Synthesis of (-)-epi-indolactam v by an intramolecular Buchwald-Hartwig C-N coupling cyclization reaction

Article abstract of DOI:10.1021/jo4013767

The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C-N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (-)-epi-indolactam V and its enantiomer have been accomplished.

Full text of DOI:10.1021/jo4013767

Article
pubs.acs.org/joc
Synthesis of (−)-Epi-Indolactam V by an Intramolecular Buchwald−
Hartwig C−N Coupling Cyclization Reaction
Michele Mari, Francesca Bartoccini, and Giovanni Piersanti*
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino (PU), Italy
S
* Supporting Information
ABSTRACT: The synthetic efforts toward the concise
synthesis of (−)-indolactam V from simple and commercially
available starting materials using palladium- and copper-
catalyzed intramolecular N-arylation strategy for the elabo-
ration of the requisite nine-membered lactam ring as the key
step are described. The incorporation of a turn-inducing
structural element along the linear precursor was fundamental
to achieve the heterocyclization step as well as obtain the
correct regio- and chemoselectivity. The stereoselective nature in the C−N coupling cyclization reaction is interpreted in terms
of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of
the (−)-epi-indolactam V and its enantiomer have been accomplished.
Generally, major challenges in the synthesis of indolactam V
(1) deal with the introduction of the tryptophanyl side chain
owing to the directing ability of the 4-amino substituent5c,d,g
and proper prefunctionalization of indole derivatives5b,f in order
to have the correct N−C4 arylation regioselectively. The
shortcomings of the existing methods have prompted us to
study a new and concise approach to synthesize this important
molecule that mimics the disconnective approach suggested by
biosynthesis. It seems to be more appealing and practical to
take advantage of the intramolecular N-arylation reaction of 4-
bromotryptophan dipeptide derivatives like 7 (Figure 1b),
although it is known that small peptides can often be
troublesome, if not impossible, to cyclize. Fortunately, substrate
preorganization and certain conformational restraints present in
the acyclic precursor usually favor hetero-macrocyclizations,
and nitrogen heterocycles can be obtained with good
efficiencies.10 Nonetheless, if the application of the intermo-
lecular arylation of N-nucleophiles to the preparation of
nitrogen heterocycles by intermolecular C−N cross-coupling
can appear as a quite simple task, it is actually far from being so
trivial. Indeed, the formation of aromatic amines or amides by
intermolecular cross coupling typically requires not only an
excess of the nucleophile, which is definitely impossible for
intramolecular reactions, but also high concentrations, which
could be a major drawback for the formation of macrocycles. In
addition, metal-mediated intramolecular N-arylations have been
reported primarily for the generation of five-, six- and seven-
membered rings;10 however, there is much less precedence for
the synthesis of eight- and nine-membered rings.
INTRODUCTION
■
(−)-Indolactam V (1)1 (Figure 1), a 3,4-fused tricyclic indole-
containing natural product isolated from Streptoverticillium
blastmyceticum NA39-17, is a potent activator of various protein
kinase C (PKC) isozymes and is the main pharmacophore of
lyngbyatoxin2 and teleocidins.3 Of particular importance is the
recent report on indolactam V’s stem cell-differentiating
abilities to pancreatic cell types.4 This newly identified activity
for indolactam V has refocused attention on developing
efficient synthetic5 and/or biosynthetic routes6 to this
compound. Furthermore, the interesting biological and
structural features of indolactam V has also been the inspiration
for other 9-membered cyclic dipeptide analogues studied as
synthetic targets and for structure−activity studies.7
The biosynthetic pathways of indolactam V have also been
investigated8 and involve a nonribosomal peptide synthetase
that condenses N-methyl-L-Val and L-Trp and releases N-
methyl-L-valyl-L-tryptophanol via an NADPH-dependent re-
ductive cleavage (Figure 1a). The ring formation further
requires the activity of a P450-dependent monooxygenase/
cyclase that allows the formation of an epoxide between the C4
and C5 of the indole ring, thus triggering the chemo- and
regioselective heterocyclization. However, to date, attempts to
synthesize indolactam V (1) by cyclization of a dipeptide to the
indole 4-position have proved unsuccessful.9 Two general
strategies are available in the literature for the synthesis of
indolactam V (1).5 The first strategy involves intermolecular N-
aryl bond formation at the less reactive 4-position of an
appropriately prefunzionalized indole nucleus with a dipepti-
de,5a,b whereas the other strategy couples preformed 4-
aminoindole derivatives with α-keto or α-hydroxy ester in
which the 9-membered ring is fashioned by late-stage amide
bond formation.5c−g
Herein we describe the development of our synthetic strategy
toward the synthesis of nine-membered-ring (−)-indolactam V
Received: June 25, 2013
Published: July 11, 2013
© 2013 American Chemical Society
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Figure 1. (a) Proposed biosynthesis and (b) our synthetic strategy for indolactam V.
Scheme 1. Synthesis of Compound 7 and 9
using a palladium-catalyzed intramolecular C−N coupling
cyclization process. Unexpectedly, the ring closure reaction
was highly stereospecific, and only the (−)-epi-indolactam V
and its enantiomer have been achieved.
addition of 3-nonsubstituted indoles with 2-amidoacrylates,
which were believed previously to be poor electrophiles.11d
Thus, an efficient synthetic procedure was developed that
allowed the preparation of racemic 4-bromotryptophane methyl
ester by reported Friedel−Crafts alkylation conditions, followed
by heating to 75 °C with HCl in aqueous methanol to cleave
the acetamide group to deliver amine 5 in 76% yield. N-Boc-L-
Val was readily appended to the core in a HBTU-mediated
peptide coupling reaction to afford, after ester reduction with
LiBH4, 4-bromotryptophan dipeptide 7 as a 1:1 mixture of the
two diastereomers (Scheme 1).
With the appropriately protected substrate 7 in hand, we first
examined various intramolecular C−N cross-coupling reaction
procedures to prepare the 9-membered lactam. Both Pd- and
Cu-catalyzed intramolecular N-arylations leading to 5-, 6-, and
to a lesser extent, 7-membered rings have been investigated,
and various efficient catalytic systems have been developed;
therefore, both metals were taken into consideration. Our initial
attempts focused on Pd-catalyzed N-arylation reactions of 7,12
RESULTS AND DISCUSSION
■
For a maximally efficient and practical synthesis of 1, our
retrosynthetic analysis commenced with the key disconnection
of the C4−N bonds of 1, affording the linear precursor 7
(Figure 1b). The 4-bromotryptophanol dipeptide derivative 7
could be obtained by simple peptide coupling of N-Boc-valine
and reduction of tryptophane derivative 5, which is easily
prepared by a Friedel−Crafts conjugate addition reaction
between commercially available 4-bromoindole (2) and methyl
2-acetamidoacrylate (3). Lately, we have been interested in
developing convergent syntheses of tryptophans and cyclo-
tryptophans (also known as pyrroloindolines) from simple
indole starting materials.11 In 2008, we demonstrated that
Lewis acids are highly efficient in promoting the conjugate
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under conditions often encountered in intramolecular amina-
tion and even amidation reactions.13 Although the intra-
molecular C−N cross-coupling version is considered dramat-
ically more facile and is not subject to the common restrictions
of its intermolecular counterpart,14 all the experiments we
carried out were uniformly unsuccessful and led to no
discernible products.15
Next, we turned our attention to Cu-catalyzed Ullmann-type
cyclization reactions, which have been used very effectively to
prepare medium- and large-sized nitrogen heterocycles via N-
arylation of carbamates with various structural complexity.16
Upon treatment of 7 with 2.5% CuI, 5% DMEDA, KI (2
equiv), and K2CO3 (2 equiv) in dioxane, the reaction was found
to smoothly give the 6-membered NH amide-arylated (10) and
7-membered O-arylated rings (11) in 43 and 41% yields,
respectively (Scheme 2). All of these cyclic products, isomers
isobutyrylcyclohexanone (a β-diketone) or proline was
unsuccessful. However, the behavior of Cu-catalyzed systems
is different from that of Pd-catalyzed systems. The factor in
which Pd- and Cu-catalyzed domains are distinguished most
radically is the role of ligands. Indeed, Pd-catalyzed C−N
coupling is among the clearest cases of transition-metal-
catalyzed processes controlled by ligand design. Pd-catalyzed
systems require strongly basic environments, and unless a few
special ligands are used, sodium tert-butylate in aprotic media is
the base of choice in common protocols. Numerous catalytic
systems and ligands were examined for Pd0-catalyzed intra-
molecular aryl amination of 9.15 After extensive experimenta-
tion, it was found that among various ligands, the performance
of Buchwald palladacycle precatalysts bearing biarylphosphine
ligands,19 particularly the XPhos precatalyst, was particularly
impressive, allowing for the expected cyclization product 12.
However, the yield was hampered by significant side product
(13) formation due to reductive dehalogenation (Scheme 3).
Scheme 2. Cu-Catalyzed Intramolecular N-Arylation
Scheme 3. Pd-Catalyzed Intramolecular N-Arylation
with the desired 9-membered ring size, were assigned after
1
careful analysis of H NMR, 13C NMR, HMQC, and HMBC.
However, no trace of the expected 9-membered tricyclic
compound was formed under a variety of conditions.15 The
efficiency of this cyclization could be attributed to the presence
of the secondary amide bond, which, by chelation with the
copper catalyst, would favor its insertion into the C−Br bond
and/or vicinal internal amidoalcohol can assist and favor the
reaction by acting as a supporting ligand. To disrupt
coordination of the substrate, we chose to elevate the
temperature and examined a range of solvents and ligands,
but all resulted in low levels of chemoselectivity.
At this point, we thought that the conformation of the linear
precursor dipeptide disfavored the approach of the N-terminus
at the 4-position (preference for the s-trans conformation at the
amide bond) of the indole and that the success of
heterocyclization relies on the ability of a linear precursor to
conformationally preorganize its reactive ends in close spatial
proximity before ring closure. Therefore, the incorporation of
turn-inducing structural elements along the linear precursor,
i.e., oxazolidines or proline surrogates (namely pseudopro-
lines), can result in a more efficient cyclization. Protection of
the vicinal hydroxyl and amide functionalities in 7 as an
oxazolidine ring with 2,2-dimethoxypropane (2,2-DMP) allows
the easy incorporation of pseudoproline units into our
dipeptide. Other added benefits of using pseudoprolines as
conformational turn inducers are to prevent aggregation of the
dipeptides and block OH and NH coordination.17
To our surprise, 12 and 13 were obtained as nearly single
diastereomers, although the starting material was a 1:1 mixture
of stereoisomers. Simple column chromatography using ethyl
acetate and methanol (97:3) as the eluent separated the two
diastereoisomers 9a and 9b, which were then resubjected to the
same Pd-catalyzed macrocyclization reaction conditions. We
ran a side-by-side comparison of the reaction with both of the
diastereomers. Very interestingly, the less polar diasteriomer 9a
delivered rapid, selective, and efficient formation of the cyclic
peptide 12,20 whereas only a trace amount of the cyclic peptide
was detected for the more polar diastereomer 9b. The
undesired proto-debromination dominated this process, which
is a testament to the sluggish kinetics of the intramolecular
process for this diastereoisomer.
The stereochemistry of 12 was determined by its conversion
to one of the possible stereoisomers of indolactam V by N-
methylation of the secondary amino group using formalin and
sodium cyanoborohydride and acidic cleavage of the acetonide
group in 81% overall yield (Scheme 4). The spectral and optical
data of the compound obtained were identical with the
reported data for (−)-epi-indolactam V (15).21 Interestingly,
the stereochemical configuration of 12 was set with complete
diastereoselectivity, albeit in the undesired sense, and the
intramolecular N-arylation occurred to furnish the unnatural
and less stable cis-isomer (epi-indolactam V) rather than on the
more stable natural indolactam (trans-isomer).
Moreover, after cyclization, pseudoproline can be cleaved
under acidic conditions, thus yielding cyclic peptides devoid of
turn-inducing elements.18 Deprotection in TFA and DCM led
to compound 9 containing a free amino group at the N-
terminus. Finally, when we subjected compound 9 to the Cu-
catalyzed procedure described above, no reaction occurred, and
the starting material was recovered unmodified.15 Even
changing the supporting ligand from DMEDA to 2-
We repeated the synthesis shown in Scheme 1 with N-Boc-D-
Val and obtained the same stereoselective and stereospecific
reaction heterocyclization (Scheme 5). (+)-Epi-indolactam V
(22) was obtained in roughly the same yield, indicating that the
stereohindrance of the isopropyl group in valine does not
prevent nucleophilic reaction of the nitrogen.
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Scheme 4. Conversion to (−)-Epi-indolactam V
Scheme 5. Synthesis of (+)-Epi-indolactam V
It is worthwhile to mention that oxidation to the aldeyde
and/or ester of (−)-epi-indolactam V followed by epimeriza-
tion and reduction using Nakatsuka’s protocol22 could be used
to achieve natural (−)-indolactam V (1).
The Pd-catalyzed intramolecular N-arylation of 9a and 9b
(Figure 2) illustrated that stereocenters on the temporary
pseudoproline functionality can exert a profound influence over
the success of such cyclizations. The origin of this remarkable
stereospecificity might be related to conformational preferences
of 9a and 9b. However, NMR studies of 9a and 9b revealed
very small differences among them as both adopt the cis-amide
conformation in high amounts. We hypothesize that the
profound differences of reactivity/controlling element in
stereoselective transformations is due to allylic 1−3-strain.
Nonbonding interactions between the allylic substituents play a
critical role in defining the stereochemical course of such
reactions. In fact, the resident allylic stereocenter (1) and its
associated substituents impart a pronounced bias toward
reactions occurring at the pi-bond or the substituent directly
bonded with it.23 In the macrocyclization of 9a, the ring-closure
process is favored when the various structural elements of a
linear precursor can accommodate the angular requirements for
both termini in the transition state with the least amount of
strain (Figure 2). In the lowest energy conformation of both
diastereomers, the amide bond is in the cis conformation in
Figure 2. Representative conformations of (R)- and (S)-pseudopro-
line.
which the steric interaction with the oxazolidine geminal
dimethyl group is minimized. Dipeptide 9a exhibits sufficient
conformational flexibility to bring the head (amino group) and
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was filtered over Celite and washed with CH2Cl2 (2 × 50 mL). The
two layers were separated, and the aqueous phase was extracted with
further CH2Cl2 (2 × 50 mL). The combined organic phases were
dried over anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The residue was purified by flash chromatography
(gradient from cyclohexane/ethyl acetate 1:1 to ethyl acetate) to give
3.9 g (82%) of 4 as a white solid: TLC (cyclohexane/ethyl acetate 1:1)
Rf = 0.12 (UV, p-anisaldehyde); MS (ESI) 339−341 [M + H]+; mp
tail (bromoindole or bromopalladio) proximal in space, at least
transiently leading to the 10-membered palladacycle followed
by an easy reductive elimination, whereas in 9b, palladacycle
formation is prevented or hampered by 1,3A-strain.
CONCLUSION
■
In summary, we have presented our efforts toward a
strategically distinct, concise approach of (−)-indolactam V,
which involved initial C3 functionalization using dehydroala-
nine, followed by Pd-catalyzed N-aryl amination ring closure at
C4. The practical and step-economical access to 4-bromo-
tryptophanol dipeptide derivatives 7−9 and 17−19 allowed us
to explore many late-stage metal-catalyzed cross-coupling
heterocyclizations by cyclization to the indole 4-position. The
ground-state E geometry of the peptide bond in 7 and 17
prevents the dipeptides from attaining the 9-membered ring-
like conformation conducive to cyclization; so in order to
obtain cyclization, the introduction of pseudoproline as a
conformational turn-inducer was necessary. The gem-dimethyl
moiety in 9 and 19 forces the dipeptide to adopt an s-cis
conformation, which is the only conformation suitable for
heterocylization. Stereochemical results suggest that allylic
strain strongly influences conformation and may be an
important determinant of reactivity and stereoselectivity. We
believe that the stereoselectivity showed during the Pd-
catalyzed N-arylation is dominated by the need to minimize
1,3A strain between the substituents and the amide NC
partial double bond. Although the performance and applic-
ability of this intramolecular C−N cross-coupling reactions
were difficult to predict, controlling the reactivity of the catalyst
through properly selected ancillary ligands allowed the selective
synthesis of both the enantiomers of epi-indolacatam V. This
report represents the first example in which the Buchwald−
Hartwig reaction has been applied to the ring-closure event of a
complex peptide-based substrate for the macrocyclization of a
medium-sized ring compound.
1
174−176 °C (MeOH); H NMR (200 MHz, CDCl3) δ 1.93 (s, 3H),
3.48 (dd, J1 = 15.0 and J2 = 8.0 Hz, 1H), 3.67 (dd, J1 = 15.0 and J2 =
5.5 Hz, 1H), 3.74 (s, 3H), 4.98 (ddd, J1 = J2 = 8.0 and J3 = 5.5 Hz,
1H), 6.11 (br d, J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 7.10 (d, J =
2.5 Hz, 1H), 7.30−7.34 (m, 2H), 8.41 (br s, 1H); 13C NMR (50 MHz,
CDCl3) δ 23.2, 28.1, 52.3, 53.7, 110.8, 111.4, 113.9, 123.0, 124.5,
124.6, 125.4, 137.4, 169.9, 172.7; FTIR (film, cm−1) 3394, 3235, 1739,
1724. Anal. Calcd. for C14H15BrN2O3 (338.03): C, 49.57; H, 4.46; N,
8.26. Found: C, 49.67; H, 4.49; N, 8.33.
Methyl 2-amino-3-(4-bromo-1H-indol-3-yl)propanoate (5). A
solution of 4 (3 g, 8.9 mmol) in MeOH (85 mL), H2O (85 mL) and
aqueous HCl (12 M, 85 mL) was heated at 75 °C for 12 h, and then
concentrated, redissolved in toluene (50 mL, two times) and
concentrated again. The residue obtained (2.2 g, 6.8 mmol) was
used for the following reaction without further purification. Yield 76%.
To afford characterization, an analytical sample was redissolved in
CH2Cl2 and washed with saturated aqueous NaHCO3. The aqueous
layer was further extracted with CH2Cl2 (2 × 10 mL). The combined
organic phases were dried over anhydrous Na2SO4, and the solvent
was evaporated under reduced pressure. The residue was purified by
flash chromatography (CH2Cl2/MeOH 96:4) to give a white solid:
TLC (CH2Cl2/MeOH 96:4) Rf = 0.16 (UV, CAM, p-anisaldehyde);
1
MS (ESI) 297−299 [M + H]+; mp 259−260 °C (MeOH); H NMR
(200 MHz, CDCl3) δ 3.05 (dd, J1 = 14.5 and J2 = 9.0 Hz, 1H), 3.67
(dd, J1 = 14.5 and J2 = 5.0 Hz, 1H), 3.74 (s, 3H), 4.01 (dd, J1 = 9.0 and
J2 = 5.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 7.07 (br d, J = 2.0 Hz, 1H),
7.27−7.31 (m, 2H), 8.56 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ
31.7, 52.0, 55.8, 110.7, 112.3, 114.1, 122.9, 124.2, 125.1, 125.3, 137.7,
175.8; FTIR (film, cm−1) 3358, 3284, 1724. Anal. Calcd. for
C12H13BrN2O2 (296.02): C, 48.50; H, 4.41; N, 9.43. Found: C,
48.38; H, 4.44; N, 9.56.
Methyl 3-(4-bromo-1H-indol-3-yl)-2-((S)-2-(tert-butoxycar-
bonylamino)-3-methylbutanamido)propanoate (6). To a sol-
ution of N-Boc-L-valine (2.9 g, 12.7 mmol), 1-hydroxybenzotriazole
(1.9 g, 13.97 mmol) and N,N-diisopropylethylamine (5.5 mL, 31.75
mmol) in CH2Cl2 (25 mL) was added HBTU (4.8 g, 12.7 mmol), and
the reaction mixture was then stirred for 30 min. Amine (5) (2.1 g,
6.35 mmol) was then added portionwise over 15 min. After stirring at
room temperature for 2 h, the mixture was diluted with CH2Cl2 (80
mL), washed with saturated sodium hydrogen carbonate solution (50
mL), saturated aqueous ammonium chloride solution (50 mL) and
brine (50 mL). The organic layer was dried over anhydrous Na2SO4,
and the solvent was evaporated under reduced pressure. The residue
obtained was purified by flash chromatography (cyclohexane/ethyl
acetate 1:1) to give 2.77 g (88%) of coupled product (6) as white
solid: TLC (cyclohexane/ethyl acetate 1:1) Rf = 0.35 (UV, p-
anisaldehyde); MS (ESI) 496−498 [M + H]+; mp 143−146 °C
EXPERIMENTAL SECTION
■
General Methods. All reactions were run in air unless otherwise
noted. Column chromatography purifications were performed in flash
conditions using 230−400 Mesh silica gel. Analytical thin layer
chromatography (TLC) was carried out on silica gel plates (silica gel
60 F254) that were visualized by exposure to ultraviolet light and an
aqueous solution of cerium ammonium molybdate (CAM) or p-
1
anisaldehyde. H NMR and 13C NMR spectra were recorded at 200/
50 MHz on spectrometer, using CDCl3 as solvent. Chemical shifts (δ
scale) are reported in parts per million (ppm) relative to the central
peak of the solvent. Coupling constants (J values) are given in Hertz
(Hz). Molecular ions (M + 1) and base peak are given for ESI-MS
analysis. Optical rotation analysis was measured with polarimeter using
a sodium lamp (λ 589 nm, D-line); [α]D20 values are reported in 10−1
deg cm2 g−1; concentration (c) is in g per 100 mL. Absorbances are
reported in cm−1 for the IR analysis. Melting points were determined
by capillary melting point apparatus and are uncorrected. Elemental
analyses were within 0.4 of the theoretical values (C,H,N). 4-Bromo-
1H-indole, methyl 2-acetamidoacrylate, N-(tert-butoxycarbonyl)-L-
valine, and N-(tert-butoxycarbonyl)-D-valine are commercially avail-
able.
Methyl 2-acetamido-3-(4-bromo-1H-indol-3-yl)propanoate
(4). To a solution of 2 (1.9 mL, 15.5 mmol) and methyl 2-
acetamidoacrylate (3) (2.0 g, 14.1 mmol) in CH2Cl2 anhydrous (42
mL) was added EtAlCl2 1 M in hexane (28.2 mL, 28.2 mmol), under
argon, at 0 °C. The solution was stirred at room temperature for 16 h.
The mixture was diluted with CH2Cl2 (50 mL), and a saturated
solution of NaHCO3 (100 mL) was added. The resulting suspension
1
(MeOH); H NMR (200 MHz, CDCl3) (both isomers) δ 0.66−079
(m, 6H), 0.87 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 1.41 (s,
9H), 1.48 (s, 9H), 1.97−2.10 (m, 1H), 2.13−2.35 (m, 1H), 3.41−3.63
(m, 4H), 3.71 (s, 6H), 3.96−4.13 (m, 2H), 4.88−5.10 (m, 4H), 6.70−
6.80 (br m, 2H), 6.98 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H),
7.24−7.30 (m, 4H), 8.70 (br s, 2H); 13C NMR (50 MHz, CDCl3)
(both isomers) δ 15.3, 17.0, 18.5, 19.0, 19.8, 25.9, 28.0, 28.3, 28.4,
30.8, 52.27, 52.33, 53.8, 59.5, 64.0, 65.8, 79.9, 80.4, 110.8, 110.9, 111.0,
111.1, 113.7, 113.8, 122.9, 124.17, 124.24, 124.90, 124.92, 125.2,
125.3, 137.5, 137.6, 155.8, 155.9, 171.5, 171.6, 172.3, 172.6; FTIR
(film, cm−1) 3379, 3326, 1729, 1687, 1654. Anal. Calcd. for
C22H30BrN3O5 (495.14): C, 53.23; H, 6.09; N, 8.47. Found: C,
53.36; H, 6.05; N, 8.61.
tert-Butyl (2S)-1-(1-(4-bromo-1H-indol-3-yl)-3-hydroxypro-
pan-2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamate (7). To a
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solution of 6 (1.0 g, 2.02 mmol) in isopropyl alcohol (4 mL) was
added dropwise LiBH4 (85 mg, 4.04 mmol) in anhydrous THF (4
mL) over 20 min. After stirring at room temperature for 4 h the
reaction mixture was diluted with ethyl acetate and quenched with an
aqueous solution of KHSO4 10%. The aqueous layer was extracted
with ethyl acetate (3 × 15 mL), the combined organic phases were
dried over anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The residue obtained was purified by flash
chromatography (cyclohexane/ethyl acetate 1:1) to give 868 mg
(92%) of 7 as a white solid: TLC (CH2Cl2/MeOH 96:4) Rf = 0.28
(UV, CAM, p-anisaldehyde); MS (ESI) 468−470 [M + H]+; mp 154−
156 °C (MeOH);1H NMR (200 MHz, CDCl3) (both isomers) δ 0.60
(d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H),
0.87 (d, J = 7.0 Hz, 3H), 1.42 (s, 9H), 1.45 (s, 9H), 1.84−1.94 (m,
1H), 2.07−2.16 (m, 1H), 3.15−3.36 (m, 6H), 3.62−3.91 (m, 6H),
4.28−4.37 (m, 2H), 4.83 (br d, J = 9.0 Hz,1H), 5.07 (br d, J = 8.5
Hz,1H), 6.31 (br d, J = 7.0 Hz, 1H), 6.53 (br d, J = 7.5 Hz, 1H), 6.99
(t, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 7.11−7.13 (m, 2H), 7.25−
7.32 (m, 4H), 8.41 (br s, 2H); 13C NMR (50 MHz, CDCl3) (both
isomers) δ 16.9, 17.8, 19.0, 19.2, 27.1, 28.3, 29.7, 30.2, 30.6, 54.1, 54.4,
60.8, 64.8, 80.2, 110.8, 110.9, 112.5, 112.6, 113.8, 113.9, 122.8, 124.07,
124.11, 124.8, 124.9, 125.3, 125.4, 137.6, 137.7, 156.1, 156.3, 172.6;
FTIR (film, cm−1) 3311, 1691, 1646. Anal. Calcd. for C21H30BrN3O4
(467.14): C, 53.85; H, 6.46; N, 8.97. Found: C, 53.96; H, 6.48; N,
8.87.
tert-Butyl (2S)-1-(4-((4-bromo-1H-indol-3-yl)methyl)-2,2-di-
methyloxazolidin-3-yl)-3-methyl-1-oxobutan-2-ylcarbamate
(8). To a suspension of 7 (553 mg, 1.18 mmol) in toluene (23.7 mL)
were added camphorsulfonic acid (28 mg, 0.12 mmol) and acetone
dimethyl acetal (145 μL, 1.18 mmol); the mixture was stirred at 120
°C for 2 h. Triethylamine (19 μL) was added, and then the solution
was diluted with ethyl acetate (15 mL) and water (15 mL). The phases
were separated, and the aqueous layer was further extracted with ethyl
acetate (2 × 15 mL). The combined organic phases were dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography (cyclo-
hexane/ethyl acetate 8:2) to give 467 mg (78%) of 8 as a white solid:
TLC (cyclohexane/ethyl acetate 7:3) Rf = 0.38 (UV, p-anisaldehyde);
MS (ESI) 450−452 [M − 57]+, 508−510 [M + H]+; mp 84−86 °C
(MeOH); 1H NMR (200 MHz, CDCl3) (both isomers) δ 0.96 (d, J =
7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 1.04
(d, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.44 (s, 9H), 1.55 (s, 3H), 1.59 (s,
3H), 1.76 (s, 3H), 1.80 (s, 3H), 1.93−2.06 (m, 2H), 3.31−3.63 (m,
4H), 3.74−3.84 (m, 2H), 3.95−4.11 (m, 2H), 4.27−4.36 (m, 2H),
4.53−4.61 (m, 1H), 4.72−4.83 (m, 1H), 4.98 (br d, J = 8.5 Hz,1H),
5.33 (br d, J = 8.5 Hz,1H), 6.97−7.06 (m, 2H), 7.23−7.34 (m, 6H),
8.45 (br s, 2H); 13C NMR (50 MHz, CDCl3) (both isomers) δ 17.6,
17.8, 19.0, 19.2, 23.0, 26.68, 26.69, 27.1, 27.2, 28.3, 28.4, 30.2, 30.6,
54.2, 54.4, 64.86, 64.93, 65.8, 80.2, 80.4, 95.5, 110.8, 110.9, 112.6,
113.8, 113.9, 122.8, 124.1, 124.2, 124.8, 124.9, 125.3, 137.5, 137.6,
155.5, 156.2, 172.3, 172.6; FTIR (film, cm−1) 3309, 1699, 1626. Anal.
Calcd. for C24H34BrN3O4 (507.17): C, 56.69; H, 6.74; N, 8.26. Found:
C, 56.54; H, 6.79; N, 8.33.
= 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 1.57 (s, 3H), 1.61−1.70 (m,
1H), 1.87 (s, 3H), 2.78 (d, J = 5.0 Hz, 1H), 3.23 (dd, J1 = 14.5 and J2 =
10.0 Hz, 1H), 3.51 (dd, J1 = 14.5 and J2 = 5.0 Hz, 1H), 3.96−4.07 (m,
2H), 4.53−4.62 (m, 1H), 6.98−7.06 (m, 2H), 7.25−7.33 (m, 2H),
9.46 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 16.8, 19.6, 23.0, 27.5,
31.3, 32.3, 58.1, 58.5, 68.1, 95.3, 111.1, 111.5, 113.6, 123.1, 124.0,
20
125.4, 126.5, 137.7, 173.3; FTIR (film, cm−1) 3146, 1614; [α]D
=
−121.5° (c = 0.2 in MeOH). Anal. Calcd. for C19H26BrN3O2 (407.12):
C, 55.89; H, 6.42; N, 10.29. Found: C, 56.01; H, 6.49; N, 10.20.
9b: TLC (ethyl acetate/MeOH 96:4) Rf = 0.21 (UV, p-
anisaldehyde); MS (ESI) 350−352 [M − 57]+, 408−410 [M + H]+;
mp 170−172 °C (MeOH); 1H NMR (200 MHz, CDCl3) δ 0.80 (d, J
= 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 1.62 (s, 3H), 1.78 (s, 3H),
1.82−1.96 (m, 1H), 3.22 (dd, J1 = 15.0 and J2 = 10.0 Hz, 1H), 3.26 (d,
J = 8.0 Hz, 1H), 3.44 (dd, J1 = 15.0 and J2 = 6.0 Hz, 1H), 3.86 (dd, J1 =
9.0 and J2 = 5.0 Hz, 1H), 3.96 (dd, J1 = J2 = 9.0 Hz, 1H), 4.52−4.63
(m, 1H), 7.00−7.10 (m, 2H), 7.27−7.37 (m, 2H), 8.64 (br s, 1H); 13C
NMR (50 MHz, CDCl3) δ 18.2, 20.0, 22.9, 26.9, 31.3, 32.2, 58.1, 59.7,
66.2, 95.4, 110.9, 112.5, 113.8, 123.2, 124.2, 125.3, 125.5, 137.7, 172.4;
20
FTIR (film, cm−1) 3273, 1622; [α]D = −27.3° (c = 0.2 in MeOH).
Anal. Calcd. for C19H26BrN3O2 (407.12): C, 55.89; H, 6.42; N, 10.29.
Found: C, 55.98; H, 6.37; N, 10.21.
tert-Butyl (2S)-1-(2-(hydroxymethyl)-2,3-dihydropyrrolo-
[4,3,2-de]quinolin-1(5H)-yl)-3-methyl-1-oxobutan-2-ylcarba-
mate (10) and tert-Butyl (2S)-3-methyl-1-oxo-1-(2,3,4,6-
tetrahydrooxepino[4,3,2-cd]indol-3-ylamino)butan-2-ylcarba-
mate (11). To a mixture of 7 (60 mg, 0.13 mmol), K2CO3 (36 mg,
0.26 mmol), KI (43 mg, 0.26 mmol) and CuI (6 mg, 0.032 mmol) in
anhydrous dioxane (0.2 M, 0.65 mL), in a dry flask under nitrogen
atmosphere, was added DMEDA (6 mg, 0.064 mmol), and the
reaction mixture was stirred at 110 °C for 18 h. After cooling, the
reaction was diluted with CH2Cl2 (10 mL), concentrated NH3 (0.5
mL) was added, the mixture was washed with brine (4 mL), and the
aqueous layer was further extracted with CH2Cl2 (2 × 5 mL). The
combined organic phases were dried over anhydrous Na2SO4, and the
solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2/MeOH 99:1) to give 23
mg (43%) of 10 (0.07 mmol) as amorphous solid and 21 mg (41%) of
11 as an amorphous solid.
10: TLC (CH2Cl2/MeOH 98:2) Rf = 0.35 (UV, CAM); MS (ESI)
1
388 [M + H]+; H NMR (200 MHz, CDCl3) δ 0.92 (d, J = 7.0 Hz,
3H), 0.94 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0
Hz, 3H), 1.46 (s, 9H), 1.48 (s, 9H), 2.06−2.25 (m, 2H), 2.76−2.89
(m, 2H), 3.03−3.15 (m, 2H), 3.74−3.87 (m, 2H), 4.10−4.44 (m, 6H),
5.03 (br d, J = 8.0 Hz, 2H), 6.30 (d, J = 7.5 Hz, 1H), 6.31 (d, J = 7.5
Hz, 1H), 6.75−6.79 (m, 4H), 7.01 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5
Hz, 1H), 7.86 (br s, 2H); 13C NMR (50 MHz, CDCl3) δ 17.69, 17.74,
19.07, 19.10, 25.3, 25.4, 28.3, 31.2, 51.6, 52.0, 58.7, 58.8, 67.8, 67.9,
79.99, 80.02, 100.5, 100.7, 101.5, 101.6, 108.5, 108.7, 115.8, 115.9,
117.50, 117.52, 124.1, 134.5, 139.0, 139.4, 155.7, 172.4; FTIR (film,
cm−1) 3388, 1736, 1702. Anal. Calcd. for C21H29N3O4 (387.22): C,
65.09; H, 7.54; N, 10.84. Found: C, 65.02; H, 7.48; N, 10.93.
11: TLC (CH2Cl2/MeOH 98:2) Rf = 0.25 (UV, CAM); MS (ESI)
1
388 [M + H]+; H NMR (200 MHz, CDCl3) δ 0.76 (d, J = 7.0 Hz,
(S)-2-Amino-1-((R)-4-((4-bromo-1H-indol-3-yl)methyl)-2,2-
dimethyloxazolidin-3-yl)-3-methylbutan-1-one (9a) and (S)-2-
Amino-1-((S)-4-((4-bromo-1H-indol-3-yl)methyl)-2,2-dimethy-
loxazolidin-3-yl)-3-methylbutan-1-one (9b). TFA (2.27 mL) was
added dropwise to a solution of 8 (463 mg, 0.91 mmol) in CH2Cl2
(9.13 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min
and then was diluted with CH2Cl2 (20 mL) and basified with a
solution of Na2CO3 2 N. The phases were separated, and the aqueous
layer was further extracted with CH2Cl2 (2 × 20 mL). The combined
organic phases were dried over anhydrous Na2SO4, and the solvent
was evaporated under reduced pressure. The residue was purified by
flash chromatography (gradient form ethyl acetate/MeOH 97:3 to
ethyl acetate/MeOH 95:5) to give 177 mg (47%) of 9a as a white
solid and 155 mg (42% mmol) of 9b as a pale yellow solid.
3H), 0.79 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0
Hz, 3H), 1.34 (s, 18H), 1.91−2.11 (m, 2H), 2.99−3.11 (m, 2H),
3.28−3.50 (m, 2H), 3.80−3.87 (m, 2H), 4.19−4.27 (m, 2H), 4.50−
4.64 (m, 4H), 5.04 (br d, J = 8.0 Hz, 2H), 6.24 (br d, J = 6.0 Hz, 1H),
6.37 (br d, J = 6.0 Hz, 1H), 6.64−6.70 (m, 2H), 6.96−7.09 (m, 6H),
8.26 (br s, 1H), 8.30 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 17.40,
17.45, 18.9, 22.7, 28.16, 28.23, 31.0, 32.0, 48.8, 72.9, 75.4, 104.6, 104.7,
106.71, 106.75, 110.0, 121.2, 122.9, 126.2, 128.2, 129.0, 138.5, 152.4,
152.5, 171.1, 171.2; FTIR (film, cm−1) 3385, 1739, 1706. Anal. Calcd.
for C21H29N3O4 (387.22): C, 65.09; H, 7.54; N, 10.84. Found: C,
64.98; H, 7.58; N, 10.72.
Compound 12. Method A: A reaction flask under nitrogen
atmosphere was charged with 9a (246 mg, 0.60 mmol), XPhos
precatalyst (22 mg, 0,03 mmol), NaOtBu (116 mg, 1.21 mmol), and
then dry 1,4-dioxane (12 mL) was added. The reaction mixture was
stirred at 110 °C for 16 h. After cooling, the reaction was quenched
9a: TLC (ethyl acetate/MeOH 96:4) Rf = 0.31 (UV, p-
anisaldehyde); MS (ESI) 350−352 [M − 57]+, 408−410 [M + H]+;
mp 186−188 °C (MeOH); 1H NMR (200 MHz, CDCl3) δ 0.75 (d, J
7732
dx.doi.org/10.1021/jo4013767 | J. Org. Chem. 2013, 78, 7727−7734

The Journal of Organic Chemistry
Article
with saturated NH4Cl solution (10 mL) and extracted with ethyl
acetate (3 × 15 mL). The combined organic phases were dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography (cyclo-
hexane/ethyl acetate 7:3) to give 167 mg (85%) of 12 as a white solid.
Method B: A Pyrex microwave vial was charged with 9a (52 mg,
0.128 mmol), XPhos precatalyst (4 mg, 0,006 mmol), NaOtBu (24
mg, 0.254 mmol), and then dry 1,4-dioxane (2.6 mL) was added. The
reaction mixture was stirred in a microwave reactor at 178 °C, 300 W,
for 1 h. After cooling, the reaction was quenched with saturated
NH4Cl solution (4 mL) and extracted with ethyl acetate (3 × 10 mL).
The combined organic phases were dried over anhydrous Na2SO4, and
the solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to
give 36 mg (86%) of 12 as a white solid.
(2S,5R)-5-(Hydroxymethyl)-2-isopropyl-1-methyl-4,5,6,8-tet-
rahydro-1H-[1,4]diazonino[7,6,5-cd]indol-3(2H)-one (15). 14
(70 mg, 0.205 mmol) was dissolved in HCl 3 M in dioxane (0.82
mL), water was added (0.1 mL), and the solution was stirred at 110 °C
for 4 h. The reaction mixture was diluted with ethyl acetate (5 mL)
and basified with a solution of Na2CO3 2 N. The phases were
separated, and the aqueous layer was further extracted with ethyl
acetate (2 × 10 mL). The combined organic phases were dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography (CH2Cl2/
MeOH 96:4) to give 51 mg (84%) of 15 as a pale yellow solid: TLC
(CH2Cl2/MeOH 95:5) Rf = 0.28 (UV, p-anisaldehyde, CAM); MS
(ESI) 302 [M + H]+; mp 214−216 °C (MeOH); 1H NMR (200 MHz,
CDCl3) δ 0.71 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H), 2.53−2.69
(m, 1H), 2.94 (br d, J = 15.5 Hz, 1H), 3.13 (s, 3H), 3.26 (br d, J =
15.5 Hz, 1H), 3.86−4.01 (m, 3H), 3.98 (d, J = 10.5 Hz, 1H), 6.77 (d, J
= 7.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 7.06
(t, J = 7.0 Hz, 1H), 7.73 (br s, 1H), 8.01 (br s, 1H); 13C NMR (50
MHz, CDCl3) δ 20.3, 20.7, 28.7, 30.1, 32.8, 58.0, 65.8, 69.4, 105.7,
109.8, 114.5, 120.9, 122.5, 122.8, 138.9, 148.4, 175.6; FTIR (film,
Data: TLC (cyclohexane/ethyl acetate 6:4) Rf = 0.23 (UV, p-
anisaldehyde); MS (ESI) 270 [M − 57]+, 328 [M + H]+; mp 258−261
1
°C (MeOH); H NMR (200 MHz, CDCl3) δ 0.71 (s, 3H), 1.02 (d, J
= 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.54 (s, 3H), 2.06−2.34 (m,
1H), 2.89 (d, J = 15.5 Hz, 1H), 3.72 (dd, J1 = 15.5 and J2 = 5.5 Hz,
1H), 3.91 (br s, 1H), 3.95 (dd, J1 = J2 = 8.5 Hz, 1H), 4.06−4.10 (m,
1H), 4.19−4.38 (m, 2H), 6.44 (d, J = 7.5 Hz, 1H), 6.81−7.01 (m,
3H), 8.30 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 19.6, 19.8, 21.8,
20
cm−1) 3293, 1654; [α]D = −70.7° (c = 0.2 in MeOH). Anal. Calcd.
for C17H23N3O2 (301.18): C, 67.75; H, 7.69; N, 13.94. Found: C,
67.83; H, 7.64; N, 14.01.
(2R)-Methyl 3-(4-bromo-1H-indol-3-yl)-2-(tert-butoxycarbo-
nylamino)-3-methylbutanamido)propanoate (16). Compound
16 was prepared according to the procedure used for compound 6. 5
was treated with N-Boc-L-valine to give compound 16 in 85% yield.
The chemical-physical data are identical to those already reported for
compound 6.
Anal. Calcd. for C22H30BrN3O5 (495.14): C, 53.23; H, 6.09; N,
8.47. Found: C, 53.34; H, 6.07; N, 8.35.
(2S)-tert-Butyl 1-(1-(4-bromo-1H-indol-3-yl)-3-hydroxypro-
pan-2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamate (17).
Compound 17 was prepared according to the procedure used for
compound 7 in 89% yield. The chemical-physical data are identical to
those already reported for compound 7.
25.4, 30.2, 33.7, 56.8, 65.4, 67.4, 95.9, 103.7, 108.4, 109.2, 117.5, 122.7,
20
123.1, 139.3, 141.4, 169.4; FTIR (film, cm−1) 3260, 1630; [α]D
=
−36.1° (c = 0.2 in MeOH). Anal. Calcd. for C19H25N3O2 (327.19): C,
69.70; H, 7.70; N, 12.83. Found: C, 69.58; H, 7.73; N, 12.93.
(S)-1-((S)-4-((1H-Indol-3-yl)methyl)-2,2-dimethyloxazolidin-
3-yl)-2-amino-3-methylbutan-1-one (13). A reaction flask under
nitrogen atmosphere was charged with 9b (168 mg, 0.41 mmol),
XPhos precatalyst (15 mg, 0,02 mmol), NaOtBu (79 mg, 0.82 mmol),
and then dry 1,4-dioxane (8.3 mL) was added. The reaction mixture
was stirred at 110 °C for 16 h. After cooling, the reaction was
quenched with saturated NH4Cl solution (10 mL) and extracted with
ethyl acetate (3 × 15 mL). The combined organic phases were dried
over anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The residue was purified by flash chromatography
(cyclohexane/ethyl acetate 7:3) to give 95 mg (70%) of 13 as an
amorphous solid: TLC (ethyl acetate/MeOH 96:4) Rf = 0.26 (UV, p-
anisaldehyde); MS (ESI) 330 [M + H]+; 1H NMR (200 MHz, CDCl3)
δ 1.04 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.62 (s, 3H), 1.77
(s, 3H), 2.02−2.17 (m, 1H), 3.08−3.12 (m, 2H), 3.45 (d, J = 8.0 Hz,
1H), 3.85−3.94 (m, 2H), 4.31−4.40 (m, 1H), 7.10 (d, J = 2.0 Hz,
1H), 7.16−7.24 (m, 2H), 7.40 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 7.0 Hz,
1H), 8.23 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 18.2, 20.5, 22.8,
26.8, 31.0, 32.2, 58.0, 60.1, 66.7, 95.6, 111.5, 111.8, 118.4, 119.9, 122.4,
122.8, 127.1, 136.2, 171.0; FTIR (film, cm−1) 3258, 1632. Anal. Calcd.
for C19H27N3O2 (329.21): C, 69.27; H, 8.26; N, 12.76. Found: C,
69.35; H, 8.31; N, 12.88.
Anal. Calcd. for C21H30BrN3O4 (467.14): C, 53.85; H, 6.46; N,
8.97. Found: C, 53.76; H, 6.50; N, 8.89.
tert-Butyl (2R)-1-(4-((4-bromo-1H-indol-3-yl)methyl)-2,2-di-
methyloxazolidin-3-yl)-3-methyl-1-oxobutan-2-ylcarbamate
(18). Compound 18 was prepared according to the procedure used for
compound 8 in 79% yield. The chemical-physical data are identical to
those already reported for compound 8. Anal. Calcd. for
C24H34BrN3O4 (507.17): C, 56.69; H, 6.74; N, 8.26. Found: C,
56.82; H, 6.70; N, 8.21.
(R)-2-Amino-1-((R)-4-((4-bromo-1H-indol-3-yl)methyl)-2,2-
dimethyloxazolidin-3-yl)-3-methylbutan-1-one (19a) and (R)-
2-Amino-1-((S)-4-((4-bromo-1H-indol-3-yl)methyl)-2,2-dime-
thyloxazolidin-3-yl)-3-methylbutan-1-one (19b). Compounds
19a and 19b were prepared according to the procedure used for
compounds 9a and 9b. The chemical-physical data are identical to
those already reported for compound 9a and 9b.
Compound 14. To a solution of 12 (94 mg, 0.29 mmol) in
acetronitrile (4.4 mL) at 0 °C were added formalin 37% (214 μL, 2.9
mmol), sodium cyanoborohydride (66 mg, 1.04 mmol) and acetic acid
(28 μL, 0.49 mmol); the solution was stirred at 0 °C for 1 h. The
reaction mixture was diluted with water and extracted with ethyl
acetate. The combined organic phases were dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography (cyclohexane/ethyl
acetate 8:2) to give 95 mg (96%) of 14 as a white solid: TLC
(cyclohexane/ethyl acetate 6:4) Rf = 0.46 (UV, p-anisaldehyde); MS
(ESI) 342 [M + H]+; mp 261−263 °C (MeOH); 1H NMR (200 MHz,
CDCl3) δ 0.63 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H), 1.62 (s,
3H), 1.77 (s, 3H), 2.59−2.70 (m, 1H), 3.03−3.12 (m, 1H), 3.12 (s,
3H), 3.51 (dd, J1 = 15.5 and J2 = 4.5 Hz, 1H), 3.97−4.03 (m, 2H),
4.18−4.26 (m, 1H), 4.35 (dd, J1 = 8.5 and J2 = 6.0 Hz, 1H), 6.71 (d, J
= 7.5 Hz, 1H), 6.90−7.09 (m, 3H), 8.13 (br s, 1H); 13C NMR (50
MHz, CDCl3) δ 20.1, 20.3, 24.0, 25.3, 29.1, 32.2, 36.4, 60.4, 72.0, 72.1,
77.2, 95.6, 104.8, 108.4, 113.9, 120.1, 122.6, 138.5, 148.1, 168.7; FTIR
19a. 41% yield. The chemical-physical data are identical to those
20
already reported for compound 9a: [α]D = +121.2° (c = 0.2 in
MeOH). Anal. Calcd. for C19H26BrN3O2 (407.12): C, 55.89; H, 6.42;
N, 10.29. Found: C, 55.77; H, 6.39; N, 10.38.
19b. 47% yield. The chemical-physical data are identical to those
20
already reported for compound 9b: [α]D = +27.6° (c = 0.2 in
MeOH). Anal. Calcd. for C19H26BrN3O2 (407.12): C, 55.89; H, 6.42;
N, 10.29. Found: C, 56.02; H, 6.46; N, 10.35.
Compound 20. Compound 20 was prepared according to the
procedure used for compound 12a in 72% yield. The chemical-
physical data are identical to those already reported for compound
12a: [α]D20 = +36.4° (c = 0.2 in MeOH). Anal. Calcd. for C19H25N3O2
(327.19): C, 69.70; H, 7.70; N, 12.83. Found: C, 69.80; H, 7.63; N,
12.74.
Compound 21. Compound 21 was prepared according to the
procedure used for compound 14 in 91% yield. The chemical-physical
20
20
(film, cm−1) 3285, 1626; [α]D = −132.1° (c = 0.2 in MeOH). Anal.
data are identical to those already reported for compound 14: [α]D
=
Calcd. for C20H27N3O2 (341.21): C, 70.35; H, 7.97; N, 12.31. Found:
C, 70.27; H, 7.89; N, 12.20.
+132.6° (c = 0.2 in MeOH). Anal. Calcd. for C20H27N3O2 (341.21): C,
70.35; H, 7.97; N, 12.31. Found: C, 70.23; H, 8.00; N, 12.39.
7733
dx.doi.org/10.1021/jo4013767 | J. Org. Chem. 2013, 78, 7727−7734

The Journal of Organic Chemistry
Article
(2R,5S)-5-(Hydroxymethyl)-2-isopropyl-1-methyl-4,5,6,8-tet-
rahydro-1H-[1,4]diazonino[7,6,5-cd]indol-3(2H)-one (22). Com-
pound 22 was prepared according to the procedure used for
compound 15 in 81% yield. The chemical-physical data are identical
to those already reported for compound 15: [α]D = +70.4° (c = 0.2
in MeOH). Anal. Calcd. for C17H23N3O2 (301.18): C, 67.75; H, 7.69;
N, 13.94. Found: C, 67.88; H, 7.75; N, 13.86.
(11) (a) Bartolucci, S.; Bartoccini, F.; Righi, M.; Piersanti, G. Org.
Lett. 2012, 14, 600. (b) Righi, M.; Bartoccini, F.; Lucarini, S.; Piersanti,
G. Tetrahedron 2011, 67, 7923. (c) Lucarini, S.; Bartoccini, F.;
Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.; Spadoni, G. Org.
Lett. 2010, 12, 3844. (d) Angelini, E.; Balsamini, C.; Bartoccini, F.;
Lucarini, S.; Piersanti, G. J. Org. Chem. 2008, 73, 5654.
(12) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1995, 117, 4708.
(13) (a) Kim, J. H.; Lee, S. G. Org. Lett. 2011, 13, 1350. (b) Ghorai,
M. K.; Sahoo, A. K.; Kumar, S. Org. Lett. 2011, 13, 5972. (c) Zhao, T.
K.; Xu, B. Org. Lett. 2010, 12, 212. (d) Hernandez, S.; Moreno, I.;
SanMartin, R.; Herrero, M. T.; Dominguez, E. Org. Biomol. Chem.
2011, 9, 2251.
20
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables S1−S9 and copies of 1H NMR, 13C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. P. J. Am. Chem. Soc.
2004, 126, 14475. (b) Fayol, A.; Fang, Y. Q.; Lautens, M. Org. Lett.
2006, 8, 4203.
(15) See the Supporting Information for further details.
(16) (a) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009,
4166. (b) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005,
7, 4781.
(17) Recently, Frank Glorius and coworker demonstrated that
aliphatic alcohols and secondary amide are not well tolerated by the
typical Buchwald−Hartwig reaction conditions: Collins, K. D.; Glorius,
F. Nat. Chem. 2013, 5, 597.
(18) (a) Kenwright, J. L.; Galloway, W. R. J. D.; Blackwell, D. T.;
Isidro-Llobet, A.; Hodgkinson, J.; Wortmann, L.; Bowden, S. D.;
Welch, M.; Spring, D. R. Chem.Eur. J. 2011, 17, 2981.
(19) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
(b) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
130, 6686.
AUTHOR INFORMATION
Corresponding Author
*E-mail: giovanni.piersanti@uniurb.it.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Prof. Gilberto Spadoni, University of
Urbino, for useful discussions.
REFERENCES
■
(1) (a) Irie, K.; Hirota, M.; Hagiwara, N.; Koshimizu, K.; Hayashi,
H.; Murao, S.; Tokuda, H.; Ito, Y. Agric. Biol. Chem. 1984, 48, 1269.
(b) Irie, K.; Koshimizu, K. Comments Agric. Food Chem. 1993, 3, 1.
(2) Aimi, N.; Odaka, H.; Sakai, S.; Fujiki, H.; Suganuma, M.; Moore,
R. E.; Patterson, G. M. L. J. Nat. Prod. 1990, 53, 1593.
(3) Fujiki, H.; Mori, M.; Nakayasu, M.; Terada, M.; Sugimura, T.;
Moore, R. E. Proc. Natl. Acad. Sci. U. S. A. 1981, 78, 3872.
(4) Chen, S.; Borowiak, M.; Fox, J. L.; Maehr, R.; Osafune, K.;
Davidow, L.; Lam, K.; Peng, L. F.; Schreiber, S. L.; Rubin, L. L.;
Melton, D. Nat. Chem. Biol. 2009, 5, 258.
(20) We subsequently found that the XPhos-based catalyst was
extremely active, as it provided 12 in 86% yield with microwave
irradiation in only 3 h.
(21) (a) Endo, Y.; Shudo, K.; Itai, A.; Hasegawa, M.; Sakai, S-i
Tetrahedron 1986, 42, 5905. (b) Nakatsuka, S.; Masuda, T.; Sakai, K.;
Goto, T. Tetrahedron Lett. 1986, 27, 5735.
(22) Masuda, T.; Nakatsuka, S.-i.; Goto, T. Agric. Biol. Chem. 1989,
53, 2257.
(5) (a) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc.
2011, 133, 3832. (b) Mascal, M.; Moody, C. J.; Slawin, A. M. Z.;
Williams, D. J. J. Chem. Soc., Perkin Trans. 1 1992, 823. (c) de Laszlo,
S. E.; Ley, S. V.; Porter, R. A. J. Chem. Soc., Chem. Commun. 1986, 344.
(d) Semmelhack, M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1395.
(e) Kogan, T. P.; Somers, T. C.; Venuti, M. C. Tetrahedron 1990, 46,
6623. (f) Meseguer, B.; Alonso-Díaz, D.; Griebenow, N.; Herget, T.;
Waldmann, H. Chem.Eur. J. 2000, 6, 3943. (g) Xu, Z.; Zhang, F.;
Zhang, L.; Jia, Y. Org. Biomol. Chem. 2011, 9, 2512.
(23) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry,
L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(6) Huynh, M. U.; Elston, M. C.; Hernandez, N. M.; Ball, D. B.;
Kajiyama, S.-i.; Irie, K.; Gerwick, W. H.; Edwards, D. J. J. Nat. Prod.
2010, 73, 71.
(7) (a) Kawamura, T.; Matsubara, K.; Otaka, H.; Tashiro, E.; Shindo,
K.; Yanagita, R. C.; Irie, K.; Imoto, M. Bioorg. Med. Chem. 2011, 19,
4377. (b) Yanagita, R. C.; Nakagawa, Y.; Yamanaka, N.; Kashiwagi, K.;
Saito, N.; Irie, K. J. Med. Chem. 2008, 51, 46. (c) Nakagawa, Y.; Irie, K.;
Yanagita, R. C.; Ohigashi, H.; Tsuda, K.; Kashiwagi, K.; Saito, N. J.
Med. Chem. 2006, 49, 2681. (d) Irie, K.; Isaka, T.; Iwata, Y.; Yanai, Y.;
Nakamura, Y.; Koizumi, F.; Ohigashi, H.; Wender, P. A.; Satomi, Y.;
Nishino, H. J. Am. Chem. Soc. 1996, 118, 10733. (e) Kozikowski, A. P.;
Wang, S.; Ma, D.; Yao, J.; Ahmad, S.; Glazer, R. I.; Bogi, K.; Acs, P.;
Modarres, S.; Lewin, N. E.; Blumberg, P. M. J. Med. Chem. 1997, 40,
1316.
(8) (a) Edwards, D. J.; Gerwick, W. H. J. Am. Chem. Soc. 2004, 126,
11432. (b) Read, J. A.; Walsh, C. T. J. Am. Chem. Soc. 2007, 129,
15762.
(9) (a) Lim, H. J.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2010,
12, 2162. (b) Jiang, J. Q.; Xu, Z. R.; Jia, Y. X. J. Chin. Pharm. Sci. 2012,
21, 113.
(10) Fischer, C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59 and
reference therein.
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