Stereochemical Complexity in Oxocarbenium-Ion-Initiated Cascade Annulations for the Synthesis of the ABCD Core of Mattogrossine

Article abstract of DOI:10.1021/acs.joc.7b00503

Mattogrossine is an indole alkaloid isolated from Strychnos mattogrossensis that contains an unusual tetrahydrofuran ring with a concomitant hemiacetal in its structure. While tetrahydrofuran intermediates have been used in the synthesis of other strychnos alkaloids, no investigations have been performed into the synthesis of alkaloids containing this structure. We have developed an oxocarbenium-ion-initiated cascade annulation that provides us access to the ABCD ring structure of mattogrossine.

Full text of DOI:10.1021/acs.joc.7b00503

Note
pubs.acs.org/joc
Stereochemical Complexity in Oxocarbenium-Ion-Initiated Cascade
Annulations for the Synthesis of the ABCD Core of Mattogrossine
Aidi Kong, Eric S. Andreansky, and Simon B. Blakey*
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: Mattogrossine is an indole alkaloid isolated
from Strychnos mattogrossensis that contains an unusual
tetrahydrofuran ring with a concomitant hemiacetal in its
structure. While tetrahydrofuran intermediates have been used
in the synthesis of other strychnos alkaloids, no investigations
have been performed into the synthesis of alkaloids containing
this structure. We have developed an oxocarbenium-ion-initiated cascade annulation that provides us access to the ABCD ring
structure of mattogrossine.
hallenged by the structural diversity of indole alkaloid
natural products, many of which exhibit potent biological
C
activities, we have pursued a research program aimed at
developing a synthetic strategy that employs divergent cascade
annulation reactions to efficiently access the core structures of
these compounds.1 In our initial investigation, we focused on
developing an iminium-ion-initiated cascade for the synthesis of
the Malagasy alkaloids, including malagashanine (1) and
myrtoidine (2) (Figure 1A).1a During these studies, we became
aware of the structural similarity between the Malagasy
alkaloids, isolated from the Madagascan shrub Strychnos
myrtoides, and mattogrossine (3), isolated from Strychnos
mattogrossensis.2 In nature, mattogrossine and malagashanine
are postulated to arise from the common synthetic precursor
strychnobrasiline (4), although the biosynthetic pathways have
yet to be unambiguously established. Both possess a common
pentacyclic framework with seven consecutive stereocenters.
Intriguingly, mattogrossine possesses an unusual C ring
tetrahydrofuran containing a C3 hemiacetal, in place of the
more common C ring pyrrolidine typically found in strychnos
alkaloids. Although indole alkaloid structures with C ring
tetrahydrofurans have been synthesized as intermediates en
route to traditional pyrrolidine containing natural products,
there are no studies specifically addressing this motif in natural
product synthesis.3 Herein we outline a strategy for the
synthesis of the ABCD core of mattogrossine by an
oxocarbenium-ion-initiated cascade annulation reaction.
Based upon our previous studies toward related alkaloids,1c
we envisioned that mattogrossine could be synthesized by
elaboration of an ABCD core 5 (Figure 1B) and that this core
could be accessed by cascade annulation of oxocarbenium ion
intermediate 6 generated by Lewis acid mediated decom-
position of a mixed acetal 7. Initial reaction of the generated
oxocarbenium ion with the tethered indole at the 3-position
leads to formation of an indolenium ion, which upon trapping
with a pendant allylsilane nucleophile would provide the ABCD
core of mattogrossine in a single step. The requisite mixed
acetal intermediate could be readily accessed by selective
Figure 1. (A) Malagasy alkaloids and their proposed biosynthetic
precursor, strychnobrasiline. (B) Retrosynthetic analysis for the
synthesis of mattogrossine.
reduction and trapping of a simple ester intermediate. An
analogous iminium ion cascade annulation was used by our
group in the synthesis of the natural product malagashanine,
providing the core of the natural product with high
Received: March 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00503
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Note
diastereoselectivity, with allylsilane geometry translating
directly into stereochemistry observed in the formed alkaloid
core.1c Unclear to us was whether this high level of
diastereoselectivity would also translate into an oxocarbenium
ion cascade annulation necessary for the synthesis of a
mattogrossine core.
Scheme 2. (A) Synthesis of E-Allylsilane 12; (B) Synthesis of
Z-allylsilane 19; (C) Synthesis of Esters 22a−c
In our preliminary studies focused on cascade annulation
reactions of iminium ions,1a we had demonstrated that this
reaction could be extended to the cyclization of analogous
oxocarbenium ion intermediates.4 Tryptophol-derived ester 8
was reduced with DIBAL-H and in situ trapped by TMS-
imidazole to form the sensitive mixed acetal 9 (Scheme 1).
Scheme 1. Synthesis and Cyclization of Mixed Acetal
Intermediate 9 to Mattogrossine Core 10
Subsequent decomposition of the mixed acetal with BF3·OEt2
in CH2Cl2 at 0 °C provided the tetrahydrofuran analog 10 in
64% yield with a 2.3:1 diastereoselectivity at the C3 position.
Although this study demonstrated that the ABCD ring system
of mattogrossine could be constructed by a cascade annulation,
it did not address the feasibility of using trisubstituted
allylsilanes necessary to introduce a required C16 substituent
with the appropriate relative stereochemistry for the synthesis
of mattogrossine.
Our investigations into the effect of trisubstituted allylsilanes
on the cascade commenced with the synthesis of the E-
allylsilane 12 and the Z-allylsilane 19.5 We have previously
reported the synthesis of E-allylsilane 12, readily available from
benzyl propargyl ether 11 in five steps (43% yield), during our
investigations into the synthesis of malagashanine (Scheme
2A).1c The complementary Z-allylsilane 19 can be prepared in
seven steps from the THP acetal of 3-butyn-1-ol 13 (Scheme
2B). Deprotonation of the terminal alkyne in 13 with n-
butyllithium followed by reaction with paraformaldehyde
provided the propargyl alcohol 14 in 80% yield. The required
alkene stereochemistry was set by trans-selective reduction of
the propargyl alcohol 14 with Red-Al followed by trapping with
N-iodosuccinimide, providing Z-vinyl iodide 15 in 83% yield.6
This vinyl iodide proved particularly sensitive to elimination
under even mildly basic conditions, proving problematic in the
subsequent benzylation step. Ultimately, the use of Dudley’s
reagent7 in the presence of a proton sponge provided
acceptable yields (52%, 75% brsm) of benzyl ether 16 to
continue the synthesis. Subsequent deprotection of the THP
acetal with PPTS provided homoallylic alcohol 17 in 98% yield,
which underwent oxidation8 to the carboxylic acid 18 followed
by Negishi cross-coupling which provided the Z-allylsilane 19
in 96% yield over three steps.9
standard DCC-promoted esterification with tryptophol 20,
providing esters 22a and 22b in 78% and 69% yield,
respectively.10 To investigate the impact of indole protection
on the cascade annulation reaction, an N-benzyl tryptophol
ester 22c, formed by DCC coupling of Z-allylsilane 12 and N-
benzyl tryptophol11 21, was also synthesized (69% yield). All
three esters 22a−c were reduced with DIBAL-H at −78 °C,
and the resulting hemiacetal aluminates were subjected to
transmetalation with trimethylsilylimidazole in the presence of
excess imidazole, providing TMS acetals 23a−c (Figure 2A).
We note that additional imidazole promoted the trans-
metalation reaction and resulted in uniformly reproducible
syntheses of the TMS acetals. In its absence, transmetalation
was capricious, and yields of the TMS acetals were routinely
inferior. In all cases, the TMS acetals were not stable to silica
gel, and crude reaction mixtures were immediately subjected to
the cyclization reactions.
When each TMS acetal substrate was subjected to BF3·OEt2-
mediated cyclization, a mixture of cyclization products was
always observed (Figure 2B). For TMS acetal 23a with a free
indole and E-allylsilane geometry, the total isolated yield of
With carboxylic acid substituted allylsilanes 12 and 19 in
hand, we proceeded to synthesize the requisite oxocarbenium
ion precursors (Scheme 2C). Each isomer was subjected to
B
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Figure 2. Cyclization reactions leading to the synthesis of mattogrossine cores.
three products was 46% from ester 22a with a product ratio of
24a:24b:24c = 1:2.2:1.8. For TMS acetal 23b with a free indole
and Z-allylsilane geometry, the total isolated yield of three
products was 55% from ester 22b with a product ratio of
24a:24b:24d = 2:2:1. In both cases, an unprotected indole
substrate provided predominantly products containing a cis C/
25c), single diastereomers that reflect the geometry of the
starting allylsilane and are consistent with a chair transition
state are isolated. This suggests a greater energy difference for
the boat- and chairlike (26c) transition state for products with
trans C/D ring fusions.
CONCLUSION
D ring fusion as a mixture of C16 epimers. In contrast, with
■
benzyl protection of the indole nitrogen in TMS acetal 23c, this
trend reversed and the Z-allylsilane isomer provided three
products in 79% yield from ester 22c with a product ratio of
25a:25b:25c = 1.9:1:4.3. In all cases, the products containing a
C/D trans fusion (24c, 24d, and 25c) were isolated as single
diastereomers. Based on the observation that a fixed cis iminium
ion geometry in the Corey group’s synthesis of aspidophytine
led to the selective formation of a cis fused C/D ring system12
and our own observations that reversing the iminium ion
geometry results in selective formation of the trans fused
system,1a we postulate that the mixture of C/D ring fusion
diastereomers reflects the ratio of oxocarbenium ion E/Z
We have demonstrated herein the feasibility of an oxocarbe-
nium-ion-initiated cascade cyclization for the formation of
tetracyclic cores of the natural product mattogrossine.
However, they are inherently more complicated than the
analogous iminium ion cascades we have used previously for
other alkaloid natural products, providing mixtures of
diastereomeric products due to lower selectivity for discrete
oxocarbenium geometries. Nevertheless, we have discovered
reaction conditions that lead to the formation of a tetracyclic
intermediate 25c in 47% yield with the appropriate stereo-
chemistry for use in a total synthesis of mattogrossine.
EXPERIMENTAL SECTION
isomers trapped by each substrate under the reaction
conditions.
■
General Information. Reactions were performed under a dry
nitrogen atmosphere with anhydrous solvents using standard Schlenk
techniques unless otherwise stated. Glassware was dried in an oven at
120 °C for a minimum of 6 h prior to use. Anhydrous tetrahydrofuran
(THF), diethyl ether (Et2O), and dichloromethane (CH2Cl2) were
obtained by passage through activated alumina using a Glass Contours
solvent purification system. Anhydrous N,N-dimethylformamide
(DMF) was obtained from EMD Millipore and stored over dry 4 Å
molecular sieves. Boron trifluoride diethyl etherate (BF3·OEt2) was
distilled under vacuum from calcium hydride directly before use.
The specific range of products observed for each cascade
cyclization correspond to specific transition states for the
allylsilane addition step (Figure 3). For substrates that lead to a
cis C/D ring fusion (24a−b and 25a−b), the mixture of
diastereomers formed regardless of allylsilane geometry reflects
a small energetic difference between boat- (26a) and chairlike
(26b) transition states for the allylsilane addition step. For
substrates that lead to a trans C/D ring fusion (24c−d and
C
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reduced pressure. Purification by vacuum distillation (84−84.5 °C/14
mmHg) provided THP acetal 13 (13.5 g, 97%) as a colorless oil.
Spectral data matched those previously reported in the literature.15 Rf
= 0.45 (5:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 4.66 (t, J
= 3.6 Hz, 1H), 3.92−3.81 (m, 2H), 3.61−3.49 (m, 2H), 2.50 (td, J =
6.8, 2.4 Hz, 2H), 1.99 (t, J = 2.4 Hz, 1H), 1.85−1.80 (m, 1H), 1.78−
1.69 (m, 1H), 1.65−1.50 (m, 4H) ppm.
Propargylic Alcohol 14. A solution of THP acetal 13 (7.7 g, 50.0
mmol, 1.0 equiv) in THF (150.0 mL) was cooled to −78 °C. n-BuLi
(2.5 M in hexanes, 22.0 mL, 55.0 mmol, 1.1 equiv) was slowly added
over 30 min, and the resulting solution was stirred at −78 °C for 1 h.
Paraformaldehyde (3.8 g, 125.0 mmol, 2.5 equiv) was added, and the
resulting mixture was gradually warmed to room temperature and
stirred for 14 h. The reaction was quenched with saturated aqueous
NH4Cl (45.0 mL), and the layers were separated. The aqueous phase
was extracted with Et2O (3 × 100.0 mL). The combined organic layer
was washed with brine (2 × 100.0 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (3:1 hexanes/EtOAc) afforded
propargylic alcohol 14 (7.3 g, 80%) as a colorless oil. Spectral data
matched those previously reported in the literature.16 Rf = 0.20 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 4.64 (t, J = 3.2 Hz,
1H), 4.24 (t, J = 2.0 Hz, 2H), 3.91−3.79 (m, 2H), 3.59−3.49 (m, 2H),
2.53 (tt, J = 6.8, 2.4 Hz, 2H), 1.99 (s, 1H), 1.86−1.78 (m, 1H), 1.73−
1.69 (m, 1H), 1.63−1.50 (m, 4H) ppm.
Vinyl Iodide 15. A solution of propargylic alcohol 14 (3.6 g, 19.2
mmol, 1.0 equiv) in THF (60.0 mL) was cooled to 0 °C. Red-Al (60
wt % in toluene, 9.8 mL, 32.6 mmol, 1.7 equiv) was slowly added over
15 min. The reaction mixture was stirred for 1 h at 0 °C and then was
cooled to −78 °C. A solution of NIS (7.3 g, 32.6 mmol, 1.7 equiv) in
THF (20.0 mL) was added. After 20 min at −78 °C, the reaction was
quenched by slow addition of aqueous 15% Rochelle’s salt solution
(110.0 mL) and Na2SO3 aqueous solution (40.0 mL). The resulting
mixture was gradually warmed to room temperature and stirred until
both layers were clear. The layers were separated, and the aqueous
phase was extracted with Et2O (2 × 50.0 mL). The combined organic
layer was washed with brine (2 × 30.0 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (3:1
hexanes/EtOAc) afforded vinyl iodide 15 (5.0 g, 83%) as a colorless
oil. Spectral data matched those previously reported in the literature.17
Figure 3. Stereochemical rationale for mattogrossine core cyclization
products.
Schwartz reagent (Cp2ZrHCl) was stored and weighed in a nitrogen-
13
filled glovebox. Pd(MeCN)2Cl2 and Dess-Martin Periodinane
(DMP)14 were synthesized according to previously reported methods.
All other reagents and solvents were obtained from commercial
suppliers and used as received. Analytical thin layer chromatography
(TLC) was performed on precoated glass backed Silicycle SiliaPure
0.25 mm silica gel 60 plates. Visualization was accomplished with UV
light, ethanolic p-anisaldehyde, ethanolic phosphomolybdic acid, or
aqueous potassium permanganate. Flash column chromatography was
performed using Silicycle SilaFlash F60 silica gel (40−63 μm).
Preparatory thin layer chromatography was performed on precoated
1
Rf = 0.30 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3) δ 5.95
(t, J = 6.0 Hz, 1H), 4.60 (t, J = 2.4 Hz, 1H), 4.18 (t, J = 4.2 Hz, 2H),
3.89−3.82 (m, 2H), 3.59−3.48 (m, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.12
(br s, 1H), 1.83−1.76 (m, 1H), 1.73−1.66 (m, 1H), 1.60−1.48 (m,
4H) ppm; 13C NMR (100 MHz, CDCl3) δ 136.0, 105.0, 99.1, 67.5,
66.1, 62.6, 45.5, 30.7, 25.6, 19.6 ppm.
glass backed Silicycle SiliaPure 1.0 mm silica gel 60 plates. 1H and 13
C
Benzyl Ether 16. A suspension of vinyl iodide 15 (5.4 g, 17.3 mmol,
1.0 equiv), Dudley’s Reagent (12.1 g, 34.6 mmol, 2.0 equiv), and
proton sponge (7.4 g, 34.6 mmol, 2.0 equiv) in PhCF3 (35.0 mL) was
heated to 83 °C for 24 h. After cooling to room temperature, the
reaction mixture was filtered through a pad of Celite, and the filtrate
was concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (10:1 hexanes/EtOAc) afforded benzyl
ether 16 (3.6 g, 52%) as a colorless oil, in addition to 31% recovered
starting material. Rf = 0.45 (9:1 hexanes/EtOAc); 1H NMR (400
MHz, CDCl3) δ 7.37−7.29 (m, 5H), 5.97 (t, J = 6.0 Hz, 1H), 4.63 (t, J
= 2.8 Hz, 1H), 4.54 (s, 2H), 4.12 (d, J = 4.2 Hz, 2H), 3.91−3.84 (m,
2H), 3.60−3.51 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H), 1.85−1.77 (m, 1H),
1.74−1.67 (m, 1H), 1.63−1.50 (m, 4H) ppm; 13C NMR (100 MHz,
CDCl3) δ 138.1, 134.0, 128.5, 128.0, 127.8, 105.5, 98.9, 74.6, 72.5,
66.0, 62.4, 45.6, 30.7, 25.6, 19.5 ppm; HRMS (+APCI) calculated for
C17H24I1O3 [M + H]+ 403.0770, found 403.0773.
Homoallylic Alcohol 17. A solution of benzyl ether 16 (2.1 g, 5.3
mmol, 1.0 equiv) and PPTS (131.9 mg, 0.53 mmol, 0.1 equiv) in
EtOH (90.0 mL) was heated to 55 °C for 90 min. The mixture was
concentrated, and additional EtOH (30.0 mL) was added. The mixture
was heated to 55 °C for 30 min. This procedure was repeated three
times until the substrate was consumed, upon which the reaction
mixture was concentrated under reduced pressure. Purification by flash
nuclear magnetic resonance (NMR) spectra were recorded on a Varian
1
Inova 600 spectrometer (600 MHz H, 151 MHz 13C) and a Varian
Inova 400 spectrometer (400 MHz + H, 100 MHz 13C) at room
temperature in CDCl3 (neutralized and dried over anhydrous K2CO3)
with internal CHCl3 as the reference (7.26 ppm for 1H and 77.23 ppm
for 13C), unless otherwise stated. Chemical shifts were reported in
parts per million (ppm), and coupling constants (J values), in Hz.
Multiplicity was indicated using the following abbreviations: s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet,
b = broad. Infrared (IR) spectra were recorded using a Thermo
Electron Corporation Nicolet 380 FT-IR spectrometer. High
resolution mass spectra (HRMS) were obtained using a Thermo
Electron Corporation Finigan LTQFTMS (at the Mass Spectrometry
Facility, Emory University). We acknowledge the use of shared
instrumentation provided by grants from the NIH and the NSF.
THP Acetal 13. PPTS (110.0 mg, 0.44 mmol, 0.005 equiv) was
added to a solution of 3-butyn-1-ol (6.3 g, 90.0 mmol, 1.0 equiv) and
DHP (6.3 g, 90.0 mmol, 1.0 equiv) in CH2Cl2 (150.0 mL) at 23 °C,
and the resulting mixture was stirred for 12 h. The reaction mixture
was quenched with water (150.0 mL), and the organic layer was
separated. The aqueous phase was extracted with CH2Cl2 (2 × 30.0
mL). The combined organic layer was washed with brine (2 × 50.0
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
D
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1
column chromatography on silica gel (5:2 hexanes/EtOAc) afforded
homoallylic alcohol 17 (1.6 g, 98%) as a colorless oil. Rf = 0.50 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.38−7.29 (m, 5H),
6.00 (t, J = 6.0 Hz, 1H), 4.55 (s, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.74 (t,
J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 1.86 (br s, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 138.0, 134.9, 128.6, 128.1, 128.0, 105.8,
74.6, 72.9, 61.0, 48.2 ppm; IR (thin film, cm−1) 3380, 2859, 1644,
1453, 1356, 1092, 1048, 1028, 735, 696; HRMS (+APCI) calculated
for C12H14O1I1 [M − OH]+ 301.0084, found 301.0085.
Carboxylic Acid 19. Dess-Martin periodinane (1.77 g, 4.16 mmol,
1.5 equiv) was added to a solution of homoallylic alcohol 17 (880 mg,
2.77 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL), and the resulting
suspension was stirred at room temperature for 5 h. The reaction was
quenched with saturated aqueous NaHCO3/20% aqueous Na2SO3
(1:1, 40.0 mL), and the resulting biphasic mixture was stirred for 15
min. The two layers were separated, and the aqueous phase was
extracted with CH2Cl2 (4 × 30.0 mL). The combined organic layer
was washed with brine (50.0 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude residue
was dissolved in CH2Cl2 (4.2 mL) and t-BuOH (23.0 mL). 2-Methyl-
2-butene (12.6 mL) was added, and the resulting mixture was stirred
for 5 min. A solution of NaClO2 (2.48 g, 27.4 mmol, 9.9 equiv) and
NaH2PO4 (2.98 g, 24.8 mmol, 9.0 equiv) in H2O (24.6 mL) was
added, and the resulting mixture was stirred for 1 h. The reaction was
quenched with brine (40.0 mL), and the layers were separated. The
aqueous phase was extracted with Et2O (3 × 30.0 mL). The combined
organic layer was washed with brine (50.0 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was azeotroped with benzene (3 × 30.0 mL) to thoroughly
remove residual t-BuOH, providing crude carboxylic acid 18, which
was used without further purification.
To a flask charged with anhydrous ZnBr2 (1.94 g, 8.6 mmol, 3.2
equiv) was added TMSCH2MgCl solution (1.0 M in Et2O, 8.1 mL, 8.1
mmol, 3 equiv), and the resultant mixture was stirred at room
temperature for 12 h. DMF (6.0 mL) and Et2O (2.0 mL) were added,
and the reaction was cooled to 0 °C. A solution of crude carboxylic
acid 18 in DMF (5.0 mL) was added via cannula to the zinc
suspension, and the reaction mixture was stirred for 5 min. A solution
of Pd(CH3CN)2Cl2 (70 mg, 0.27 mmol, 0.1 equiv) in DMF (1.0 mL)
was added over 5 min, and the reaction mixture was warmed to room
temperature and stirred for 4 h. The reaction was quenched with
saturated aqueous NH4Cl (20.0 mL) and EtOAc (40.0 mL), and the
layers were separated. The aqueous phase was extracted with Et2O (3
× 20 mL). The combined organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was filtered through Celite and rinsed with Et2O
(3 × 20.0 mL). The filtrate was washed with 10% aqueous LiCl (3 ×
50.0 mL) and brine (3 × 50.0 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to provide
carboxylic acid (744.9 mg, 94%) as a yellow oil, which was
subsequently used without further purification. Rf = 0.09 (7:3
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.36−7.28 (m,
5H), 5.48 (t, J = 6.4 Hz, 1H), 4.51 (s, 2H), 4.99 (d, J = 6.4 Hz, 2H),
3.04 (s, 2H), 1.67 (s, 2H), 0.02 (s, 9H) ppm; 13C NMR (150 MHz,
CDCl3) δ 173.2, 137.3, 128.7, 128.3, 127.9, 121.9, 72.6, 66.0, 40.0,
29.8, 27.9, −1.2 ppm; IR (thin film, cm−1) 3550−2560, 2952, 1707,
1657, 1247, 840; HRMS (+NSI) calculated for C16H25O3Si [M + H]+
293.1568, found 293.1566.
colorless oil. Rf = 0.65 (2:1 hexanes/EtOAc); H NMR (400 MHz,
CDCl3) δ 8.02 (br s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.39−7.28 (m,
6H), 7.21 (t, J = 7.2 Hz, 1H), 7.16−7.12 (m, 1H), 7.01 (t, J = 2.0 Hz,
1H), 5.44 (t, J = 7.2 Hz, 1H), 4.49 (s, 2H), 4.36 (t, J = 7.2 Hz, 2H),
4.05 (d, J = 6.8 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 3.05 (s, 2H), 0.06 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.2, 138.7, 136.3, 135.1,
128.6, 127.9, 127.7, 127.6, 123.2, 122.3, 122.2, 119.6, 118.9, 112.0,
111.3, 71.8, 66.7, 65.0, 38.6, 28.3, 24.9, −1.1 ppm; IR (thin film, cm−1)
3412, 2952, 1731, 1456, 1248, 1160, 1095, 850, 740, 698; HRMS
(+NSI) calculated for C26H34O3N1Si1 [M + H]+ 436.2303, found
436.2300.
Ester 22b. Purification by flash column chromatography on silica
gel (6:1 hexanes/EtOAc) provided ester 22b (300.4 mg, 69%) as a
colorless oil. %). Rf = 0.20 (5:1 hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.83 (br s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.27−7.21 (m,
5H), 7.15 (td, J = 8.0, 0.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.00 (t, J =
7.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 5.34 (t, J = 6.4 Hz, 1H), 4.41 (s,
2H), 4.26 (t, J = 6.8 Hz, 2H), 3.90 (d, J = 6.4 Hz, 2H), 2.98 (t, J = 6.8
Hz, 2H), 2.89 (s, 2H), 1.52 (s, 2H), −0.09 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3) δ 171.7, 138.5, 136.2, 135.2, 128.6, 128.3, 127.9,
127.5, 122.8, 122.6, 122.1, 119.5, 118.8, 111.9, 111.3, 72.5, 67.1, 64.9,
45.1, 24.8, 22.5, −0.8 ppm; IR (thin film, cm−1) 3420, 2952, 1731,
1456, 1249, 1165, 1092, 1007, 853, 740; HRMS (+NSI) calculated for
C26H33O3N1Na1Si1 [M + Na]+ 458.2122, found 458.2120.
Ester 22c. Purification by flash column chromatography on silica gel
(20:1 to 10:1 hexanes/EtOAc) provided ester 22c (361.3 mg, 69%) as
1
a colorless oil. Rf = 0.40 (5:1 hexanes/EtOAc); H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 7.6 Hz, 1H), 7.33−7.23 (m, 10H), 7.18−7.07
(m, 3H), 6.96 (s, 1H), 5.42 (t, J = 6.4 Hz, 1H), 5.25 (s, 2H), 4.48 (s,
2H), 4.35 (t, J = 7.6 Hz, 2H), 3.96 (d, J = 6.8 Hz, 2H), 3.09 (t, J = 7.2
Hz, 2H), 2.98 (s, 2H), 1.61 (s, 2H), 0.00 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3) δ 171.7, 138.7, 137.8, 136.8, 135.1, 129.0, 128.6, 128.4,
128.1, 127.8, 127.7, 127.0, 126.5, 123.0, 122.1, 119.4, 119.2, 111.3,
109.9, 72.3, 67.0, 65.0, 50.1, 45.1, 25.0, 22.6, −0.7 ppm; IR (thin film,
cm−1) 3029, 2952, 1731, 1467, 1454, 1249, 1163, 853, 738, 698;
HRMS (+NSI) (m/z): calculated for C33H39O3N1Na1Si1 [M + Na]+
548.2591, found 548.2591.
General Procedure for the Synthesis of TMS Acetals 23a−c and
Subsequent Cyclization Reactions. A solution of ester 22a−c (1.0
equiv) in CH2Cl2 (0.07 M) was cooled to −78 °C, and DIBAL-H (1.0
M in CH2Cl2 or hexanes, 3.0 equiv) was added over 10 min. The
reaction was stirred for 45 min at −78 °C, and then imidazole (1.2
equiv) and TMS-imidazole (4.0 equiv) were added. The reaction
mixture was warmed to −25 °C and stirred for 16 h, and then was
further warmed to 0 °C and stirred for 3 h. The reaction was quenched
with aqueous 15% Rochelle’s salt and Et2O, and the biphasic mixture
was stirred vigorously until both layers were clear. The layers were
separated, and the aqueous phase was extracted twice with Et2O. The
combined organic layer was washed with saturated aqueous CuSO4
and brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to provide the crude TMS acetals 23a−c.
These compounds were used without further purification due to their
instability.
A solution of TMS acetal 23a−c (1.0 equiv) in CH2Cl2 (0.04 M)
was cooled to 0 °C. BF3·OEt2 (3.0 equiv) was added, and the reaction
mixture was stirred at 0 °C for 3 h. The reaction was quenched with
saturated aqueous NaHCO3, and the biphasic mixture was stirred for
15 min. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 three times. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure.
General Procedure for the Synthesis of Esters 22a−c. A solution
of acid 12 or 19 (1.0 equiv) and tryptophol 20 or 21 (1.2 equiv) in
CH2Cl2 (0.17 M in acid) was cooled to 0 °C. A solution of DCC (1.2
equiv) and DMAP (0.05 equiv) in CH2Cl2 (0.2 M in DCC) was
slowly added to the acid solution. The resulting mixture was warmed
to room temperature and stirred for 14 h. The reaction mixture was
filtered through Celite, and the pad was rinsed twice with Et2O. The
filtrate was washed twice with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Subsequent
purification provided the desired esters 22a−c.
The crude mixture of reaction products formed from TMS acetal
23a was purified by flash column chromatography on silica gel (10:1 to
3:1 hexanes/EtOAc), providing 24a:24b:24c (82.2 mg, 46%) in a
1:2.2:1.8 ratio.
Mattogrossine Core 24a. Rf = 0.40 (5:1 hexanes/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.41−7.34 (m, 5H), 7.11 (d, J = 7.2 Hz,
1H), 7.06 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 7.2
Hz, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.66 (d, J = 12.6 Hz, 1H), 4.52 (d,
J = 12.6 Hz, 1H), 4.15 (td, J = 9.0, 4.8 Hz, 1H), 4.05 (d, J = 3.6 Hz,
Ester 22a. Purification by flash column chromatography on silica gel
(10:1 to 5:1 hexanes/EtOAc) provided ester 22a (338.9 mg, 78%) as a
E
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The Journal of Organic Chemistry
Note
1H), 4.01 (q, J = 8.4 Hz, 1H), 3.91 (dd, J = 9.6, 4.8 Hz, 1H), 3.69 (t, J
= 9.0 Hz, 1H), 3.68 (t, J = 4.2 Hz, 1H), 2.97 (br s, 1H), 2.57 (ddd, J =
13.2, 8.4, 4.8 Hz, 1H), 2.53−2.52 (m, 2H), 2.14 (dt, J = 13.2, 8.4 Hz,
1H) ppm; 13C NMR (150 MHz, CDCl3) δ 150.3, 142.0, 138.3, 133.7,
128.8, 128.3, 128.2, 123.0, 119.4, 111.2, 110.1, 84.3, 73.4, 70.1, 67.5,
66.5, 53.6, 40.0, 38.3, 34.0 ppm; IR (thin film, cm−1) 3360, 2927, 2862,
1699, 1652, 1558, 1486, 1457, 1076, 741; HRMS (+APCI) calculated
for C23H26O2N [M + H]+ 348.1958, found 348.1954.
1H), 4.49 (t, J = 6.8 Hz, 1H), 4.45−4.41 (m, 2H), 4.14−4.06 (m, 2H),
3.98 (td, J = 8.4, 6.8 Hz, 1H), 3.93−3.88 (m, 2H), 3.72 (dd, J = 9.2,
7.2 Hz, 1H), 3.49 (t, J = 9.2 Hz, 1H), 3.20−3.12 (m, 1H), 2.70−2.56
(m, 2H), 2.50 (ddd, J = 13.2, 8.4, 5.6 Hz, 1H), 2.23−2.16 (m, 1H)
ppm; 13C NMR (150 MHz, CDCl3) δ 153.8, 142.1, 139.8, 138.4,
134.7, 132.5, 128.63, 128.60, 127.9, 127.8, 126.9, 126.8, 122.0, 118.7,
111.1, 107.9, 83.5, 73.3, 71.8, 69.2, 67.3, 54.5, 53.7, 42.1, 40.7, 32.5
ppm; IR (thin film, cm−1) 2925, 2855, 1603, 1485, 1077, 738, 698
ppm; HRMS (+APCI) calculated for C30H32O2N [M + H]+ 438.2428,
found 438.2423.
Mattogrossine Core 24b. Rf = 0.35 (5:1 hexanes/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.42−7.33 (m, 5H), 7.10 (d, J = 7.8 Hz,
1H), 7.09 (t, J = 7.8 Hz, 1H), 6.78 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8
Hz, 1H), 4.94 (s, 1H), 4.62 (s, 1H), 4.60−4.59 (m, 2H), 4.44 (t, J =
3.0 Hz, 1H), 4.02 (td, J = 9.0, 3.0 Hz, 1H), 3.94 (td, J = 9.0, 6.6 Hz,
1H), 3.89 (dd, J = 9.6, 4.2 Hz, 1H), 3.77 (t, J = 9.0 Hz, 1H), 3.45 (d, J
= 8.4 Hz, 1H), 2.57 (dd, J = 13.8, 3.0 Hz, 1H), 2.43−2.40 (m, 1H),
2.39−2.33 (m, 2H), 1.91 (td, J = 12.6, 9.0 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ 150.0, 141.7, 138.0, 131.2, 128.8, 128.5, 128.1,
128.0, 122.2, 119.1, 110.5, 80.2, 76.7, 73.9, 71.8, 67.0, 54.5, 43.3, 40.9,
37.6; IR (thin film, cm−1) 3360, 2924, 2856, 2031, 1670, 1575, 1558,
1473, 1071, 743; HRMS [+ APCI] (m/z): calcd for C23H26O2N [M +
H]+: 348.1958, found 348.1953.
Mattogrossine Core 25c. Rf = 0.46 (5:1 hexanes/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.42−7.35 (m, 5H), 7.26−7.22 (m, 3H),
7.16−7.14 (m, 2H), 7.10 (dd, J = 7.2, 1.2 Hz, 1H), 7.08 (td, J = 7.2,
1.8 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 7.2 Hz, 1H), 4.72 (d,
J = 15.6 Hz, 1H), 4.66 (s, 1H), 4.56−4.49 (m, 3H), 4.28 (d, J = 15.6
Hz, 1H), 4.22 (dd, J = 11.4, 6.6 Hz, 1H), 4.12−4.01 (m, 3H), 3.87−
3.84 (m, 1H), 3.65 (dd, J = 9.0, 4.2 Hz, 1H), 2.82−2.77 (m, 2H), 2.34
(dd, J = 15.6, 11.4 Hz, 1H), 1.81 (dt, J = 11.4, 10.2 Hz, 1H), 1.69−
1.66 (m, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 152.4, 142.2,
139.1, 138.2, 134.0, 128.7, 128.4, 128.2, 128.1, 128.0, 127.9, 127.2,
125.3, 118.1, 111.2, 108.9, 77.6, 73.6, 68.9, 66.8, 65.9, 55.8, 53.9, 42.9,
40.8, 33.2 ppm; IR (thin film, cm−1) 3028, 2871, 1599, 1481, 1452,
1126, 1074, 1025, 742, 698; HRMS (+NSI) calculated for C30H31O2N
[M]+ 437.2349, found 437.2347.
Mattogrossine Core 24c. Rf = 0.34 (5:1 hexanes/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.42−7.33 (m, 6H), 7.13 (t, J = 7.8 Hz,
1H), 6.92−6.84 (m, 2H), 4.89 (s, 1H), 4.61 (s, 2H), 4.55 (s, 1H),
4.14−4.01 (m, 2H), 3.88 (dd, J = 9.0, 4.8 Hz, 1H), 3.69−3.64 (m,
2H), 3.59−3.54 (m, 1H), 2.64 (dd, J = 12.0, 4.2 Hz, 1H), 2.41 (t, J =
12.6 Hz, 1H), 2.34−2.29 (m, 1H), 2.20−2.14 (m, 1H), 2.04−2.18 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 143.5, 137.8, 128.8, 128.7,
128.2, 128.1, 127.9, 125.5, 111.1, 81.1, 74.0, 72.7, 68.6, 66.1, 55.9, 44.3,
38.7, 37.4 ppm; IR (thin film, cm−1) 3374, 2922, 2879, 1736, 1604,
1477, 1462, 1101, 1052, 749; HRMS (+NSI) calculated for
C23H26O2N [M + H]+ 348.1958, found 348.1953.
The crude mixture of reaction products formed from TMS acetal
23b was purified by flash column chromatography on silica gel (5:1
hexanes/EtOAc) and then preparatory thin layer chromatography (5:1
hexanes/EtOAc, deactivated with 6% Et3N), providing 24a:24b:24d
(52.1 mg, 55%) in a 2:2:1 ratio.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00503.
■
S
Structural elucidation of mattogrossine cores 24a−d and
25a−c; NMR spectra of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sblakey@emory.edu.
■
Mattogrossine Core 24d. Rf = 0.34 (5:1 hexanes/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.43−7.35 (m, 5H), 7.09 (d, J = 7.2 Hz,
1H), 6.97 (t, J = 7.2 Hz, 1H), 6.63 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 7.2
Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.58 (s, 1H), 4.52 (d, J = 12.0 Hz,
1H), 4.42 (s, 1H), 4.22 (dd, J = 11.5, 7.2 Hz, 1H), 4.19−4.14 (m, 3H),
3.70−3.69 (m, 2H), 2.81−2.76 (m, 1H), 2.69−2.67 (m, 1H), 2.31 (dd,
J = 15.6, 11.4 Hz, 1H), 2.25−2.19 (m, 1H), 2.16−2.12 (m, 1H) ppm;
13C NMR (CDCl3, 150 MHz) δ 141.9, 138.1, 132.0, 128.8, 128.12,
128.10, 125.3, 118.2, 111.1, 73.7, 68.2, 67.3, 62.3, 55.7, 41.6, 40.1, 33.4
ppm; IR (thin film, cm−1) 3360, 2924, 1993, 1698, 1652, 1558, 1540,
1456, 1081, 749; HRMS (+APCI) calculatedd for C23H26O2N [M +
H]+ 348.1958, found 348.1955.
ORCID
Simon B. Blakey: 0000-0002-4100-8610
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the National Science
Foundation (CHE-1362502).
■
REFERENCES
■
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23c was purified by flash column chromatography on silica gel (20:1 to
5:1 hexanes/EtOAc), providing 25a:25b:25c (103.4 mg, 79%) in a
1.9:1:4.3 ratio.
Mattogrossine Core 25a. Rf = 0.50 (5:1 hexanes/EtOAc); 1H
NMR (400 MHz, CDCl3) δ 7.38−7.22 (m, 10H), 7.08 (dd, J = 7.6, 1.2
Hz, 1H), 7.03 (td, J = 7.6, 1.2 Hz, 1H), 6.74 (td, J = 7.6, 0.8 Hz, 1H),
6.37 (d, J = 8.0 Hz, 1H), 5.05 (s, 1H), 4.94 (s, 1H), 4.61 (d, J = 12.0
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(m, 2H), 3.88 (d, J = 4.8 Hz, 1H), 3.78 (t, J = 9.6 Hz, 1H), 3.74 (t, J =
4.0 Hz, 1H), 3.58 (dd, J = 9.6, 6.0 Hz, 1H), 3.17−3.13 (m, 1H), 2.64−
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8.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 151.9, 141.8, 139.3,
138.3, 134.9, 128.6, 128.5, 128.3, 128.1, 127.9, 127.4, 127.1, 122.5,
118.7, 114.5, 108.4, 84.4, 73.1, 72.5, 70.7, 67.3, 52.4, 51.9, 41.4, 41.3,
33.0 ppm; IR (thin film, cm−1) 2929, 2853, 1604, 1484, 1453, 1354,
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437.2349, found 437.2348.
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J. Org. Chem. XXXX, XXX, XXX−XXX