeptides Based on Ring-Closing Metathesis
1617
Bn
Bn
Bn
H
O2
S
O2
S
O2
S
N
N
N
H
LiAlH4
DIBAL-H
O
OH
THF
–78 °C to r.t.
THF
–78 °C to 0 °C
O
OH
HO
OH
21
20
18
Scheme 10
undergoes concomitant rearrangement and methylation to
give the O-methyl ether of 4¢. By comparison of the NMR
spectra (CDCl3) of this ether and 4a we were able to locate,
in the spectrum of the latter compound, the signals of 4¢
which is present to the extent of ca 3%. The O-methyl ether
was in turn found to readily cyclize by RCM in 95% yield
into the corresponding dihydropyridone.
diisobutylaluminum hydride (1 equiv is necessary to
quench the phenolic proton) to give in 60% yield the
internal hemiacetal form 21 resulting from reductive
opening of the dihydropyridone (Scheme 10).19 Diisobu-
tylaluminum hydride is known to reduce Weinreb amides
into aldehydes, but to the best to our knowledge it is the
first time that this reagent has been used to reduce acylsul-
fonamides.
(8) Oppolzer, W.; Lienard, P. Helv. Chim. Acta 1992, 75, 2572.
(9) Boucard, V.; Sauriat-Dorizon, H.; Guibé, F. Tetrahedron
2002, 58, 7275.
In conclusion, only parts of our original expectations have
been fulfilled by the present study. Dihydropyridone 18
has finally been ring opened but in a reductive fashion
leading to aldehyde or alcohol instead of acid or acid de-
rivatives. Of course many methods are at hand to oxidize
these compounds to carboxylic acids20 that will be tested
but we also plan to try and devise ring-opening methods
leading directly to acids. The extension of the present
study to compounds bearing substituents a to the carbonyl
group of the vinylacetyl fragment has yet to be attained.
Finally, in this work we have incidentally developed a
new technique, based on tin chemistry, for vinylacetyl-
ation of phenoxides. It efficiently reduces the risk of re-
conjugation of the double bond and could be useful in
other related reactions.
(10) Babin, P.; Benneteau, B.; Bourgeois, P.; Rajarison, F.;
Dunogues, J. Bull. Soc. Chim. Fr. 1992, 19, 25.
(11) The reaction was carried out at 95 °C in a tightly stoppered
Schlenk tube in the presence of freshly distilled SOCl2 (1.6
equiv) without solvent and under an argon atmosphere. After
12 h the reaction mixture was cooled to r.t. and pumped out
on a vacuum line. The Schlenk tube was reloaded with
SOCl2 (1.6 equiv) and heated again at 95 °C for 12 h. The
process was repeated twice more. The progress of the
reaction was conveniently followed by examination of
the 1H NMR pattern of the aromatic protons. The final
crystalline residue was recrystallized from heptane–EtOAc.
Yield: 83%.
(12) Typical Experimental Procedure: The hydrochloric salt of
(S)-a-benzylallylamine (6.76 mmol) and DIPEA (13.5
mmol) were dissolved in anhyd MeCN (20 mL) under an
argon atmosphere. To the reaction mixture was added
dropwise (o-benzoyloxy)benzenesulfonyl chloride 12 (6.76
mmol) and the reaction mixture was further stirred for 1 h at
0 °C and for 10 h at r.t. After evaporation of acetonitrile, the
residue was taken up in Et2O and washed with dilute aq HCl
and dilute aq sodium bicarbonate. After evaporation, the
crude N-(1-benzyl)-(o-benzoyloxy)benzenesulfonamide
was dissolved in anhyd MeCN (20 mL) at 0 °C. Allylamine
(15 mmol) was added dropwise and the reaction mixture was
further stirred for 10 h at r.t. After acetonitrile evaporation,
the residue was taken up in Et2O. The ethereal solution was
extracted with 2 N aq NaOH (2 ×). The aqueous phase was
acidified to pH 1–2 with aq HCl and extracted with Et2O.
After evaporation, 13b was purified by column chromatog-
raphy (silica, cyclohexane–EtOAc, 90:10; yield: 62%).
(13) Compounds 13a–c were converted into their O-tributyl-
stannyl derivatives by reaction of Bu3SnCl in a two-phase
system [HCO3Na (2–3 equiv), Bu3SnCl (1 equiv), Et2O–
H2O, the tin phenoxide is recuperated in the organic phase]
or by reaction of (Bu3Sn)2O (0.5 equiv, benzene or toluene,
azeotropic elimination of H2O). The tin phenoxides were
reacted with vinylacetyl chloride in hexane at 60 °C for 1–4
h depending on the cases. The O-vinylacetyl derivatives 4a–
c progressively separated from the reaction mixture as
crystals or as oils that crystallized on cooling. The whole
reaction mixtures were then taken up in hexane–MeCN and
most of the tin by-products were eliminated in the usual way
by repetitive partition between the two solvents. Final
purification was achieved by recrystallization (hexane–
EtOAc) or column chromatography (silica gel, hexane–
References and Notes
(1) (a) Wang, X. J.; Xu, B.; Mullins, A. B.; Neiler, F. K.;
Etzkorn, F. A. J. Am. Chem. Soc. 2004, 126, 15533.
(b) Wang, X. J.; Hart, S. A.; Xu, B.; Mason, M. D.; Goodell,
J. R.; Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343.
(c) Hart, S. A.; Etzkorn, F. A. J. Org. Chem. 1999, 64, 2998.
(d) Hart, S. A.; Sabat, M.; Etzkorn, F. A. J. Org. Chem. 1998,
63, 7580.
(2) Boucard, V.; Sauriat-Dorizon, H.; Guibé, F. Tetrahedron
2002, 58, 7275.
(3) See, for instance: (a) Breck, V.; Berheyden, P.; Tourwé, D.
Lett. Pept. Sci. 1998, 5, 67. (b) Van Binst, G.; Tourwé, D.
Peptide Res. 1992, 5, 8. (c) Vander Elst, P.; Van den Berg,
E.; Pepermans, H.; Vander Auwera, L.; Zeeuws, R.;
Tourwé, D.; Van Binst, G. Int. J. Peptide Protein Res. 1987,
29, 318.
(4) For recent and general reviews on olefin metathesis, see:
(a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (b) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
(c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(5) (a) Ref. 2 (b) Sauriat-Dorizon, H.; Guibé, F. Tetrahedron
Lett. 1998, 39, 6711. (c) Garro-Hélion, F.; Guibé, F. Chem.
Commun. 1996, 641.
(6) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun.
1997, 1017.
(7) In confirmation of this hypothesis, we found that, upon
exposure to an ethereal solution of diazomethane 4
Synlett 2009, No. 10, 1614–1618 © Thieme Stuttgart · New York

1618
L. Vandromme et al.
LETTER
EtOAc) of the residue from the MeCN phase. See: Newman
W. P.; Synthesis; 1987, 665
(62.5 MHz, CDCl3): d = 168.4, 147.7, 135.3, 135.0, 132.4,
131.6, 130.8, 128.3, 127.0, 125.9, 125.7, 122.9, 84.8, 59.4,
42.8, 33.8, 27.6. IR (CHCl3): 1770 (C=O, Boc), 1694 (C=O,
amide) cm–1. [a]D20 +113.3 (c = 1, CHCl3).
Spectroscopic data : Compound 4a: 1H NMR (250 MHz,
CDCl3): d = 7.90 (1 H, dd, J = 7.8 Hz, J′ = 1.2 Hz), 7.20–7.56
(3 H, m), 6.11–6.14 (1 H, m), 5.64–5.68 (1 H, m), 5.35–5.39
(2 H, m), 5.05–5.11 (2 H, m), 4.75 (1 H, br s, NH), 3.58 (2
H, t, J = 6.0 Hz), 3.37 (2 H, d, J = 7.0 Hz). 13C NMR (62.5
MHz, CDCl3): d = 169.2, 147.5, 134.2, 132.8, 130.3, 128.9,
126.5, 124.7, 120.3, 118.0, 48.9, 39.2. IR (CHCl3): 1773
(C=O), 3368 (NH) cm–1. MS (CI, NH3): m/z = 298 [M +
Compound 17c: 1H NMR (200 MHz, CDCl3): d = 8.16 (1 H,
dd, J = 8.0 Hz, J¢ = 1.5 Hz), 7.64 (1 H, td, J = 15.0 Hz, J¢ =
1.5 Hz), 7.30–7.45 (7 H, m), 6.24–6.28 (1 H, m), 5.71–6.16
(2 H, m), 2.90–3.31 (2 H, m), 1.63 (9 H, s). 13C NMR (62.5
MHz, CDCl3): d = 167.9, 147.8, 140.3, 134.9, 132.5, 129.1,
128.1, 127.6, 126.2, 126.1, 125.9, 124.2, 119.9, 84.9, 62.2,
34.1, 27.8. IR (CHCl3): 1770.5 (C=O, Boc), 1699.3 (C=O,
lactam) cm–1.
+
NH4 ], 282 [MH+].
Compound 4b: 1H NMR (200 MHz, CDCl3): d = 6.86–7.90
(9 H, m), 5.90–6.10 (1 H, m), 5.54–5.71 (1 H, m), 5.21–5.33
(2 H, m), 4.92–5.01 (2 H, m), 4.79 (1 H, d, J = 7.3 Hz, NH),
3.95–4.10 (1 H, m), 3.33 (2 H, d, J = 7.2 Hz), 2.80 (2 H, d,
J = 6.8 Hz). 13C NMR (62.5 MHz, CDCl3): d = 168.7, 147.3,
136.7, 136.1, 133.8, 129.9, 129.5, 129.4, 128.6, 128.5,
126.9, 126.1, 124.5, 119.9, 116.4, 57.4, 42.0, 39.0.
(18) Experimental Procedure: To a solution of 18 (40 mg, 0.116
mmol) in THF (2 mL) was added LiAlH4 (4 mg, 0.116
mmol, 1 equiv) at r.t. The reaction was stirred for 3 h and
quenched with a solution of 0.1 M HCl. The aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were dried with MgSO4 and concentrated in
vacuo. The resulting oil was then chromatographed on silica
gel column (EtOAc–heptane, 20:80) to give the alcohol 20.
Yield: 74% (30 mg, 0.086 mmol).
Compound 4c: 1H NMR (250 MHz, CDCl3): d = 6.90–7.80
(9 H, m), 5.76–6.11 (2 H, m), 5.00–5.30 (4 H, m), ca. 5.2
(1 H, NH) 4.80–4.95 (1 H, t, J = 15 Hz), 3.35 (2 H, d, J = 6.9
Hz). 13C NMR (62.5 MHz, CDCl3): d = 168.7, 147.3, 138.9,
136.7, 133.9, 132.4, 130.0, 129.8, 128.7, 127.9, 127.1,
126.1, 124.3, 120.3, 117.1, 60.2, 39.3. IR (liquid film):
1772.2 (C=O), 3294.2 (NH) cm–1. MS (CI, NH3): m/z = 375
Compound 20: 1H NMR (300 MHz, CDCl3): d = 8.71 (1 H,
s), 6.96–7.56 (m, 9 H), 5.31–5.42 (2 H, m), 4.91–4.94 (1 H,
br d, NH), 4.23–4.32 (1 H, m), 3.45 (2 H, t, J = 6.4 Hz), 2.91
(1 H, dd, J = 13.5 Hz, J¢ = 6.0 Hz), 2.78 (1 H, dd, J = 13.5
[M + NH4 ], 358 [MH+].
Hz, J¢ = 7.9 Hz), 1.91–2.11 (2 H, 2 × symmetrical m). 13
NMR (75 MHz, CDCl3): d = 155.2, 136.2, 135.3, 130.9,
C
+
(14) Greene, T. W.; Wuts, P. G. M. Protective Group in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(15) The absence of ester IR carbonyl absorption in the range
1750–1700 cm–1 is coherent with the O-silylated N-acylated
structure as represented in 15; the alternative N-silylated O-
acylated may be confidently dismissed.
(16) Typical Experimental Procedure: To a solution of
N-1-benzylallyl-o-(but-3-enoyloxy)benzene-sulfonamide
(4b; 1.7 mmol) in anhyd CH2Cl2 (12 mL) were added
successively Boc2O (1.72 mmol) and DMAP (0.08 mmol, ca
0.05 equiv). The reaction mixture was then stirred at r.t. with
TLC monitoring. After completion, the reaction mixture was
diluted with EtOAc and washed successively with aq 1 M
HCl and aq NaHCO3. The organic phase was dried,
concentrated and the residue was purified by column
chromatography (silica gel, cyclohexane–EtOAc, 9:1) to
give N-1-benzylallyl-N-but-3-enoyl-(o-tert-butoxycarbonyl-
oxy)benzenesulfonamide (16b) as a colorless oil (yield:
79%).
129.7, 129.6, 128.7, 128.6, 127.1, 123.2, 120.5, 118.8, 61.6,
52.5, 42.2, 30.8. HRMS (ESI): m/z [M + Na+] calcd for
C18H21O4NNaS: 370.1068; found: 370.10787.
(19) Experimental Procedure: To a stirred solution of 18 (50
mg, 0.146 mmol) in THF (2 mL) at –78 °C was added slowly
a 1.1 M solution of diisobutylaluminum hydride in cyclo-
hexane (0.4 mL, 0.44 mmol, 3 equiv). The solution was
warmed to 0 °C and quenched with a solution of 0.1 M HCl.
The layers were separated and the aqueous phase was
extracted with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried with MgSO4 and concentrated in vacuo.
The resulting oil was then chromatographed on silica gel
column (EtOAc–heptane, 30:70). Compound 21 was
obtained as a 85:15 mixture of the two possible diastereo-
isomers. Yield: 60% (32 mg, 0.088 mmol).
Spectroscopic data: Compound 21 (major diastereoisomer):
1H NMR (360 MHz, CDCl3): d = 7.80 (1 H, dd, J = 8.1 Hz,
J¢ = 1.5 Hz), 7.44–7.47 (1 H, m), 7.19–7.35 (5 H, m), 6.92 (1
H, d, J = 8.6 Hz), 6.17–6.19 (1 H, m), 5.76–5.82 (2 H, m),
4.20–4.22 (1 H, m), 3.41 (1 H, dd, J = 13.1 Hz, J¢ = 2.8 Hz),
3.11 (1 H, dd, J = 13.2 Hz, J¢ = 8.3 Hz), 2.41–2.57 (1 H, m),
2.18–2.24 (1 H, m). 13C NMR (75 MHz, CDCl3): d = 134.2,
134.1, 130.4, 129.4, 128.5, 128.0, 127.3, 126.5, 125.2,
124.7, 122.3, 121.7, 119.7, 119.5, 118.2, 83.9, 54.9, 42.9,
24.6. HRMS (ESI): m/z [MH+ – H2O] calcd for C18H18O3NS:
328.1002; found: 328.10030.
Spectroscopic data: Compound 16b: 1H NMR (200 MHz,
CDCl3): d = 7.30–8.03 (9 H, m), 5.91–6.23 (2 H, m), 5.10–
5.23 (2 H, m), 4.58–4.90 (2 H, m), 4.50–4.58 (1 H, m), 3.71
(2 H, d, J = 6.8 Hz), 3.31–3.42 (1 H, dd, J = 13.2 Hz, J¢ = 9.3
Hz), 3.00–3.09 (1 H, dd, J = 13.2 Hz, J¢ = 5.0 Hz), 1.58
(s, 9 H). IR (CHCl3): 1769 (C=O, Boc), 1702.1 (C=O,
amide) cm–1.
Compound 16c (yield: 93%): 1H NMR (200 MHz, CDCl3):
d = 7.30–8.20 (9 H, m), 6.35–6.55 (1 H, m), 5.80–6.00 (1 H,
m), 5.76 (1 H, d, J = 6.4 Hz), 5.10–5.20 (2 H, m), 5.00–5.48
(2 H, m), 3.50–3.80 (m, 2 H), 1.58 (s, 9 H). IR (CHCl3): 1769
(C=O, Boc), 1702.1 (C=O, amide) cm–1.
(20) In particular, several alkene pseudodipeptidic entities have
been obtained by oxidation of alcohols precursors: (a) cis-
Proline mimics: ref. 1b, 1d. (b) E-Alkene analogues: Bol,
K. M.; Liskamp, R. M. J. Tetrahedron 1992, 48, 6425.
(c) Bohnsted, A.; Prasad, V.; Rich, D. H. Tetrahedron Lett.
1993, 34, 5217. (d) Yong, Y. F.; Lipton, M. A. Bioorg. Med.
Chem. Lett. 1993, 3, 2879. (e) Xiao, J.; Weisblum, B.; Wipf,
P. Org. Lett. 2006, 8, 4731.
(17) Spectroscopic data: Compound 17b: 1H NMR (200 MHz,
CDCl3): d = 7.27–8.25 (9 H, Ar, m), 5.84–5.93 (1 H, m),
5.64–5.72 (1 H, m), 5.40–5.53 (1 H, m), 3.10–3.31 (2 H, m),
2.46–2.59 (1 H, dd, J = 21.5 Hz, J¢ = 5.1 Hz), 1.90–2.02
(1 H, dd, J = 21.5 Hz, J¢ = 2.9 Hz), 1.58 (s. 9H). 13C NMR
Synlett 2009, No. 10, 1614–1618 © Thieme Stuttgart · New York

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