Orthogonal protecting groups in the synthesis of tryptophanyl- hexahydropyrroloindoles

Article abstract of DOI:10.1002/ejoc.201101057

The synthesis of various polycyclic systems containing aC ^3a-Nⁱ bond between a hexahydropyrrolo[2,3-b]indole and an indole tryptophan is described here. A series of experiments were performed to determine the best combination of five orthogonal protecting groups and the best reaction conditions for formation of said bond, which is a common feature among many recently discovered marine natural products.

Full text of DOI:10.1002/ejoc.201101057

FULL PAPER
DOI: 10.1002/ejoc.201101057
Orthogonal Protecting Groups in the Synthesis of Tryptophanyl-
Hexahydropyrroloindoles
Pau Ruiz-Sanchis,[a,b] Svetlana A. Savina,[a,c] Gerardo A. Acosta,[a,c]
Fernando Albericio,*[a,c,d] and Mercedes Álvarez*[a,b,c]
Keywords: Natural products / Heterocycles / Amino acids / Protecting groups
The synthesis of various polycyclic systems containing a
C3a–Ni bond between a hexahydropyrrolo[2,3-b]indole and
an indole tryptophan is described here. A series of experi-
ments were performed to determine the best combination of
five orthogonal protecting groups and the best reaction con-
ditions for formation of said bond, which is a common feature
among many recently discovered marine natural products.
Introduction
chaetocochins[10] contain an unusual bond between the 3a-
position of the HPI and the indole nitrogen of either a
tryptamine or a tryptophan (Scheme 1). Kapakahines are
natural products with a bond between the C4a of an α-carb-
oline and the indole nitrogen of an N-Trp.[11]
The tricyclic motif hexahydropyrrolo[2,3-b]indole (HPI)
is present in many natural compounds with important bio-
activities.[1] These compounds all feature a substituent at
the 3a-position of the HPI such as a methyl group, in (–)-
physostigmine;[2] a prenyl, in flustramines,[3] brevicompan-
To date, four total syntheses of psychotrimine have been
ines,[4] and roquefortines;[5] and a newly discovered HPI reported.[12] Takayama and co-workers were the first to syn-
linked by one aromatic carbon, in idiospermuline,[6] psycho- thesize this compound,[12a] assembling the HPI motif from
tridine,[7] and quadrigemine.[8] Recently isolated natural a phenylacetonitrile that contained an indoline at the ap-
compounds such as psychotrimine,[9] chaetomin, and the propriate α-nitrile position. In contrast, Newhouse and
Scheme 1. Natural products containing a bond between the C3a of an HPI, or the C4a of an α-carboline, and the indole nitrogen of either
a tryptamine or a tryptophan.
[a] Institute for Research in Biomedicine, Barcelona Science Park,
Baran[12b] prepared psychotrimine through simultaneous
Baldiri Reixac 10, 08028 Barcelona, Spain
formation of the HPI and the N–C3a bond. They later em-
E-mail: albericio@irbbarcelona.org
mercedes.alvarez@irbbarcelona.org
ployed the same strategy to synthesize kapakahines B and
[b] Laboratory of Organic Chemistry, Faculty of Pharmacy,
F,[13] and (+)-psychotetramine.[14]
University of Barcelona,
08028 Barcelona, Spain
During the course of the present work, Espejo and Rain-
ier published a study on N–C3a bond formation through
bromo-displacement of 3a-bromo-HPIC with the N-anion
of indole.[15] The same group harnessed this chemistry to
obtain kapakahines E and F,[16] and, more recently, pro-
posed a mechanism for the substitution.[17]
[c] CIBER-BBN, Networking Center on Bioengineering,
Biomaterials and Nanomedicine, Barcelona Science Park,
Baldiri Reixac 10, 08028 Barcelona, Spain
[d] Department of Organic Chemistry, University of Barcelona,
08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101057.
Eur. J. Org. Chem. 2012, 67–73
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
67

F. Albericio, M. Álvarez et al.
FULL PAPER
Compound 1, which contains a bond between the C3a of Table 1. Synthesis of the bromo-compounds 3a–p.
HPI and the nitrogen atom of an indole, could be used as
a scaffold for the synthesis of many natural products and
analogues. In the work reported here, 1 was synthesized
through nucleophilic substitution of the bromine at position
3a of 3a-bromo-HPI with an N-indole anion (Scheme 2).
To ensure chemoselectivity during this chemistry, five or-
thogonal protecting groups were required. Studies to deter-
Entry Comp. R1
R2
R3
Method endo/exo
(yield%)
mine the best protecting groups and conditions for this
bond formation were then performed and are described
herein.
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Boc
Boc
Boc
Boc
Boc
Alloc
Boc
Boc
Cbz
Troc
OMe
OAllyl
OMe
OMe
OMe
OtBu
OMe
B (83)
exo
4:96[b]
B (30)[a] exo
B (86)
B (78)
B (77)
B (80)
A (9)
exo
11:89[c]
7:93[c]
endo
Nosyl Cbz
Nosyl Troc
3g
B (57)
B (59)
B (92)
B (82)
B (83)
A (37)
B (96)
A (28)
B (58)
B (47)
8:92[c]
6:94[b]
7:93[b]
4:96[b]
exo
8
9
10
11
12
3h
3i
3j
3k
3l
Nosyl Troc
SO2Ph Boc
SO2Ph Cbz
SO2Ph Cbz
SO2Ph Moc
OtBu
OMe
OMe
OtBu
OMe
endo
Scheme 2. Retrosynthesis of compound 1.
5:95[b]
91:9[c]
25:75[c]
exo
13
3m
SO2Ph Moc
OtBu
14
15
16
3n
3o
3p
Boc
Boc
Boc
Nα-Alloc-Ala OMe
Alloc
Boc
Results and Discussion
Ile-OMOM B (47)[a] exo
Ile-OAllyl
B (41)[a] exo
First, various bromo analogues of 3a-bromo-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylate
(3a-Br-HPI; 3) were synthesized using two different pro-
cedures, which were subsequently compared for perform-
ance (Table 1). The first approach followed the route de-
scribed by Taniguchi and Hino,[18] and was based on cycli-
zation of a protected Trp in acidic medium, followed by
[a] Compounds 3b, 3o, and 3p were synthesized from 3c, 3a, and
3c, respectively, after hydrolysis and subsequent esterification or
coupling with the protected Ile (see the Supporting Information).
[b] Ratio determined by HPLC analysis.[20] [c] Ratio determined by
1H NMR spectroscopic analysis.
aniline protection and subsequent benzylic bromination of tecting groups (Table 1, entries 7, 12, and 13) and had the
HPI-2-carboxylate. The second procedure involved a one- important additional advantage of being amenable to the
step bromination–cyclization of a completely protected Trp use of various protecting groups for the α-amino group
using N-bromosuccinimide (NBS) and pyridinium p-tolu- (R2). Cyclization with H3PO4 (Method A) gave better yields
enesulfonate (PPTS).[19] The resulting products 3 and their when methoxycarbonyl (R2 = Moc) was used as the Nα-Trp
stereochemistries (endo/exo) are listed in Table 1. For pro- protecting group compared to those obtained when trichlo-
tection of the carboxylate moiety, common esters such as roethoxycarbonyl (R2 = Troc) was used (see Table 1, entries
methyl, tert-butyl, and allyl were tested. On the other hand, 12 and 7, respectively).
for the amino function, both alkoxycarbonyl [i.e., tert-
Despite numerous attempts under diverse conditions, we
butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), benzyloxy- were unable to remove the Moc group from the N1 of HPI-
carbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), and 2-carboxylate.[21] Furthermore, to the best of our knowl-
methoxycarbonyl (Moc)], and sulfonyl [i.e., 2-nitrobenz- edge,[1] there have been no reports of removal of the Moc
enesulfonyl (Nosyl) and SO2Ph] were tested. Although a group from N8 of HPI-2-carboxylate; instead, this group is
three-way orthogonal system is desirable (two amino and typically reduced to obtain a N-Me product.[12b,22]
one carboxylic protecting groups), the use of the same
Compounds 3b and 3c possess two Boc groups at posi-
amino protecting groups (R1 = R2) for both amino groups tions N1 and N8 that could be cleaved simultaneously; how-
was also studied (Table 1, entries 2, 3, and 16) bearing in ever, the amine of N1 is more reactive than the aniline of
mind the different nucleophilicity of the amino functions N8, which enabled chemoselective acylation of N1, as re-
in forthcoming experiments. Additionally, protected amino ported by Kamenecka and Danishefsky.[23]
acids (R2 and R3 Table 1, entries 14–16) were assayed with
The 1H NMR signals corresponding to the protecting
the aim of studying the effects of size and/or electronic groups of R2 – namely, the signals for the CH2 of Cbz or
properties of the protecting groups. Troc – are broad or split, because the protons are dia-
The overall transformation of l-Trp-OMe (the starting stereotopic.
material) into 3 was highly demanding, as illustrated by the
The difference in stereochemistry of the products 3 ob-
yields, which ranged from poor to moderate. Method B, tained from each method is noteworthy. Comparison of the
which is shorter, gave better yields for the same set of pro- 1H NMR spectra of the products 3g obtained from Method
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Orthogonal Protection of Tryptophanyl-Hexahydropyrroloindoles
A and from Method B revealed significant differences in the
signals for the proton at position 2 (δ = 4.67 vs. 3.98 ppm,
respectively) and for the methyl ester (δ = 3.21 vs. 3.74 ppm,
respectively). Based on these data, the stereochemistry of
the product from Method A was determined to be endo-3g,
and that of the product from Method B, exo-3g (see Fig-
ure 1). The diamagnetic anisotropy of the phenyl ring
shields the endo-methyl group (δ = 3.21 ppm) and the exo-
H2 (δ = 3.98 ppm).[24] The same phenomenon occurred
with the endo/exo products 3l and 3m obtained with the
appropriate method (see the Supporting Information).
Scheme 3. Dimerization of 4 under acidic conditions.
pounds. A significant signal in the 13C NMR spectroscopic
data for compounds 1 and 3 was the chemical shift of the
quaternary C3a, which is less shielded in 1 (δ = 72.4 to
82.2 ppm) than in 3 (δ = 53.7 to 67.9 ppm). The results of
these substitutions are summarized in Table 2.
1
Figure 1. Comparison of the H NMR spectroscopic data for endo
and exo 3g (left). Three-dimensional models of the corresponding
tricyclic systems with N-protecting groups omitted for clarity
(right).[25]
Table 2. Nucleophilic substitution of 3a-Br-HPI.
Compounds 3a, 3b, 3d, 3k, and 3n–p (Table 1, entries 1,
2, 4, 11, and 14–16) revealed the presence of only one dia-
stereomer in the NMR spectroscopic data. Their stereo-
chemical assignments were determined by comparing the
chemical shifts of the proton and the substituent at C2 of
HPI.
To obtain a more versatile intermediate during the syn-
thesis of 3n, 3o, and 3p by Method B, protected Ala or Ile
were used as Nα- (R2 in compound 2, Table 1) and O- (R3
in compound 2, Table 1) protecting groups, respectively.
However, in the synthesis of compound 6, bromination at
position 3a (Method A) required an indirect route because
subjecting dipeptide 4, which was Nα-Alloc-Ala-protected,
to the acidic conditions for cyclization furnished the dimer
5 (Scheme 3). Formation of 5 could be explained by electro-
philic substitution between 4 and the indoline, which forms
upon protonation.
Consequently, in the first step of HPI formation using
Method A, use of an Nα-carbamate protecting group, in-
stead an amide, is rather important.
The second part of this work comprised formation of the
bond between the C3a of HPI and the Ni of Trp. Several
pairs of base and solvent were tested to generate the indole
anion that would drive the substitution to give compound
1.[26] The best conditions involved the use of NaH in N,N-
Entry 3[a]
R4
R5
3[b] 7[b] 1[b] Comp. [%][c]
1
2
3
4
5
6
7
8
9
10
exo-3a
Phth
Moc
Phth
Phth
OMe
OMe
OMe
OMe
OMe
OtBu
OtBu
OMe
OAllyl
OMe
39
49
66
28
24
62
–
18
22
11
14
21
22
24
1
43
29
24
58
48
15
50
91
48
11
1a (41)
1b (20)
1c (21)
1d (26)
1e (29)
1f (22)
1g (41)
1h (77)
1i (30)
1j (30)
exo-3c
exo-3c
exo-3d
endo-3g Alloc
exo-3g Alloc
endo-3l Alloc-Ile
endo-3l Moc
endo-3m Boc-Ile
–
29
13
20
42
exo-3p
Phth
[a] See Table 1 for the protecting groups used in each compound 3.
[b] Percentage of each compound in the crude reaction product
(determined by HPLC analysis).[20] [c] Yield of isolated compound.
The best yields of 1 in the nucleophilic substitution were
dimethylformamide (DMF) at 70 °C for 1.5 h. Each bromo- found using 3a, 3l, 3m, and 3p (Table 2, entries 1 and 7–10,
derivative (3a–p) was tested with several protected Trp com- respectively). Moderate yields were obtained for the substi-
Eur. J. Org. Chem. 2012, 67–73
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69

F. Albericio, M. Álvarez et al.
FULL PAPER
tutions with bromides 3c, 3d, and 3g (Table 2, entries 3–6). = 3.38 ppm (H3β of HPI) gave a positive NOE correlation
However, very poor yields (less than 10%, data not shown) with the protons at δ = 2.77 (H3α of HPI), 4.83 (H2 of HPI),
were observed when bromides 3b, 3e, 3f, 3h–k, and 3n were 6.68 (H8a), and 7.12 ppm (H2 of Trp) (see Scheme 4). These
treated with different protected versions of 7, which con- results demonstrate that an identical substitution mecha-
tains two additional protecting groups.
nism takes place for both endo-3 and exo-3, and that epi-
The phthalamide (Phth) group was introduced as R4 be- merization of exo-3 at C2 of HPI occurs under the basic
cause it is orthogonal to the remaining protecting groups reaction conditions to give the more stable endo-products
(Table 2, entries 1, 3, 4 and 10) and it eliminates all the Nα 1.
acid protons in 7. The wide range of yields in the resulting
substitution (from 21 to 41%) demonstrates the importance
of the protecting groups in the starting bromide. Bromides
3l and 3m contain the same protecting groups in both
amino groups of HPI (R1 = SO2Ph, R2 = Moc). Interest-
ingly, the yield was lower when the group at R5 was tert-
butyl ester (1g; Table 2, entry 7) compared to methyl ester
(1h; Table 2, entry 8). Likewise, the yield was lower when
R3 was tert-butyl ester (1i; Table 2, entry 9) compared to
methyl ester (1h; Table 2, entry 8). The same trend was ob-
served for 1f (Table 2, entry 6) and 1e (Table 2, entry 5),
albeit to a lesser extent; the tert-butyl in 1f is more sterically
hindered than the methyl ester in 1e. The results obtained
with a protected Ile-Trp dipeptide as nucleophile (Table 2,
Scheme 4. Significant NOE interactions used to assign the stereo-
chemistry of the HPI motif in 1c.
Reaction of bromide 3n and Nα-Phth-Trp-OMe unexpec-
entries 7 and 9), and with a Br-HPI and a protected Ile tedly gave compound 8. The product was characterized by
(Table 2, entry 10), are interesting because they can serve as 1D and 2D NMR analyses and by HRMS (see the Support-
a stepping stone to the synthesis of peptides found in many ing Information). Important features of compound 8 are
natural compounds. Additionally, owing to this Ile protec- the lack of Br, the α-proton of the Trp, and the fact that
tion, 1j (R3 = Ile-OAllyl; Table 2, entry 10) was obtained in the two protons of the cyclopropane CH2 (δ = 3.43 and
higher yield than was 1c (R3 = OMe; Table 2, entry 3), the 3.91 ppm; 2 d, J = 15.4 Hz) only exhibit a geminal coupling
protecting groups of which were the same, except for R3.
constant. The significant difference in the chemical shift of
An interesting result of these experiments relates to the the α-proton of the Ala in 3n (δ = 5.02 ppm) and that of the
stereochemistry of compounds 1a–j. All the substitutions Ala in 8 (δ = 4.11 ppm) could be justified by the different
furnished the more stable product endo-1, which shows a electronic effects in each compound. One hypothetical
cis relative stereochemistry between protons H2 and H8a mechanism for the formation of 8 begins with deproton-
1
and the substituent at C3a of HPI. H NMR experiments ation of the C2 of the HPI, made possible by the basic con-
show a chemical shift range of the methyl ester at C2 ditions, followed by intramolecular bromine displacement
[δ = 3.16–3.27 ppm] that is characteristic of endo-HPI.[24b] and subsequent formation of cyclopropane, to afford inter-
In addition, exhaustive 1D and 2D NMR experiments dem- mediate B (Scheme 5). The high strain in B could drive
onstrated the formation of endo-1c starting from a 4:96 opening of the aminal and subsequent cyclization, to give
endo/exo mixture of 3c. Several gHSQC, HMBC, and a more relaxed cyclohexane (Scheme 5).
NOESY experiments permitted the total stereochemistry
Compound 3n is a unique example of a Br-HPI with an
assignment of 1c (see the Supporting Information). The amide as the protecting group of N1, and 8 was isolated
most significant result was obtained when irradiation at δ after the nucleophilic substitution reaction under the afore-
Scheme 5. Hypothetical mechanism for the formation of 8.
70
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Orthogonal Protection of Tryptophanyl-Hexahydropyrroloindoles
117.6 and 117.7 (t), 119.2 and 119.3 (d), 120.0 (d), 122.3 and 122.4
(d), 123.4 (4ϫ d), 124.4 and 124.7 (d), 129.7 (s), 129.8 (s), 130.9
(d), 131.6 (s), 131.7 (s), 132.5 (d), 134.0 (3ϫ d), 134.7 (s), 143.3 (s),
143.4 (s), 151.8 (s), 151.9 (s), 167.2 (s), 167.4 (s), 169.4 (s), 170.6
mentioned conditions. Recently, Rainier and co-workers re-
ported the behavior of 3c under basic conditions (KOtBu)
and isolated a tetracycle-containing compound that re-
sembles B.[27]
(s) ppm. IR (KBr): ν = 2952, 1716, 1390, 1255, 1158, 1019,
˜
721 cm–1. HRMS (ESI): calcd for C41H40N4O10Na [M + Na+]
771.2642; found 771.2634.
Conclusions
Compound 1b: Purified by flash chromatography (hexane/EtOAc,
from 80:20 to 50:50). 1H NMR (400 MHz, CDCl3): δ = 1.50 (s,
9 h), 1.52 (s, 9 H), 2.98–3.20 (m, 3 H), 3.23 (s, 3 H), 3.54–3.65 (m,
7 H), 4.60 (m, 1 H), 4.90 (br. s, 1 H), 5.19 (t, J = 8.3 Hz, 1 H),
6.69 (d, J = 7.3 Hz, 1 H), 6.75 (s, 1 H), 7.07–7.33 (m, 5 H), 7.35–
7.42 (m, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.67 (br. s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.6 (t), 28.2 (3ϫ q), 28.3 (3ϫ q),
38.4 (t), 52.2 (q), 52.3 (q), 52.4 (q), 54.5 (d), 59.4 (d), 72.5 (s), 79.8
(d), 81.6 (s), 82.4 (s), 109.3 (s), 111.6 (d), 119.4 (d), 120.2 (2ϫ d),
122.5 (d), 123.6 (d), 124.9 (d), 125.3 (d), 130.2 (s), 131.0 (d), 131.1
(s), 134.8 (s), 143.5 (s), 152.2 (s), 156.6 (s), 164.3 (s), 171.5 (s),
Various analogues of 3, protected with different combi-
nations of three orthogonal protecting groups, were pre-
pared by two different routes. The routes were then com-
pared for performance. Method A, which was based on se-
quential cyclization, protection, and bromination, provided
the thermodynamic product, the endo-bromide; whereas
Method B, which was based on a one-pot bromination/cy-
clization of a fully protected Trp, afforded mainly the ki-
netic product, the exo-bromide. The influence of the pro-
tecting groups on the formation of the N–C3a bond between
the Trp and HPI to give compounds 1f, 1g, and 1i (contain-
ing five orthogonal protecting groups) and compounds 1a,
1d, 1e, and 1j (containing four orthogonal protecting
groups) was also evaluated. Some of these compounds con-
tain a protected Ile as R4 to protect the α-amino Trp; the
orthogonal protecting groups enable synthetic versatility for
constructing more structurally complex molecules. The pro-
172.3 (s) ppm. IR (KBr): ν = 3352, 2978, 1719, 1394, 1368, 1158,
˜
740 cm–1. HRMS (ESI+): calcd for C36H45N4O10 [M + H+]
693.3130; found 693.3118.
Compound 1c: Purified by flash chromatography (MeCN/H2O,
1
from 30:70 to 90:10). H NMR (400 MHz, CDCl3): δ = 1.46 and
1.48 (2ϫ s, 9 H), 1.50 and 1.52 (2ϫ s, 9 H), 2.77 and 2.90 (2ϫ d,
J = 12.9 Hz, 1 H), 3.17 and 3.21 (2ϫ s, 3 H), 3.38 (dd, J = 9.3,
12.9 Hz, 1 H), 3.50–3.66 (m, 2 H), 3.76 (s, 3 H), 4.83 (br. s, 1 H),
tecting groups in the bromides 3 determined the yields of 5.08–5.18 (m, 1 H), 6.64–6.75 (m, 3 H), 6.82 (t, J = 7.6 Hz, 1 H),
7.03–7.14 (m, 4 H), 7.24–7.31 (m, 1 H), 7.57 (dd, J = 7.6, 7.8 Hz,
1 H), 7.66–7.79 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.4 (t), 28.2 (3ϫ q), 28.3 (3ϫ q), 38.8 (t), 52.1 (q), 52.6 (d), 52.8
(q), 59.3 (d), 72.4 (s), 79.6 (d), 79.7 (s), 82.0 (s), 110.4 (s), 111.4 (d),
119.2 (d), 119.9 (d), 122.3 (d), 123.1 (d), 123.4 (2ϫ d), 124.4 (d),
124.7 (d), 125.0 (d), 128.9 (s), 129.7 (s), 130.8 (d), 131.7 (s), 134.0
(s and 2ϫ d), 134.7 (s), 143.5 (s), 151.8 (2ϫ s), 167.2 (s), 167.4 (s),
compounds 1a, 1c, 1d, and 1j, the starting point of which
(Nα-Phth-Trp-OMe; 7) is the same. Moreover, the impor-
tance of the carbamate protecting group at R2 should be
emphasized; unexpectedly, compound 5 was obtained from
an attempted cyclization of 4 in acidic medium (using an
Ala amide bond for protecting the nitrogen atom in 4) and
compound 8 was obtained from an attempted nucleophilic
substitution of the bromine atom at C3a of 3n.
169.4 (s), 171.0 (s) ppm. IR (KBr): ν = 2977, 1716, 1390, 1255,
˜
1158, 1019, 739, 721 cm–1. HRMS (ESI+): calcd for C42H45N4O10
[M + H+] 765.3130; found 765.3091.
Compound 1d: Purified by flash chromatography (hexane/EtOAc,
from 90:10 to 50:50); endo/exo (69:31) mixture. 1H NMR
(400 MHz, CDCl3): δ = 1.45 (s, 9 H), 2.80 (d, J = 13.0 Hz, 1 H),
3.16 and 3.20 (2ϫ s, 3 H), 3.37 (dt, J = 9.3, 13.0 Hz, 1 H), 3.49–
3.68 (m, 2 H), 3.76 (s, 3 H), 4.88 (t, J = 10.6 Hz, 1 H), 5.07–5.30
(m, 3 H), 6.62–6.89 (m, 3 H), 7.02–7.10 (m, 4 H), 7.26–7.36 (m, 6
H), 7.54–7.61 (m, 1 H), 7.66 (dd, J = 3.1, 5.5 Hz, 1 H), 7.70 (dd,
J = 3.1, 5.5 Hz, 1 H), 7.74 (dd, J = 3.1, 5.5 Hz, 1 H), 7.76 (dd, J
= 3.1, 5.5 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 24.4
(t), 28.1 (3ϫ q), 38.3 (t), 52.2 (q), 52.5 (d), 52.8 (q), 59.4 (d), 67.5
(t), 72.4 (s), 79.7 (d), 82.2 (s), 110.5 (s), 111.3 (d), 119.2 (d), 120.0
(d), 122.4 (2ϫ d), 123.4 (4ϫ d), 124.6 (d), 127.8 (d), 128.0 (d),
128.4 (3ϫ d), 129.7 (s), 130.9 (d), 131.6 (s), 134.0 (2ϫ d), 134.7
(s), 136.2 (s), 143.2 (s), 143.4 (s), 151.8 (s), 167.2 (s), 167.3 (s), 169.4
Experimental Section
General Procedure for the Synthesis of 1: A solution of 6 (3.0 mmol)
in dry DMF (10 mL) was added to a suspension of 60% NaH in
mineral oil (1.2 equiv.) in dry DMF (20 mL), and the resulting mix-
ture was stirred at room temperature for 15 min. A solution of 3
(3.0 mmol) in dry DMF (10 mL) was then added. The mixture was
stirred at 70 °C for 1.5 h. The reaction mixture was then cooled to
room temperature and quenched with H2O. The aqueous phase
was saturated with NaCl and extracted with EtOAc. The organic
solution was dried with anhyd. Na2SO4, the solvent was removed,
and the residue was purified by column chromatography on silica
gel to afford 1.
Compound 1a: Purified by flash chromatography (hexane/EtOAc,
from 90:10 to 50:50); endo/exo (57:43) mixture. 1H NMR
(400 MHz, CDCl3): δ = 1.48 and 1.49 (2ϫ s, 9 H), 2.82 and 2.92
(2ϫ d, J = 13.0 Hz, 1 H), 3.17 and 3.21 (2ϫ s, 3 H), 3.33–3.45 (m,
1 H), 3.49–3.68 (m, 2 H), 3.76 (s, 3 H), 4.59–4.74 (m, 2 H), 4.88 (t,
J = 9.8 Hz, 1 H), 5.08–5.16 (m, 1 H), 5.17–5.31 (m, 2 H), 5.85–
5.99 (m, 1 H), 6.62–6.88 (m, 3 H), 6.95–7.14 (m, 4 H), 7.30 (dd, J
= 7.4, 14.8 Hz, 1 H), 7.57 (t, J = 6.8 Hz, 1 H), 7.68 (dd, J = 3.1,
(s), 169.4 (s), 170.6 (s) ppm. IR (KBr): ν = 2952, 1716, 1389, 1255,
˜
1158, 1020, 721 cm–1. HRMS (ESI): calcd for C45H42N4O10Na [M
+ Na+] 821.2799; found 821.2804.
Compound 1e: Purified by flash chromatography (hexane/EtOAc,
1
from 70:30 to 60:40). H NMR (500 MHz, CDCl3): δ = 2.81–2.95
(m, 1 H), 2.98 (d, J = 13.4 Hz, 1 H), 3.07 (ddd, J = 5.0, 5.4,
14.8 Hz, 1 H), 3.27 (s, 3 H), 3.57 and 3.63 (2ϫ s, 3 H), 3.62–3.68
5.5 Hz, 1 H), 7.71 (dd, J = 3.0, 5.6 Hz, 1 H), 7.73–7.79 (m, 3 (m, 1 H), 4.06–4.17 and 4.59–4.67 (2ϫ m, 1 H), 4.74–4.82 and
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.4 (t), 28.1 (3ϫ q), 5.27–5.33 (2ϫ m, 1 H), 4.50–4.57 (m, 3 H), 4.96–5.08 (m, 1 H),
38.1 (t), 52.2 (q), 52.3 (d), 52.5 and 52.8 (q), 53.4 (s), 59.3 and 59.4
(d), 66.6 (t), 79.6 (d), 82.2 (2ϫ s), 110.6 (s), 111.2 and 111.3 (d),
5.09–5.30 (m, 3 H), 5.80–5.96 (m, 1 H), 6.32 and 6.43 (2ϫ s, 1 H),
6.80 and 6.93 (2ϫ d, J = 13.7 Hz, 1 H), 7.10 (dd, J = 7.6, 8.1 Hz,
Eur. J. Org. Chem. 2012, 67–73
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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71

F. Albericio, M. Álvarez et al.
FULL PAPER
1 H), 7.12–7.18 (m, 2 H), 7.21 (br. s, 1 H), 7.37 (br. s, 1 H), 7.39–
7.49 (m, 4 H), 7.52–7.59 (m, 1 H), 7.62 (dd, J = 2.9, 8.1 Hz, 1 H),
7.86 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 27.7 and
27.8 (t), 37.9 (t), 52.3 (q), 52.6 (q), 54.1 and 54.4 (d), 59.4 and 60.1
(d), 65.8 (t), 72.9 and 74.0 (s), 74.6 and 75.3 (t), 81.0 and 81.7 (d),
94.8 and 95.3 (s), 109.3 (s), 110.9 (d), 117.8 and 117.9 (t), 119.7
(d), 119.8 (d), 120.5 (d), 122.8 (d), 124.0 and 124.2 (d), 124.8 (d),
Compound 1i: Purified by flash chromatography (MeCN/H2O, from
30:70 to 50:50). H NMR (400 MHz, CDCl3): δ = 0.84 (m, 6 H),
1
1.07 (m, 1 H), 1.18 (s, 9 H), 1.40 (s, 10 H), 1.80 (m, 1 H), 2.80 (m,
2 H), 3.10 (dd, J = 5.9, 14.6 Hz, 1 H), 3.50 (dd, J = 10.1, 13.4 Hz,
1 H), 3.81 (s, 3 H), 3.85 (m, 1 H), 4.41 (dd, J = 5.7, 13.2 Hz, 1 H),
4.51 (dd, J = 5.7, 13.2 Hz, 1 H), 4.70–4.87 (m, 2 H), 5.10 (br. s, 1
H), 5.20 (m, 2 H), 5.70 (m, 1 H), 5.78 (br. s, 1 H), 6.20 (d, J =
125.8 (d), 126.2 (d), 126.5 (s), 129.7 (d), 130.2 (s), 130.5 (s), 131.5 7.0 Hz, 1 H), 6.65 (br. s, 1 H), 6.85 (t, J = 7.6 Hz, 2 H), 7.25 (m,
(d), 132.1 (d), 132.6 (d), 133.3 (d), 133.8 and 133.9 (s), 143.0 and
143.1 (s), 147.3 (s), 151.6 and 152.6 (s), 155.4 and 155.5 (s), 169.9
8 H), 7.50 (m, 2 H), 7.80 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.6 (q), 15.4 (q), 24.7 (t), 27.7 (3ϫ q),
28.2 (t), 28.4 (3ϫ q), 31.5 (q), 36.6 (q), 37.3 (t), 37.7 (d), 53.2 (d),
59.1 (d), 60.0 (d), 66.0 (t), 79.8 (s), 82.1 (d), 82.3 (s), 109.0 (d),
111.1 (d), 118.8 (t), 119.6 (d), 120.1 (s), 120.6 (d), 122.8 (d), 124.4
(d), 126.0 (d), 126.5 (d), 126.6 (d), 128.6 (2ϫ d), 130.4 (d), 131.0
(s), 131.4 (d), 131.7 (d), 132.3 (d), 133.7 (s), 138.3 (s), 141.7 (s),
143.2 (s), 145.0 (s), 155.6 (s), 162.7 (s), 168.8 (s), 171.0 (s), 171.3
(s), 171.9 and 172.0 (s) ppm. IR (KBr): ν = 3369, 2953, 1733, 1545,
˜
1402, 1368, 1231, 1174, 1055, 852, 740, 580 cm–1. HRMS (ESI+):
calcd for C37H35N5O12SCl3 [M + H+] 878.1063; found 878.1059.
Compound 1f: Purified by flash chromatography (MeCN/H2O,
1
from 0:100 to 70:30). H NMR (400 MHz, CDCl3): δ = 1.22 and
1.34 (2ϫ s, 9 H), 2.74–3.11 (m, 3 H), 3.27 (s, 3 H), 3.49–3.68 (m,
1 H), 4.45 (br. s, 1 H), 4.49–4.58 (m, 2 H), 4.59–4.84 (m, 2 H), 5.02
(br. s, 1 H), 5.09–5.33 (m, 3 H), 5.79–5.96 (m, 1 H), 6.36 and 6.46
(2ϫ s, 1 H), 6.82 and 6.94 (2ϫ d, J = 18.7 Hz, 1 H), 7.04–7.25 (m,
4 H), 7.29–7.58 (m, 6 H), 7.62 (d, J = 8.3 Hz, 1 H), 7.75–7.97 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.8 and 28.0 (3ϫ
q), 27.9 (t), 37.9 (t), 52.6 (q), 54.4 and 54.6 (d), 59.4 (d), 65.7 (t),
74.6 (s), 75.3 (t), 81.6 (s), 82.2 (d), 109.5 (s), 110.8 (d), 117.8 (t),
119.8 (d), 120.2 (d), 120.5 (d), 122.7 (d), 124.2 (d), 124.6 (d), 125.8
(d), 126.3 (s), 126.7 (d), 129.7 (d), 130.5 (s), 131.7 (d), 132.1 (d),
132.7 (d), 133.3 (d), 133.7 (s), 137.9 (s), 143.1 (s), 147.4 (s), 155.6
(s) ppm. IR (KBr): ν = 3323, 2965, 2929, 1716, 1448, 1367,
˜
1171 cm–1. HRMS (ESI): calcd for C48H60N5O11S [M + H+]
914.4010; found 914.3986.
Compound 1j: Purified by flash chromatography (hexane/EtOAc,
1
70:30). H NMR (400 MHz, CDCl3): δ = 0.85–1.03 (m, 6 H), 1.13
(dd, J = 3.2, 6.7 Hz, 2 H), 1.54 (s, 9 H), 1.56 (s, 9 H), 2.52 (br. s,
1 H), 2.68–2.90 (m, 1 H), 2.97–3.15 (m, 1 H), 3.54–3.66 (m, 2 H),
3.77 (s, 3 H), 3.94–4.07 (m, 1 H), 4.49–4.73 (m, 3 H), 5.08–5.31 (m,
3 H), 5.75–5.90 (m, 1 H), 6.50 (d, J = 7.7 Hz, 1 H), 6.65 (d, J =
11.2 Hz, 1 H), 6.75 (d, J = 9.2 Hz, 1 H), 6.87–7.18 (m, 5 H), 7.33–
7.41 (m, 1 H), 7.61 (dd, J = 6.1, 7.4 Hz, 1 H), 7.66–7.83 (m, 5 H),
7.87–8.01 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.7
and 11.3 (q), 15.8 and 16.8 (q), 24.3 (t), 25.8 and 27.4 (t), 28.2 (6ϫ
q), 34.1 and 34.4 (d), 39.9 (t), 52.2 and 52.3 (d), 52.8 (q), 56.8 and
58.2 (d), 61.2 (d), 61.5 (s), 66.3 (t), 78.4 (d), 78.7 (s), 83.1 (2ϫ s),
109.7 (s), 110.7 (d), 111.0 (d), 116.0 and 116.1 (d), 118.8 (t), 119.4
(d), 120.3 (d), 122.8 (d), 123.3 (d), 123.4 (d), 123.5 and 123.6 (s),
124.5 (2ϫ d), 126.4 (s), 129.9 (s), 131.4 (d), 131.5 (d), 131.7 (s),
134.1 (2ϫ d), 134.3 (s), 134.4 (s), 151.2 (s), 167.1 (s), 167.3 (s),
(s), 155.7 (s), 169.9 (s), 170.6 (s) ppm. IR (KBr): ν = 3419, 2979,
˜
1733, 1545, 1368, 1230, 1173, 1129, 1055, 740, 581 cm–1. HRMS
(ESI+): calcd for C40H41N5O12SCl3 [M + H+] 920.1538; found
920.1578.
Compound 1g: Purified by flash chromatography (hexane/EtOAc,
60:40). 1H NMR (400 MHz, CDCl3): δ = 0.81–0.88 (m, 6 H), 1.00–
1.12 (m, 1 H), 1.31 (s, 9 H), 1.39 (br. s, 1 H), 1.72–1.82 (m, 1 H),
2.67 (dd, J = 4.7, 14.7 Hz, 1 H), 2.82 (d, J = 13.3 Hz, 1 H), 3.08
(dd, J = 5.9, 14.7 Hz, 1 H), 3.21 (s, 3 H), 3.50 (m, 1 H), 3.83 (s, 3
H), 3.89 (dd, J = 6.6, 8.4 Hz, 1 H), 4.54 (m, 2 H), 4.64 (m, 1 H),
4.92 (br. s, 1 H), 5.21 (d, J = 10.5 Hz, 1 H), 5.26–5.34 (m, 2 H),
5.83 (br. s, 1 H), 5.84–5.96 (m, 1 H), 6.10 (d, J = 7.7 Hz, 1 H), 6.70
(br. s, 1 H), 6.90 (t, J = 7.8 Hz, 2 H), 7.15 (br. s, 2 H), 7.16–7.22
(m, 2 H), 7.23–7.35 (m, 4 H), 7.50 (t, J = 7.3 Hz, 2 H), 7.77 (d, J
= 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.4 (q),
15.3 (q), 24.7 (t), 27.6 (t), 28.0 (3ϫ q), 37.2 (t), 37.8 (d), 52.3 (q),
53.3 (q and d), 59.2 (d), 59.5 (d), 65.8 (t), 73.4 (s), 81.9 (s), 82.1
(d), 109.2 (s), 110.9 (d), 117.7 (t), 119.9 (2ϫ d), 120.5 (d), 122.7
(d), 124.3 (d), 125.7 (d), 126.4 (2ϫ d), 126.7 (d), 128.5 (2ϫ d),
130.3 (s), 130.6 (s), 131.7 (d), 132.2 (d), 132.7 (d), 133.5 (s), 138.2
(s), 143.2 (s), 154.8 (s), 155.9 (s), 170.1 (s), 170.5 (s), 170.6 (s) ppm.
168.0 (s), 168.1 (s), 169.3 (2ϫ s) ppm. IR (KBr): ν = 3413, 2969,
˜
1718, 1483, 1455, 1388, 1253, 1162, 1019, 739, 720 cm–1. HRMS
(ESI+): calcd for C46H49N5O11 [M – tBu] 847.3429; found 847.3658.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data of compounds
1
3a–p, 5, and 8 and copies of the H and 13C NMR spectra of 1a–
j, 3g, 5 and 8.
Acknowledgments
This study was partially supported by Centro de Investigación Ci-
entífica y Tecnológica (CICYT) (grant number CTQ2009-07758),
the Generalitat de Catalunya (2009SGR 1024), the Institute for Re-
search in Biomedicine, and the Barcelona Science Park. P. R. S. re-
ceived a PhD fellowship from the Institute for Research in Biomed-
icine (02/06-IRB).
IR (KBr): ν = 3367, 2954, 1721, 1447, 1363, 1170 cm–1. HRMS
˜
(ESI): calcd for C45H54N5O11S [M + H+] 872.3541; found 872.3557.
Compound 1h: Purified by flash chromatography (hexane/EtOAc,
60:40). 1H NMR (400 MHz, CDCl3): δ = 2.66 (dd, J = 9.5, 5.3 Hz,
1 H), 2.79 (d, J = 13.3 Hz, 1 H), 3.03–3.14 (m, 1 H), 3.20 (s, 3 H),
3.42–3.54 (m, 1 H), 3.58–3.68 (m, 6 H), 3.84 (s, 3 H), 4.42–4.57 (m,
1 H), 4.91 (br. s, 1 H), 5.10 (d, J = 8.1 Hz, 1 H), 5.73 (s, 1 H), 6.71
(br. s, 1 H), 6.87 (t, J = 7.5 Hz, 2 H), 7.12–7.35 (m, 5 H), 7.43–
7.58 (m, 3 H), 7.80 (br. d, J = 7.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.0 (t), 37.5 (t), 52.5 (3ϫ q), 53.5 (q), 54.8
(d), 59.4 (d), 73.6 (s), 82.1 (d), 109.4 (s), 111.2 (d), 119.8 (d), 120.2
(d), 120.7 (d), 123.0 (d), 124.3 (d), 124.5 (s), 125.8 (s), 126.6 (2ϫ
d), 126.8 (d), 128.7 (2ϫ d), 130.5 (s), 132.1 (2ϫ d), 132.4 (d), 133.7
(s), 138.3 (s), 143.5 (s), 156.5 (s), 170.6 (s), 172.3 (s) ppm. IR (KBr):
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: July 20, 2011
Published Online: November 22, 2011
Eur. J. Org. Chem. 2012, 67–73
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