Introduction of glyco, peptido, carboxy, and alkyno substituents at the calixarene exo rim via the p -bromodienone route

Article abstract of DOI:10.1021/jo300107g

The conceptually novel "p-bromodienone route", which allows the direct introduction of nucleophiles at the calixarene exo rim, has been extended to anionic C-nucleophiles (acetylides) to give chiral meta-substituted alkynocalix[4]arenes and to appropriate

Full text of DOI:10.1021/jo300107g

Note
pubs.acs.org/joc
Introduction of Glyco, Peptido, Carboxy, and Alkyno Substituents at
the Calixarene Exo Rim via the p-Bromodienone Route
Carmine Gaeta, Francesco Troisi, Carmen Talotta, Teresa Pierro, and Placido Neri*
̀
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Ponte don Melillo, I-84084 Fisciano, Salerno, Italy
S
* Supporting Information
ABSTRACT: The conceptually novel “p-bromodienone route”, which allows the direct introduction of nucleophiles at the
calixarene exo rim, has been extended to anionic C-nucleophiles (acetylides) to give chiral meta-substituted alkynocalix[4]arenes
and to appropriate O-nucleophiles to obtain para-substituted glyco, peptido, and carboxy derivatives.
unctionalization at the exo rim (also called upper or wide
Thus, starting with a sugar moiety, we decided to study the
bromine substitution of 1a,b with the primary hydroxyl group
of 1,2,3,4-tetra-O-acetyl-β-D-glucose 2a (TAG, Scheme 1).
Therefore, the exo/endo mixture of calix[4]arene p-bromodie-
none 1a,b was treated with 2a in the presence of AgClO4 in
DME at 0 °C for 2 h (Scheme 1) to give the corresponding TAG-
calixarene derivative 3a in 60% yield after column chromatography
of the reaction mixture. The structure of 3a was easily assigned by
means of spectral analysis. In particular, the presence of a pseudo-
molecular ion peak at m/z 1065 in the ESI(+) mass spectrum
F
rim)1 of calixarene macrocycles2 has been the subject of
considerable interest because it is considered the most logical
and convenient way to transform their preformed calix cavity in
an appropriate recognition site. Usually, this can be achieved
with a range of electrophilic aromatic substitutions3 or with the
classical “Claisen rearrangement route”,4 “p-quinone-methide
route”,5 and “p-chloromethylation route”.6
Very recently, we introduced the “p-bromodienone route”7 as
a conceptually novel approach8 for the direct introduction of
nucleophiles at the calixarene exo rim using easily accessible
calixarene p-bromodienone derivatives9 (exemplified by 1a,b in
Scheme 1). In a similar way, Varma and co-workers concomitantly
reported a related procedure in which alkoxy groups are introduced
into the calixarene exo rim starting from calixarene spirodienone
derivatives.10 In the p-bromodienone route, derivatives like 1a (as
well as its exo/endo mixture 1a,b) undergo a silver-mediated nucle-
ophilic substitution and a subsequent rearomatization with a range
of different O-nucleophiles (alcohols and carboxylates) to give p-
alkoxy- or p-acyloxycalixarenes in workable yields.7a In a subsequent
paper,7b we demonstrated that its extension to activated aromatic
substrates allows the introduction of aromatic moieties at the para
or meta position of calixarene aromatic rings.11 In particular, C−C
meta-coupled products are likely obtained through a dienone−
phenol rearrangement of the intermediate dienone derivative.7b
In order to expand the potentiality of the p-bromodienone route,
we decided to investigate the use of appropriate nucleophiles con-
taining glyco, peptido, carboxy, and alkyno substituents, which
could be useful for biomimetic recognition12 or for further synthetic
elaboration.
1
confirmed the molecular formula. H and 13C NMR spectra of 3a
were consistent with an asymmetric calix[4]arene structure due to
the presence of the chiral sugar substituent. In particular, the
presence of two singlets relative to calixarene t-Bu groups at 0.84
and 1.34 ppm (18 and 9H, respectively) was a clear evidence of the
displacement of one t-Bu group, while the presence of the TAG
moiety at the exo rim of 3a was confirmed by the presence of four
singlets at 1.99, 2.04, 2.05, and 2.12 ppm relating to acetyl protons
and three signals at 169.2, 169.5 (2C), and 170.4 ppm relating to
carbonyl groups. In accordance with these results, a specific optical
rotation [α]25 of +15.7 (c 0.12, CHCl3) was measured for 3a.
D
Successively, deacetylation of TAG group at the exo rim of 3a
was obtained upon treatment with NaOMe in MeOH as solvent to
give glycocalixarene derivative 4 (Scheme 2). Naturally, the glucose
moiety of 4 can exist in two α and β anomeric forms. In fact,
1
the H NMR spectrum of 4 shows two doublets at 5.17 ppm
Received: January 20, 2012
Published: March 15, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1
Scheme 2
As previously demonstrated, the introduction of a peptide
substituent via the p-bromodienone route can be easily obtained
using a serine protected with benzyl groups at both the N- and C-
termini.7a In order to have a more useful orthogonally protected
amino acid derivative, we decided to use N-Boc-L-serine methyl
ester 2b as a nucleophile. Thus, the corresponding calixarene
amino acid derivative 3b was obtained in 40% yield under the above
conditions (AgClO4, DME, 0 °C, 2 h) (Scheme 1). The structure
of 3b was easily confirmed by spectral analysis, and a specific optical
rotation [α]25 = +125.8 (c 0.23, CHCl3) was measured for it.
D
This approach should be easily extendable to a calixarene bis-
(amino acid) derivative if the mixture of stereoisomeric distal bis-
(p-bromodienone) calix[4]arene derivatives 5a−c,7a easily obtained
by treating distal dipropoxycalix[4]arene 6 with trimethylpheny-
lammonium tribromide, is used as the substrate. Therefore, this
mixture was treated as above with N-Boc-L-serine methyl ester 2b
to give bis(amino acid) derivative 7 in 22% yield (Scheme 3).
As above, the structure of 7 was fully consistent with all
spectral data. In particular, its C2-symmetry was confirmed by
(J = 7.7 Hz) and 5.20 ppm (J = 3.7 Hz) relating to β and α
anomeric protons, respectively. Signal integration indicated that the
α anomer is preferentially formed over the β one in a ratio of 5:1. It
is worth pointing out that, to the best of our knowledge, 4
represents the sole example of glycocalixarene linked by means of a
primary alcoholic function and with a free anomeric carbon,13
which may show new interesting properties.
Scheme 3
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The Journal of Organic Chemistry
Note
Scheme 5
the presence of a single tert-butyl singlet (18H) at 1.16 ppm
and two ArCH2Ar AX systems in the H NMR spectrum.
1
As pointed out previously, calix[4]arene amino acid
derivatives 3b and 7 can be considered a novel type of peptido-
calixarenes because, different from other known examples,12,14,15 in
this instance peptide chains can be equally grown either from the C-
or N-terminus through a selective deprotection of amino or carboxy
group. Obviously, this kind of linkage of amino acid moieties to
calixarene exo rim would be more difficult to obtain through syn-
thetic procedures alternative to p-bromodienone route.7b,16
The selective deprotection of amino groups of 7 was
obtained under acid treatment in CH2Cl2 to give derivative 8 in
80% yield (Scheme 3). Subsequent basic cleavage of methyl
ester groups of 8 led to the formation of zwitterionic derivative
9 in 60% yield (Scheme 3).
Recently, the supramolecular properties of calix[4]arene
derivatives bearing anionic carboxylato groups at the exo rim (p-
carboxylatocalixarenes) have attracted considerable interest. In
particular, Dalgarno and co-workers17 have reported a beautiful
example of a solid-state nanotube based on a p-carboxylatocalix-
[4]arene, while we have shown that p-carboxylatocalix[4]arenes
are able to recognize organic cationic guests through an
induced-fit mechanism.18 Thus, prompted by this growing
interest, we decided to exploit the p-bromodienone route as a
simple and direct method to introduce carboxy moieties at the
calixarene exo rim. Therefore, we reacted benzylglycolate 2c
with the mixture of p-bromodienones 1a,b to obtain derivative
3c in 33% yield (Scheme 1). Then, hydrogenolysis of the
benzylic group of 3c (H2, Pd/C) gave carboxy derivative 10 in
85% yield (Scheme 4).
1.07, 1.22, and 1.23 ppm (9H each). In analogy with previous
results with activated aromatic nucleophiles,7b these data were
compatible with a chiral asymmetric calix[4]arene structure in
which a phenol ring is meta- and para-substituted with an
hexynyl and a t-Bu group, respectively, or vice versa.
The real substitution pattern was established by means of a
diagnostic NOESY cross-peak between the t-Bu group at 0.56
ppm and the isolated ArH singlet at 5.94 ppm, only compatible
with a p-t-Bu and m-hexynyl linkage. Interestingly, the unusual
high-field positioning (0.56 ppm) of the t-Bu group can be
explained by the shielding effect of the adjacent triple bond.
As proposed previously for aromatic nucleophiles,7b the
formation of 12a can be explained by a dienone-phenol rearrange-
ment19 of alkyne moiety of intermediate dienone I (Scheme 5),
which migrates to the adjacent meta-position. The migratory
aptitude of alkyne moiety was corroborated by a recent report of
Kim and co-workers in which a Pt-catalyzed dienone-phenol rearr-
angement of alkyne-bearing quinols give rise to 5-hydroxybenzo-
furan systems.20
Scheme 4
To verify the influence of the alkyne moiety on the reaction
outcome, a longer lithium acetylide 11b was reacted with exo/
endo mixture 1a,b. Also in this instance, a meta-substituted calix[4]-
arene 12b was obtained in similar yield (43%), thus confirming that
the p-bromodienone route with carbon nucleophiles provides a
practicable method for the synthesis of meta-substituted inherently
chiral calix[4]arene derivatives.7c In addition, the use of acetylide
nucleophiles provides an easy entry to calixarenes bearing alkyno
substituents at the meta-position, which are complementary to those
para-substituted previously obtained with propargylic alcohol.7a
All these alkynocalixarenes are particularly interesting as recogni-
tion platforms to be used in the fast-expanding field of click
chemistry.16,21
In conclusion, we have demonstrated that the calixarene p-
bromodienone route, previously applied to alcohols, carbox-
ylates, and activated aromatic substrates, can be extended to
anionic C-nucleophiles and can be exploited to append novel
functional groups, which would be more difficult to introduce
through classical routes. In this way, para-substituted glyco,
peptido, and carboxy calixarenes were obtained by using appr-
opriate O-nucleophiles, while inherently chiral m-substituted
alkyno-calixarenes were prepared by using acetylide ions as C-
nucleophiles. We believe that the potentiality of p-bromodie-
none route can be further expanded by using other appropriate
nucleophiles including the N-, and S-ones.
The structure of 10 was easily assigned in the usual way, and
in particular, the presence of a glycolyl group was confirmed by
a singlet at 4.66 ppm relating to OCH2COOH protons.
Derivative 10 represents a novel example of carboxycalixarene
in which a COOH function is linked to the calixarene aromatic
walls through an OCH2 spacer.
Prompted by these results, we decided to investigate the p-
bromodienone route with anionic carbon nucleophiles such as
acetylide ions. Thus, a THF solution of lithium acetylide 11a,
prepared by reaction of 1-hexyne with n-BuLi, was added to a
solution of p-bromodienone 1a,b in dry THF (Scheme 5). The
reaction mixture was kept under stirring for 1 h and then
subjected to column chromatography to give derivative 12a in
48% yield. Derivative 12a showed an 1H NMR spectrum
consistent with an asymmetric calix[4]arene structure. In fact,
diastereotopic ArCH2Ar protons appeared as eight doublets,
while the aromatic protons of the calixarene skeleton gave six
doublets with a typical meta-coupling and one singlet at 5.94
ppm attributable to an isolated ArH proton of the substituted
phenol ring. In addition, four t-Bu singlets were present at 0.56,
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The Journal of Organic Chemistry
Note
4.63 (br d, OCH2CH(NHBoc)COOMe, 1H) 5.13 (s, OH, 1H), 5.55
(d, OCH2CH(NHBoc)COOMe, J = 8.5 Hz, 1H), 6.50−6.58
(overlapped, ArH, 4H), 6.62 (br s, ArH, 2H), 7.11 (br s, ArH, 2H).
13C NMR (CDCl3, 75 MHz, 298 K): δ 10.0, 11.0, 22.7, 23.7, 27.5, 28.6,
30.0, 30.2, 31.4, 31.8, 31.9, 34.0, 34.4, 52.8, 54.2, 70.0, 76.6, 78.0, 80.4,
115.0, 115.1, 115.2, 124.9, 125.3, 126.0, 131.6, 131.9, 132.2, 132.8,
136.2, 145.5, 145.9, 147.3, 148.2, 151.3, 152.2, 154.0, 155.8, 171.0. Anal.
Calcd for C58H81NO9: C, 74.40; H, 8.72; N, 1.50. Found: C, 74.31; H,
8.81; N, 1.42.
EXPERIMENTAL SECTION
■
General: ESI(+)-MS measurements were performed on a quadrupole
mass spectrometer equipped with electrospray ion source, using a
mixture of H2O/CH3CN (1:1) and 5% HCOOH as solvent. Optical
rotations were measured at the indicated concentration and temper-
ature using the sodium D line. Flash chromatography was performed
on silica gel (40−63 μm). All chemicals were reagent grade and were
used without further purification. When necessary, compounds were
dried in vacuo over CaCl2. THF was distilled over CaH2. Reaction
temperatures were measured externally. Reactions were monitored by
TLC on silica gel plates (0.25 mm) and visualized by UV light or by
Derivative 3c. Eluent: CH2Cl2/petroleum ether (8/2, v/v), white
solid, 0.25 g, 33% yield. Mp: >180 °C dec. ESI(+) MS: m/z = 883
1
(MH+). H NMR (CDCl3, 250 MHz, 298 K): δ 0.84 [s, C(CH3)3,
1
spraying with H2SO4−Ce(SO4)2. H NMR spectra were recorded at
18H], 0.95 (t, OCH2CH2CH3, J = 7.3 Hz, 3H), 1.08 (t, OCH2-
CH2CH3, J = 7.4 Hz, 6H), 1.34 [s, C(CH3)3, 9H], 1.90 (m, OCH2-
CH2CH3, 4H), 2.35 (m, OCH2CH2CH3, 2H), 3.17 (br d, overlapped,
ArCH2Ar, 4H), 3.73 (t, OCH2CH2CH3, J = 7.0 Hz, 4H), 3.84
(t, OCH2CH2CH3, J = 8.2 Hz, 2H), 4.32 (d, ArCH2Ar, J = 13.0 Hz,
2H), 4.36 (d, ArCH2Ar, J = 12.5 Hz, 2H), 4.63 (s, OCH2COOR, 2H),
5.16 (s, OH, 1H), 5.26 (s, OCH2Ph, 2H), 6.49 (d, ArH, J = 2.0 Hz,
2H), 6.54 (d, ArH, J = 2.0 Hz, 2H), 6.69 (s, ArH, 2H), 7.13
(s, ArH, 2H), 7.38 (overlapped, ArH, 5H). 13C NMR (CDCl3, 63 MHz,
298 K): δ 9.8, 11.0, 22.6, 23.4, 31.1, 31.4, 31.5, 31.9, 33.9, 34.3, 67.01,
67.05, 76.5, 78.0, 115.2, 124.7, 125.2, 125.8, 128.7, 128.8, 131.4, 131.5,
131.7, 132.5, 136.2, 145.8, 148.4, 148.5, 150.7, 151.7, 152.1, 154.0, 169.5.
Anal. Calcd for C58H74O7: C, 78.87; H, 8.45. Found: C, 78.96; H, 8.37.
Synthesis of Derivative 4. Compound 3c (0.11 g, 0.10 mmol)
was dissolved in 15 mL of anhydrous methanol at room temperature,
and then sodium methoxide (NaOMe) (10 mg) was added to the
reaction mixture. The solution was stirred, at room temperature, for
2 h. Dowex H+ exchange resin, was added until pH = 6−7, and the
reaction was stirred for an additional 10 min. The solution was gravity
filtered and concentrated in vacuo to give 4 as a white solid, 0.065 g,
72% yield. [α]25D = +23.7 (c 0.12, MeOH). Mp: 170−174 °C. ESI(+)
MS: m/z = 897 (MH+). 1H NMR (CD3OD, 400 MHz, 298 K): δ 0.91
[overlapped, C(CH3)3, 18H], 1.00 (t, OCH2CH2CH3, J = 7.6 Hz, 3H),
1.17 (t, OCH2CH2CH3, J = 7.6 Hz, 3H), 1.21 (t, OCH2CH2CH3,
J = 6.8 Hz, 3H), 1.36 [s, C(CH3)3, 9H], 1.88−2.04 (overlapped,
OCH2CH2CH3, 4H), 2.31−2.40 (m, OCH2CH2CH3, 2H), 3.22
(d, ArCH2Ar, J = 10.4 Hz, 2H), 3.25 (d, ArCH2Ar, J = 10.4 Hz,
2H), 3.38−3.89 (overlapped, CHOH + OCH2CH2CH3, 10H), 4.10−
4.22 (m, −OCH2−, 2H), 4.36 (d, ArCH2Ar, J = 10.4 Hz, 2H), 4.40
(d, ArCH2Ar, J = 10.4 Hz, 2H), 5.17 (d, −OCHOHβ‑anomer, J = 7.7 Hz,
0.2 × 1H), 5.20 (d, −OCHOHα‑anomer, J = 3.7 Hz, 1H), 6.62, 6.67,
6.79, and 7.20 (br s, ArH, 8H). 13C NMR (CD3OD, 100 MHz, 298
K): δ 10.9, 12.1, 15.3, 16.3, 24.6, 25.4, 31.6, 32.8, 32.9, 33.1, 33.9, 35.5,
35.8, 50.7, 67.7, 70.8, 72.4, 72.8, 74.6, 75.8, 77.1, 78.3, 79.0, 79.7, 79.8,
80.1, 80.4, 94.9, 99.1, 116.9, 126.6, 127.2, 127.7, 133.6, 133.9, 134.8,
137.9, 147.3, 147.8, 149.2, 154.0, 155.9. Anal. Calcd for C55H76O10: C,
73.63; H, 8.54. Found: C, 73.72; H, 8.45.
250, 300, or 400 MHz, and 13C NMR spectra were recorded at 63, 75,
or 100 MHz. Chemical shifts are reported relative to the residual
solvent peak (CHCl3: δ 7.26, CDCl3: δ 77.23). The temperature was
1
maintained at 298 K for all NMR spectra. One-dimensional H and
13C spectra, DEPT-90, DEPT-135, COSY-45, heteronuclear multiple-
bond correlation (HMBC), heteronuclear single quantum correlation
(HSQC), and NOESY were used for NMR peak assignment of all
derivatives. COSY-45 spectra were taken using a relaxation delay of 2 s
with 30 scans and 170 increments of 2048 points each. HMBC spectra
1
were performed without H decoupling, with low-pass J-filter to sup-
press one-bond correlations, and with a delay of 70 ms for the
evolution of long-range couplings. The number of scans taken was 50,
with 413 increments of 4096 points each. HSQC spectra were
performed with gradient selection, sensitivity enhancement, and phase-
sensitive mode using Echo/Antiecho-TPPI procedure. A typical
experiment comprised 20 scans with 113 increments of 2048 points
each. NOESY spectra were recorded in phase-sensitive mode using a
mixing time of 650 ms. A typical experiment comprised 30 scans with
270 increments of 2048 points each. Derivatives 1a,b,9 2a,22 and 5a−c7a
were synthesized according to literature procedures.
Synthesis of Derivative 3a−c Starting from the Mixture of
Stereoisomers 1a,b. A solution of AgClO4 (1.20 mmol) and the
appropriate alcohol 2a−c (5.8 mmol) in DME (7.0 mL) at 0 °C was
added to the solid mixture of stereoisomers 1a,b (0.58 mmol). The
reaction mixture was allowed to warm at room temperature and stirred
in the dark for 2 h. The reaction was stopped by addition of water (20
mL) and CH2Cl2 (20 mL). The organic phase was washed three times
with water, dried on Na2SO4, and filtered, and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography on silica gel.
Derivative 3a. Eluent: CH2Cl2, white solid, 0.11 g, 30% yield. [α]25
D
= +15.7 (c 0.12, CHCl3). Mp: 180−183 °C. ESI(+) MS: m/z = 1065
1
(MH+). H NMR (CDCl3, 250 MHz, 298 K): δ 0.84 and 1.34 [s,
C(CH3), 18H and 9H], 0.92 (t, OCH2CH2CH3, J = 7.5 Hz, 3H), 1.08 (t,
OCH2CH2CH3, J = 7.5 Hz, 6H), 1.79−1.95 (m, OCH2CH2CH3, 4H),
1.99, 2.04, 2.05, and 2.12 (s, COCH3, 3H each one), 2.27−2.42 (m,
OCH2CH2CH3, 2H), 3.17 (overlapped, ArCH2Ar, 4H), 3.71 (t,
OCH2CH2CH3, J = 7.0 Hz, 4H), 3.83 (m, OCH2CH2CH3, 2H),
3.95−3.99 (overlapped, CHOAc, 3H), 4.10−4.38 (overlapped, ArCH2Ar,
Synthesis of Derivative 7 Starting from the Mixture of
Stereoisomers 5a−c. A solution of AgClO4 (0.49 g, 2.4 mmol) and
N-Boc-L-serine benzyl ester 2b (1.72 g, 7.9 mmol) in DME (6.0 mL)
at 0 °C was added to the solid mixture of stereoisomers 5a−c (0.70 g,
0.79 mmol). The reaction mixture was allowed to warm at room
temperature and stirred in the dark for 2 h. The reaction was stopped
by addition of water (20 mL) and CH2Cl2 (20 mL). The organic phase
was washed three times with water, dried on Na2SO4, and filtered,
and the solvent was removed under reduced pressure. The crude
material was purified by column chromatography on silica gel, eluent
CH2Cl2/petroleum ether, 65/35, v/v; white solid, 0.18 g, yield, 22%.
[α]25D = +29.0 (c 0.20, CHCl3). Mp: >200 °C dec. ESI(+) MS: m/z =
4H), 5.07 (s, OH, 1H), 5.14−5.33 (overlapped, CHOAc + −CH2OArcalix
,
3H), 5.80 (d, −OCHOAc, J = 8.0 Hz, 1H), 6.48 (m, ArH, 2H), 6.54 (m,
ArH, 2H), 6.65 (s, ArH, 2H), 7.14 (s, ArH, 2H). 13C NMR (CDCl3, 63
MHz, 298 K): δ 9.8, 11.0, 20.8, 20.9, 21.1, 22.6, 23.6, 31.4, 31.7, 31.9, 33.9,
34.3, 68.3, 68.9, 70.7, 73.2, 73.6, 77.4, 77.9, 78.0, 92.1, 115.5, 124.7, 125.1.
125.19, 125.9, 131.5, 131.5, 131.6, 131.7, 132.51, 132.5, 136.2, 136.2,
145.4, 145.4, 145.9, 148.3, 151.2, 152.1, 152.2, 154.1, 169.2, 169.5, 170.4.
Anal. Calcd for C63H84O14: C, 71.03; H, 7.95. Found: C, 71.13; H, 7.86.
Derivative 3b. Eluent: petroleum ether/CH2Cl2, (65/35, v/v),
white solid, 0.22 g, 40% yield. [α]25 = +125.8 (c 0.23, CHCl3). Mp:
1
1055 (MH+). H NMR (CDCl3, 400 MHz, 298 K): δ 1.15 (s, t-Bu,
D
200−203 °C. ESI(+) MS: m/z = 936 (MH+). 1H NMR (CDCl3,
400 MHz, 298 K): δ 0.86 (s, t-Bu, 9H), 0.87 (s, t-Bu, 9H), 0.94
(t, OCH2CH2CH3, J = 7.6 Hz, 3H), 1.08 (t, OCH2CH2CH3, J = 7.4
Hz, 6H), 1.32 (s, t-Bu, 9H), 1.48 (s, t-BuBOC, 9H), 1.91 (m, OCH2-
CH2CH3, 4H), 2.31 (m, OCH2CH2CH3, 2H), 3.09−3.20 (overlapped,
ArCH2Ar, 4H), 3.71−3.86 (overlapped, OCH2CH2CH3 + OCH3, 9H),
4.17 (dd, OCH2CH(NHBoc)COOMe, J1 = 9.3 Hz, J2 = 3.0 Hz, 1H),
4.32−4.38 (overlapped, ArCH2Ar + OCH2CH(NHBoc)COOMe, 5H),
18H), 1.22 (t, OCH2CH2CH3, J = 8.0 Hz, 6H), 1.42 (s, t-Bu, 18H),
2.08 (m, OCH2CH2CH3, 4H), 3.26 (d, ArCH2Ar, J = 13.2 Hz, 4H),
3.58 (s, OCH3, 6H), 3.94 (t, OCH2CH2CH3, J = 6.8 Hz, 4H), 4.01
[dd, OCH2CHNH(Boc)COOMe, J1 = 9.2 Hz, J2 = 2.8 Hz, 2H], 4.22
[dd, OCH2CH(NHBoc)COOMe, J1 = 9.2 Hz, J2 = 2.8 Hz, 2H], 4.32
(d, ArCH2Ar, J = 13.2 Hz, 4H), 4.55 [br d, OCH2CHNH(Boc)-
COOMe, 2H], 5.43 [d, OCH2CH(NHBoc)COOMe, J = 8.6, 2H],
6.54 (br s, ArHtBu, 4H), 6.96 (br s, ArHOR, 4H), 8.17 (s, OH, 2H).
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Note
13C NMR (CDCl3, 100 MHz, 298 K): δ 10.7, 11.0, 23.5, 28.5, 31.5,
32.2, 34.4, 52.6, 53.6, 53.8, 68.9, 78.6, 80.3, 114.4, 114.7, 115.1, 126.0,
130.0, 132.7, 133.5, 147.3, 147.6, 150.5, 151.2, 155.6, 170.9. Anal. Calcd
for C60H82N2O14: C, 68.29; H, 7.83. Found: C, 68.38; H, 7.74.
allowed to warm at room temperature and stirred for 1 h. The reaction
was stopped by addition of water (20 mL) and CH2Cl2 (20 mL). The
organic phase was washed three times with water, dried on Na2SO4,
and filtered, and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography on silica
gel (n-hexane/CH2Cl2, v/v, 2/8).
Synthesis of Derivative 8. Derivative 7 (0.12 g, 0.12 mmol) was
dissolved in CH2Cl2 (2 mL) and CF3COOH (2 mL) was added. The
mixture was stirred at room temperature for 2 h. The solvent was
removed and the crude material was dissolved in MeOH (0.5 mL) and
the product was precipitated by the addition of Et2O (3 mL) to give
derivative 8 as a white solid, 0.082 g; yield 80%. [α]25D = +76.7 (c 0.20,
Derivative 12a: 0.09 g, 48% yield. Mp: >200 °C dec. ESI(+) MS:
1
m/z = 855 (MH+). H NMR (CDCl3, 400 MHz, 298 K): δ 0.56
[s, C(CH3)3, 9H], 0.91 (t, OCH2CH2CH3, J = 7.5 Hz, 3H), 0.95
(overlapped, OCH2CH2CH3, 6H), 1.03 (t, −CC−CH2(CH2)2CH3,
J = 7.6 Hz, 3H), 1.07 [s, C(CH3)3, 9H], 1.22 [s, C(CH3)3, 9H], 1.23
[s, C(CH3)3, 9H], 1.26−1.53 (overlapped, CCCH2CH2CH2CH3,
4H), 1.81−2.14 (overlapped, OCH2CH2CH3, 6H), 2.19 (t, C
CCH2CH2CH2CH3, J = 8.0 Hz, 2H), 2.70 (d, J = 12.6 Hz, ArCH2Ar,
1H), 2.97 (d, J = 12.5 Hz, ArCH2Ar, 1H), 3.16 (d, J = 12.8 Hz,
ArCH2Ar, 1H), 3.24 (d, J = 12.8 Hz, ArCH2Ar, 1H), 3.58−3.90
(overlapped, OCH2CH2CH3, 4H), 3.92 (d, J = 12.8 Hz, ArCH2Ar,
1H), 4.08 (m, OCH2CH2CH3, 2H), 4.39−4.49 (overlapped,
ArCH2Ar, 3H), 5.77 (s, OH, 1H), 5.94 (br s, ArH, 1H), 6.77 (d,
ArH, J = 2.5 Hz, 1H), 6.80 (d, ArH, J = 2.5 Hz, 1H), 6.82 (d, ArH, J =
2.5 Hz, 1H), 6.84 (d, ArH, J = 2.5 Hz, 1H), 7.03 (d, ArH, J = 2.5 Hz,
1H), 7.06 (d, ArH, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 63 MHz, 298 K).
13C NMR (CDCl3, 63 MHz, 298 K): δ 10.5, 14.4, 19.7, 20.1, 22.9,
23.0, 23.6, 23.8, 28.8, 29.1, 29.4, 29.7, 29.8, 31.8, 31.9, 32.3, 33.8, 34.1,
37.0, 39.1, 48.1, 68.3, 75.3, 79.6, 83.6, 84.5, 86.7, 119.8, 121.9, 123.9,
124.1, 124.6, 124.9, 125.7, 125.8, 132.3, 132.7, 134.5, 135.2, 135.5,
140.2, 140.9, 143.7, 144.9, 145.6, 153.3, 153.4, 153.6, 153.9. Anal.
Calcd. for C59H82O4: C, 82.85; H, 9.66. Found: C, 82.94; H, 9.57.
Derivative 12b: white solid, 0.095 g, 43% yield. Mp: >220 °C dec.
ESI(+) MS: m/z = 953 (MH+). 1H NMR (CDCl3, 250 MHz, 298 K):
δ 0.89 (t, CCCH2(CH2)9CH3, 3H), 0.92 [s, C(CH3)3, 9H], 1.03
[s, C(CH3)3, 18H], 1.24 [s, C(CH3)3, 9H], 0.94−1.11 (overlapped,
OCH2CH2CH3, 9H), 1.27 (overlapped, CCCH2(CH2)9CH3, 18H),
1.64 (m, CH2CH2CH3, 2H), 1.91 (m, CH2CH2CH3, 2H), 2.18 (m,
CH2CH2CH3, 2H), 2.34 (t, CCCH2(CH2)9CH3, J = 7.1 Hz, 2H),
2.67 (d, J = 12.6 Hz, ArCH2Ar, 1H), 2.98 (d, J = 12.5 Hz, ArCH2Ar,
1H), 3.15 (d, J = 12.8 Hz, ArCH2Ar, 1H), 3.20 (d, J = 12.8 Hz,
ArCH2Ar, 1H), 3.64−3.92 (overlapped, OCH2CH2CH3, 6H), 3.94 (d,
J = 12.8 Hz, ArCH2Ar, 1H), 4.21 (d, J = 12.8 Hz, ArCH2Ar, 1H), 4.37
(d, J = 12.8 Hz, ArCH2Ar, 1H), 4.40 (d, J = 12.8 Hz, ArCH2Ar, 1H),
5.55 (s, OH, 1H), 5.59 (s, ArH, 1H), 6.69 (d, ArH, J = 2.2 Hz, 1H),
6.77 (d, ArH, J = 2.3 Hz, 1H), 6.80 (d, ArH, J = 2.3 Hz, 1H), 6.96
(d, ArH, J = 2.2 Hz, 1H), 6.99 (d, ArH, J = 2.3 Hz, 1H), 7.04 (d, ArH,
J = 2.4 Hz, 1H). 13C NMR (CDCl3, 63 MHz, 298 K): δ 10.3, 10.8,
14.3, 19.3, 19.8, 22.8, 22.9, 23.5, 23.6, 28.8, 28.9, 29.4, 29.7, 29.8, 31.6,
31.7, 32.1, 33.8, 33.9, 34.2, 36.9, 38.9, 48.1, 68.3, 75.2, 79.6, 83.4, 84.5,
86.6, 119.6, 121.9, 123.5, 124.1, 124.6, 124.9, 125.7, 125.8, 132.3,
132.8, 134.6, 135.1, 135.4, 140.1, 140.9, 143.6, 144.8, 145.4, 153.1,
153.2, 153.3, 153.8. Anal. Calcd for C66H96O4: C, 83.15; H, 10.15.
Found: C, 83.23; H, 10.07.
1
CH3OH). Mp: >210 °C dec. ESI(+) MS: m/z = 855 (MH+). H
NMR (CD3OD, 400 MHz, 298 K): δ 1.14 (s, t-Bu, 18H), 1.36
(t, OCH2CH2CH3, J = 7.6 Hz, 6H), 2.10 (m, OCH2CH2CH3, 4H),
3.41 (d, ArCH2Ar, J = 13.2 Hz, 4H), 3.78 (s, OCH3, 6H), 3.99
(t, OCH2CH2CH3, J = 6.8 Hz, 4H), 4.31−4.37 (overlapped, ArCH2Ar +
OCH2CH, 6H), 4.41−4.48 (overlapped, OCH2CH + NH2, 6H), 6.84
(d, ArHtBu, J = 2.4 Hz, 2H), 6.85 (d, ArHtBu, J = 2.4 Hz, 2H), 7.10
(s, ArHOR, 4H). 13C NMR (CD3OD, 100 MHz, 298 K): δ 10.9, 22.9,
31.1, 31.2, 34.1, 52.3, 78.2, 114.5, 114.7, 125.5, 125.8, 129.1, 129.9,
133.4, 146.0, 147.2, 150.1, 150.2, 167.0. Anal. Calcd for C50H66N2O10:
C, 70.23; H, 7.78. Found: C, 70.32; H, 7.86.
Synthesis of Derivative 9. Derivative 8 (0.082 g, 0.096 mmol)
was dissolved in MeOH (2 mL), and a 1 N solution of NaOH (1 mL)
was added. The mixture was stirred at room temperature for 2 h. Then
a 1 N solution of HCl was added dropwise until pH = 5−6 was
reached, and the precipitated product 9 was collected by filtration as a
white solid, 0.048 g, 60% yield. [α]25D = +160.7 (c 0.21, CH3OH). Mp:
1
>220 °C dec. ESI(+) MS: m/z = 828 (MH+). H NMR (CD3OD,
400 MHz, 298 K): δ 1.10 (s, t-Bu, 18H), 1.33 (t, OCH2CH2CH3,
J = 7.6 Hz, 3H), 2.07 (m, OCH2CH2CH3, 4H), 3.37 (d, ArCH2Ar,
J = 12.4 Hz, 4H), 3.62−3.98 (overlapped, CHNH + OCH2CH2CH3,
6H), 4.16−4.35 (overlapped, NHCHCH2 + ArCH2Ar, 8H), 6.81
(d, ArH, J = 2.8 Hz, 2H), 6.82 (d, ArH, J = 2.8 Hz, 2H), 7.07 (d, ArH,
J = 2.0 Hz, 2H), 7.08 (d, ArH, J = 2.0 Hz, 2H), 7.06 (br s, ArHOR, 4H).
13C NMR (DMSO-d6, 63 MHz, 298 K): δ 10.8, 28.8, 31.1, 31.2, 34.1,
78.2, 114.5, 114.7, 125.5, 125.7, 129.1, 129.9, 133.4, 146.0, 147.2,
150.1, 150.2, 167.0. Anal. Calcd for C48H62N2O10: C, 69.71; H, 7.56.
Found: C, 69.80; H, 7.47.
Synthesis of Derivatives 10. A solution of 3c (0.025 g, 0.028
mmol) in CH2Cl2 (0.4 mL) was stirred in the presence of a catalytic
amount of Pd/C (10% w/w) under H2 for 5 h. Then, the reaction
mixture was filtered through Celite and washed three times with
CH2Cl2. The solvent was removed under reduced pressure to give 10
as a white solid, 0.019 g, 85% yield. Mp: >180 °C dec. ESI(−) MS:
m/z = 791 (M−). 1H NMR (CDCl3, 400 MHz, 298 K) δ 0.86
[s, C(CH3), 18H], 0.95 (t, OCH2CH2CH3, J = 7.6 Hz, 3H), 1.09
(t, OCH2CH2CH3, J = 7.2 Hz, 6H), 1.34 [s, C(CH3), 9H], 1.91
(m, OCH2CH2CH3, 4H), 2.32 (m, OCH2CH2CH3, 2H), 3.19 (d,
ArCH2Ar, J = 12.8 Hz, 2H), 3.22 (d, ArCH2Ar, J = 12.8 Hz, 2H),
3.71−3.77 (m, OCH2CH2CH3, 4H), 3.84 (t, OCH2CH2CH3, J = 8.0
Hz, 2H), 4.34 (d, ArCH2Ar, J = 12.8 Hz, 2H), 4.37 (d, ArCH2Ar, J =
12.8 Hz, 2H), 4.66 (s, OCH2COOH, 2H), 5.28 (s, OH, 1H), 6.50 (d,
ArH, J = 2.4 Hz, 2H), 6.56 (d, ArH, J = 2.4 Hz, 2H), 6.72 (s, ArH,
2H), 7.14 (s, ArH, 2H), 12.1 (broad, COOH). 13C NMR (CDCl3, 63
MHz, 298 K): δ 9.5, 11.2, 22.2, 23.6, 31.2, 31.8, 33.8, 34.2, 66.4, 114.9,
124.6, 125.3, 125.7, 131.2, 131.8, 132.5, 136.0, 145.4, 145.7, 148.6,
150.0, 151.9, 153.9, 173.5. Anal. Calcd for C51H68O7: C, 77.24; H,
8.64. Found: C, 77.32; H, 8.55.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds. 2D NMR spectra
and table of all observed HMBC, HSQC, NOE, and COSY
interactions used for assignment of 3c. This material is available
free of charge via the Internet at http://pubs.acs.org.
Synthesis of Derivatives 12a,b. Preparation of Alkynyllithium
Derivatives 11a,b. An appropriate alkyne (0.84 mmol) was
dissolved in dry THF (5 mL), and the solution was cooled
at −78 °C. Then a 2.5 M solution of n-butyllithium in n-hexane
(1.38 mL, 3.45 mmol) was added dropwise over 20 min, and
the resulting suspension was stirred for 10 min at −78 °C. The
solid obtained after decantation was washed two times with dry
THF to give a final suspension.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: neri@unisa.it.
Notes
The authors declare no competing financial interest.
Synthesis of Derivatives 12a,b. A suspension of appropriate
alkynyllithium 11a or 11b (3.45 mmol) in THF (1.0 mL) at −78 °C
was slowly added to the solution of calix[4]arene p-bromodienones
1a,b (0.20 g, 0.23 mmol) in THF (1.0 mL). The reaction mixture was
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