Enantioselective synthesis of (+)-malbrancheamide B

Article abstract of DOI:10.1021/jo3026059

The asymmetric total synthesis of the chlorinated [2.2.2]-diazabicyclic indole alkaloid (+)-malbrancheamide B is reported. Key to the synthesis is a domino reaction sequence that employs an aldol condensation, alkene isomerization, and intramolecular Diels-Alder cycloaddition. Diastereofacial selection between the azadiene stereofaces is enforced with a chiral aminal auxiliary. A formal 7-step (longest linear route) synthesis of (±)-malbrancheamide B is also reported.

Full text of DOI:10.1021/jo3026059

Article
pubs.acs.org/joc
Enantioselective Synthesis of (+)-Malbrancheamide B
Stephen W. Laws and Jonathan R. Scheerer*
Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States
S
* Supporting Information
ABSTRACT: The asymmetric total synthesis of the chlorinated [2.2.2]-diazabicyclic indole alkaloid (+)-malbrancheamide B is
reported. Key to the synthesis is a domino reaction sequence that employs an aldol condensation, alkene isomerization, and
intramolecular Diels−Alder cycloaddition. Diastereofacial selection between the azadiene stereofaces is enforced with a chiral
aminal auxiliary. A formal 7-step (longest linear route) synthesis of ( )-malbrancheamide B is also reported.
tween a 5-hydroxypyrazine-2(1H)-one and the terminal alkene
derived from reverse prenylation on the starting tryptophan
module. This biosynthetic hypothesis was originally proposed by
Porter and Sammes6 in 1970 and has been extensively probed
and supported over the decades by Williams and co-workers
through a number of biomimetic total syntheses7,8 and model
studies.9 In addition to the body of synthetic evidence, a number
of isotopic precursor feeding experiments have in many cases
discerned the order of bond formation and advanced informed
biosynthetic pathways.10 These natural products have also
recently enjoyed investigation at the genomic and biochemical
levels.11 The biosynthetic gene clusters for four alkaloids have
been cloned, and several biosynthetic enzymes have been
expressed and characterized, although evidence for the
intervention of a Diels−Alderase has not yet been fully
established.
In addition to the impressive structural diversity and intriguing
biosynthetic questions, many [2.2.2]-diazabicyclic alkaloids
possess potent and diverse biological activities including
antihelmintic, antitumor, and insecticidal properties.12 Both the
motivating bioactivities and intricate structure of these alkaloids
have sustained the interest of synthetic chemists, and as a result,
several methods for construction of the [2.2.2]-diazabicyclic core
have been developed.7,13 Improvements in the generality,
efficiency, and selectivity of these synthetic methods are valuable
objectives that stand to benefit the larger field and streamline
investigation into the biological properties of these alkaloids as
well as aid in the preparation of new bioactive molecules (and the
understanding of structure−activity relationships). Our previous
synthetic efforts in this area have focused on the development of
diastereoselective hetero-DA reactions of diketopiperazine
azadiene intermediates.14,15 We selected as targets the
INTRODUCTION
■
Prenylated indole alkaloids containing the [2.2.2]-diazabicyclic
skeleton are the focus of vibrant research efforts across diverse
scientific disciplines, from chemistry through biology and
medicine. Beginning with the initial discovery of the
brevianamides in 1969,1 new metabolites continue to be revealed
from Aspergillus, Pennicillium and Malbranchea fungal species,
and nearly 70 distinct metabolites are now known to share in
common the [2.2.2]-diazabicyclic core.2 Despite this shared
skeletal feature, striking structural diversity is observed across the
family. Variations in ring size and fusion, oxidation state, as well
as the extent and location of methylation, halogenation, and
prenylation are found between various congeners.3 Stereo-
chemical differences within the natural product family are also
noted. Metabolites display both the syn and anti architecture4 at
the [2.2.2]-diazabicyclic core, and several natural products have
been isolated from different sources in the opposite enantiomeric
series (e.g., (+)- and (−)-notoamide A).5 Brevianamide B,
notoamide A, and avrainvillamide are illustrated as representative
examples that highlight some of the structural diversity found
within this natural product class.
The [2.2.2]-diazabicyclic core is believed to arise from a
biogenic intramolecular hetero-Diels−Alder cycloaddition be-
Received: November 29, 2012
Published: January 29, 2013
© 2013 American Chemical Society
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malbrancheamide group of [2.2.2]-diazabicyclic alkaloids on
which to apply our asymmetric synthetic methods.
the intermediate resembling 8 (Scheme 1).23 Because this
intermediate is achiral, the ensuing cycloaddition in the absence
of an intervening catalyst to discriminate between the azadiene
stereofaces will result in racemic cycloadducts. Williams has
validated this sequence in his biomimetic total synthesis.21 Our
synthetic strategy directed toward the malbrancheamide family
of alkaloids also centers on the powerful IMDA strategy but
employs a removable aminal auxiliary in order to achieve
diastereofacial selection in the IMDA cycloaddition event (see
intermediate 11). We expected that the derived cycloadduct
from our asymmetric synthetic route (12) could be converted to
the target molecule in a short sequence. In this way, we
anticipated that the first enantioselective synthesis of natural
(+)-malbrancheamides could be achieved.
The malbrancheamides (1−7) are a group of metabolites
within the larger [2.2.2]-diazabicyclic alkaloid family that feature
halogenation at the indole nucleus. Malbrancheamide (1) and
malbrancheamide B (2) were isolated from cultured Malbran-
chea aurantiaca RRC1813, a fungal strain originally collected
from bat guano found in a Mexican cave.16 More recently, several
new members have been isolated including the regioisomeric
chlorinated derivate 4 and spiromalbramide (7) as well as the
brominated derivatives 5 and 6, which were produced from
cultures grown on bromide-enriched media.17
In addition to an asymmetric stereoselective synthesis, we
strived to design for a general convergent assembly that could
provide access to all members within the malbrancheamide
group. Correspondingly, our retrosynthetic analysis led us
toward a two-component approach, where the indole and chiral
diketopiperazine (DKP) functions would be separated. In the
forward direction, we anticipated that a domino24 reaction
sequence might be possible that brought about the union of
indole 9 and DKP 10 through aldol condensation and, under the
basic reaction conditions, would also permit alkene isomerization
to the reactive azadiene, an intermediate that would subsequently
react via cycloaddition and terminate the reaction sequence.
We directed our initial efforts toward the synthesis of
malbrancheamide B (2) because the constitutionally associated
6-chloroindole starting material was commercial available. The
desired indole carboxaldehyde 13 was prepared from 6-
chloroindole in four steps. For this sequence of transformations
leading to 13, we were mostly able to follow precedented
chemistry.21 We prepared DKP 14 (3 steps, 1 chromatographic
separation, 80% overall yield from proline methyl ester) as a
simplified substrate that would permit evaluation of our
proposed domino chemistry. On exposure to base (NaOMe in
MeOH at 90 °C sealed tube), the mixture of the N-
benzyloxymethyl (BOM) protected indole 1325 and DKP 14
afforded a mixture of three diazabicyclic cycloadducts 17a−c in
nearly quantitative combined yield (Scheme 2). This reaction
sequence can be rationalized by initial enolization of DKP 14
followed by addition to the aldehyde in 13 to give the
intermediate aldol condensation product 15. Isomerization of
the exocyclic alkene in 15 to the reactive endocyclic azadiene 16
is effected under the basic reaction conditions. IMDA cyclo-
addition of the azadiene terminates the reaction sequence and
provides 17a and 17b. Diketopiperazine product 17c arises from
Although not all malbrancheamides have been extensively
evaluated for biological activity, 1 and 2 are known to effect
selective inhibition of calmodulin (CaM)-dependent phopho-
diesterase (PDE1) activity.16,18 PDE1 is a clinically validated19
drug target, and selective inhibitors hold promising implications
for the treatment of neurodegenerative20 and vascular disease
and cancer. Previous synthetic efforts on the malbrancheamides
include a biomimetic IMDA approach by Williams and co-
workers, which led to the synthesis of racemic 1, 2, and a number
of C12a epimeric derivatives;21 additionally, Simpkins and co-
workers have disclosed their synthesis of ent-(−)-2 using a
cation-olefin cyclization strategy.22
RESULTS AND DISCUSSION
■
As a result of studies by Williams, Sherman and co-workers, a
number of aspects of malbrancheamide biosynthesis have been
revealed, the sequence of biogenic bond construction is more
clearly understood, and the key IMDA is postulated to occur on
Scheme 1. Proposed Biosynthesis and Our Synthesis Plan for the Malbrancheamides
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Scheme 2. Domino Reaction Sequence for the Synthesis of ( )-Malbrancheamide B
lactim hydrolysis of cycloadduct 17b during the course of the
reaction. Interestingly, hydrolysis is selective for syn-fused 17b;
no lactim ether hydrolysis product is observed for the more
congested anti-configured diastereomer 17a. Overall, anti-17a
and the sum of syn-fused lactim ether 17b and syn-
diketopiperazine 17c correspond to a diastereomer ratio (at
C12a) of 1:2.3 as judged by the unpurified 1H NMR. This “one
pot” domino sequence effectively couples the two starting
components and rapidly generates molecular complexity in
excellent yield.
Scheme 3. Diastereoselective Domino Reaction Sequence
Featuring the IMDA
Because this simplified model intercepts the achiral IMDA
precursor 16, the resulting cycloadducts are produced as racemic
mixtures. Both 17b and 17c can be easily converted to oxo-
malbrancheamide B (18). Although we have employed several
strategies to deprotect the lactim O-methyl ether and remove the
BOM indole residue on 17b and 17c, because of operational
simplicity and optimal results, we favor hydrolysis with
TsOH·H2O (2 equiv) in CH2Cl2 at room temperature. These
mild conditions effect BOM (and imine cleavage on 17b),
producing an intermediate ammonium methyl ester (not
shown).26 On basification (NaHCO3), the derived free amine
condenses with the pendant ester to give lactam 18 and thereby
re-establish the [2.2.2]-bridged architecture. In practice, the
cyclization to lactam 18 was facilitated by heating in toluene.
Overall, this process reliably afforded product 18 (87% yield
from 17c; 61% from 17b), intercepting the penultimate
precursor from Williams synthesis of ( )-2. Correspondingly,
this synthetic sequence represents a formal 10 step (7 step by the
longest linear sequence) synthesis of ( )-malbrancheamide B,
an improvement over the previous syntheses of ( )-2 or ent-
(−)-(2).
The racemic synthetic route served to validate our chemistry
and helped us to determine optimal conditions for the domino
reaction sequence. Our attention was then focused on the
analogous asymmetric route using the chiral nonracemic DKP 19
(Scheme 3). This necessary starting material was prepared in
four steps from commercially available L-serine methyl ester.15
The domino reaction sequence with DKP 19 and indole
carboxaldehyde 13 proceeded in analogous fashion to deliver the
diastereomeric cycloadducts 20a and 20b in a 1:2 ratio and 85%
combined yield. This result demonstrates that the aminal
stereocenter effectively controls the azadiene diastereofacial
selectivity during cycloaddition; however, the aminal imparts no
noticeable effect on the alkene face selection, as evident by the
similar (1:2.3) ratio of C12a diastereomeric products that we
observed in the racemic route. Additionally, this ratio is in
agreement with numerous cases by Williams and co-workers.
The diastereomeric mixture of cycloadducts 20a and 20b
could not be effectively separated by chromatography on silica
gel. As a result, the mixture was subjected to acidic hydrolysis
with an equimolar amount of TsOH·H2O in CH2Cl2 at 0 °C,
followed by basification and conversion to the diketopiperazine.
Under these conditions, which carefully control the stoichiom-
etry, the BOM indole protecting group could be preserved.27
Although the lactam diastereomers could be easily separated at
this point by chromatography, we found that the major isomer
21b was less soluble than the corresponding C12a diastereomer,
and 21b could be more easily obtained by selective precipitation
from the mixture (60% yield).
With the desired DKP cycloadduct 21b in hand, four tasks
remained to complete the synthesis of 2: (1) selective reduction
of the diketopiperazine to reveal the monoketopiperazine
function found in the malbrancheamides, (2) excision of the
phenyl aminal auxiliary, (3) extension of C1 (malbrancheamide
numbering) by two carbons and cyclization to form the
pyrrolidine ring, and (4) removal of BOM indole protection.
In light of these synthetic objectives, selective reduction of the
tertiary amide in 21b with Dibal-H28 delivered the desired
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monoketopiperazine and decomposed the aminal auxiliary to
reveal the corresponding benzyl amine and C1-alcohol.
Scheme 5. Completion of the Synthesis of (+)-2
Oxidation (SO ·pyr, DMSO, Hunig’s base) of the C1-alcohol
̈
3
to the corresponding aldehyde preceded Horner−Wadsworth−
Emmons olefination under the soft enolization conditions
developed by Masamune and Roush,29 which delivered the
requisite chain extension product. Using either phosphonoamide
2330 or phosphonoacetate 24, products 25 and 26 could be
prepared.31
The Weinreb amide in 25 was reduced to the α,β-unsaturated
aldehyde 27 in preparation for a reduction cascade that we
anticipated would reduce the alkene as well as remove both the
amine (Bn) and indole (BOM) nitrogen protection (Scheme 4).
Scheme 4. Catalytic Hydrogenation to the Malbrancheamide
Core
In order to advance toward the target molecule and append the
final pyrrolidine ring, the primary alcohol function in 29 was
activated as the derived mesylate. This mesylate proved stable at
ambient temperatures and was not readily displaced by the
nonbonding electrons on the pendant benzyl amine. Heating in
toluene (120 °C, sealed tube) achieved the desired intra-
molecular N-alkylation and led to precipitation of quaternary salt
30 from the reaction medium.35 Addition of KI and NEt3 to the
reaction mixture followed by additional heating led to efficient
dealkylation of the benzyl function from the quaternized amine
and delivered the malbrancheamide ring system.36 Using the
mild acidic hydrolysis conditions previously described, the N-
BOM protection was removed to reveal (+)-2 in 40% yield from
29 over the three steps. Synthetic (+)-2 had an identical HPLC
retention time as well as matching spectroscopic properties (UV,
1H and 13C NMR) to an authentic sample of the natural product.
In conclusion, a convergent asymmetric synthesis of
(+)-malbrancheamide B was completed in 13 steps as
determined by the longest linear route.37 Additionally, a formal
7 step (LLR) synthesis of ( )-2 was described. Both racemic and
asymmetric synthetic routes feature a domino reaction sequence
comprised of an aldol condensation, alkene isomerization and
IMDA cycloaddition. This domino reaction sequence and the
subsequent chemistry in this manuscript establishes an efficient
asymmetric route to [2.2.2]-diazabicyclic prenylated indole
alkaloids.
The resulting intermediate amino aldehyde would then be poised
to undergo cyclization and reductive amination, effecting the
final annulation to the pyrrolidine ring and delivering the natural
product. In the event, the reduction cascade was capable of
forming the pyrrolidine ring and removing the indole protection;
however, the C6-indole chlorination proved delicate and could
not be preserved under these reaction conditions. Modulation of
reaction conditions was met with no success, and premalbran-
cheamide 3 was consistently observed as the major product.32
When the duration of reaction was shortened to as little as 5 min,
the observed reduction products appeared to lack chlorination as
determined by mass spectrometry. In order to circumvent over-
reduction and loss of the indole halogen, we turned our attention
to an alternative endgame reduction strategy that avoided
catalytic hydrogenation.
Toward this end, the α,β-unsaturated ester 26 was prepared in
analogous fashion by HWE olefination. We envisioned that 1,4-
hydride reduction of 26 followed by iterative 1,2-addition of
hydride to the ester moiety would deliver saturated alcohol 29, an
intermediate that we anticipated could be converted to 2 without
the use of catalytic hydrogenation (Scheme 5). Sodium
borohydride proved competent for this reduction; however,
the formation of allylic alcohol 28 was the dominant product (2:1
ratio) under the initial conditions explored (EtOH, THF, 0 → 50
°C). Although formation of 28 could not be entirely avoided,
inclusion of LiI as an additive and performing the reaction
without protic solvents reversed the dominant product and led to
a 3:1 ratio favoring 29. Following removal of 28 by
chromatography, this reaction provided the desired saturated
material in 58% isolated yield.33 Additional quantities of 29 could
be prepared from allylic alcohol 28 by reduction with diimide
(generated from thermal decomposition of toluenesulfonyl
hydrazide in EtOH).34
EXPERIMENTAL SECTION
■
Experimental conditions and spectral data were published previously for
compounds 13, 19, and 20a,b.15
(S)-1-Methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-
4(3H)-one (14). To a suspension of L-proline methyl ester·HCl (8.04 g,
43 mmol) in CH2Cl2 (86.0 mL) at 0 °C was added NEt3 (12.0 mL, 86
mmol), followed by chloroacetyl chloride (1.1 equiv, 3.72 g, 47 mmol)
dropwise via syringe. The reaction mixture was allowed to warm to rt
with stirring. After 16 h, the mixture was diluted with sat. aqueous
NaHCO3, and the organic layer was removed. The aqueous portion was
extracted with CH2Cl2 (25 mL). The combined organic layers were
washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated
in vacuo to afford N-chloroacetyl-L-proline methyl ester as a brown oil
(7.85 g, 38 mmol). A portion of the resulting oil (5.25 g, 26 mmol) was
dissolved in butanone (51 mL) at rt, and NaN3 (3.67 g, 51 mmol) was
added in one portion. The reaction vessel was fitted with a reflux
condenser, and the heterogeneous mixture was heated at 80 °C for 20 h.
The resulting mixture was filtered and concentrated in vacuo to afford
N-azidoacetyl-L-proline methyl ester as a red oil (5.37 g, 25 mmol). A
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portion of the oil (1.97 g, 9 mmol) was dissolved in anhydrous PhMe
(38 mL), and PPh3 (2.55 g, 10 mmol) was added in one portion. After
gas evolution steadied, the reaction mixture was heated at 90 °C for 20 h.
The reaction mixture was concentrated in vacuo and triturated with a 1:1
mixture of Et2O/hexanes in order to remove the desired DKP from the
bulk of phosphine oxide byproduct. The trituration solution was
concentrated, and the resulting residue was purified by flash column
chromatography on silica gel (elution: 1% MeOH to 10% MeOH in 1:1
EtOAc/PhMe + 1% NEt3). The resulting diketopiperazine lactim ether
product (1.43 g, 8 mmol, 80% yield, 3 steps) was obtained as a light
yellow oil: TLC (60% EtOAc in hexane), Rf 0.20 (CAM); [α]D25 = +102
(c 2.07, CH2Cl2); IR (film) 2951, 2984, 2889, 2360, 2107, 1685, 1457,
20.3; Exact mass calcd for C29H30ClN3O3Na [M + Na]+, 526.1868,
found 526.1862
Oxomalbrancheamide B (18). To a solution of compound 17b (6
mg, 0.012 mmol) in CH2Cl2 (0.5 mL) at 0 °C was added TsOH·H2O (6
mg, 0.029 mmol). The solution was allowed to warm to room
temperature with stirring, and an additional portion of TsOH·H2O (6
mg, 0.029 mmol) was added after 2 h. After a total of 4 h, sat. aqueous
NaHCO3 (2 mL) was added. The aqueous layer was separated and
extracted with EtOAc (4 × 10 mL). The organic layers were combined,
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
unpurified residue (4 mg) was dissolved in toluene (1 mL) and heated to
125 °C in a sealed tube with stirring. After 22 h, heat was removed, and
the solution was concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (elution: 5% MeOH in CHCl3) to afford
product 18 (3.0 mg, 61% yield). 18 was also prepared from 17c as
follows: to a solution of compound 17c (11 mg, 0.021 mmol) in CH2Cl2
(0.5 mL) at 0 °C was added TsOH·H2O (10 mg, 0.053 mmol). The
solution was allowed to warm to room temperature with stirring, and an
additional portion of TsOH·H2O (10 mg, 0.053 mmol) was added after
2 h. After a total of 4 h, sat. aqueous NaHCO3 (2 mL) was added. The
aqueous layer was separated and extracted with EtOAc (4 × 10 mL).
The organic layers were combined, washed with brine, dried (Na2SO4),
and concentrated in vacuo. The unpurified residue (12.4 mg) was
dissolved in toluene (1 mL) and heated to 125 °C in a sealed tube with
stirring. After 17 h, heat was removed, and the solution was concentrated
in vacuo. The residue was purified by flash chromatography on silica gel
(elution: 5% MeOH in CHCl3) to afford product 18 (7.0 mg, 87%
yield). Spectral data were in agreement with published data.21a
Diketopiperazine 21b. To a solution of compounds 20a and 20b15
(200 mg, 0.34 mmol) in CH2Cl2 (33.5 mL) was added TsOH·H2O (70
mg, 0.37 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5
h, and then sat. aqueous NaHCO3 (2 mL) was added. The aqueous layer
was separated and extracted with EtOAc (4 × 10 mL). The unpurified
1
1322, 1263, 1022, 751, 673, 625, 573 cm−1; H NMR (400 MHz,
CDCl3) 4.21 (dd, J = 9.5 Hz, 1.6 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H) 4.03
(m, 1H), 3.68 (s, 3H), 3.65 (m, 1H) 3.47 (m, 1H), 2.25 (m, 1H), 2.03
(m, 1H), 1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.8,
56.5, 53.3, 52.3, 44.2, 29.3, 22.2; Exact mass calcd for C8H12N2O2[M +
Na+], 191.0791, found 191.0790. Spectral data for chloroacyl and
azidoacyl proline intermediate products are in agreement with published
data.38
Cycloadducts 17a, 17b, 17c. To diketopiperazine 14 (18 mg, 0.11
mmol) in MeOH (0.1 mL, degassed with nitrogen) at rt in a sealed tube
was added 13 (20 mg, 0.05 mmol) and a freshly prepared solution of
NaOMe in MeOH (5 equiv, 0.3 mL, 5.0 M). The reaction vessel was
heated to 90 °C (bath temperature) for 68 h. After cooling to rt, the
reaction mixture was diluted with sat. aqueous NH4Cl (1 mL) and
extracted with EtOAc (4 × 5 mL). The combined organic layers were
washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in
vacuo to give a 1.7:1.0:2.9 mixture of cycloadducts 17a, 17b, and 17c as
1
determined by H NMR on the unpurified mixture of products. The
residue was purified by flash chromatography on silica gel (elution: 0−
5% MeOH in CHCl3) to afford products 17a (8.0 mg, 29% yield), 17b
(6.0 mg, 22% yield), and 17c (13.0 mg, 48% yield).
1
product was a 1:2 ratio of diastereomers as judged by H NMR. The
17a: (light yellow oil) TLC (5% MeOH in CHCl3), Rf 0.55 (CAM);
unpurified residue (223.7 mg) was dissolved in toluene (30 mL) and
heated to 110 °C. After 19 h, heat was removed, and the solution was
concentrated in vacuo. The residue was purified by recrystallization from
25% EtOAc in hexane to afford product 21b (127 mg, 65% yield) as a
colorless amorphous solid: TLC (40% EtOAc in hexane) Rf 0.20
IR (film) 1685, 1633, 1476, 1419, 1354, 1324, 1260, 1205, 1179, 1092,
1
1077, 1055, 1001, 920, 886, 838, 799, 740, 702 cm−1; H NMR (400
MHz, CDCl3) 7.50 (d, J = 8.2 Hz, 1H), 7.38−7.30 (m, 5H), 7.19 (s,
1H), 7.10 (dd, J = 8.2, 1.6 Hz, 1H), 5.59 (d, J = 11.3 Hz, 1H), 5.53 (d, J =
11.3 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 3.91
(d, J = 17.6 Hz, 1H), 3.71 (s, 3H), 3.54−3.43 (m, 2H), 3.28 (d, J = 17.2
Hz, 1H), 2.71−2.64 (m, 1H), 2.41 (dd, J = 9.6, 4.1 Hz, 1H), 2.09−1.84
(m, 5H), 1.39 (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
172.2, 170.9, 141.3, 139.3, 137.3, 128.8, 128.2, 128.1, 126.4, 120.6, 120.0,
109.5, 109.4, 73.3, 70.0, 66.8, 64.4, 54.6, 47.6, 43.8, 36.9, 34.5, 29.3, 27.9,
26.4, 24.9, 24.1; Exact mass calcd for C30H32ClN3O3Na [M + Na]+,
540.2024, found 540.2017.
17b: (light yellow oil) TLC (5% MeOH in CHCl3), Rf 0.52 (CAM);
IR (film) 1678, 1638, 1475, 1419, 1356, 1310, 1265, 1200, 1060, 882,
800, 736, 699 cm−1; 1H NMR (400 MHz, CDCl3) 7.46 (d, J = 8.2 Hz,
1H), 7.39−7.30 (m, 5H), 7.18 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.2, 2.0
Hz, 1H), 5.55 (d, J = 5.1 Hz, 2H), 4.56 (d, J = 12.1 Hz, 1H), 4.48 (d, J =
12.1 Hz, 1H), 3.99 (d, J = 16.4 Hz, 1H), 3.80 (s, 3H), 3.51−3.33 (m,
2H), 3.08 (d, J = 16.4 Hz, 1H), 2.68−2.66 (m, 1H), 2.34 (dd, J = 10.4,
5.1 Hz, 1H), 2.04−1.92 (m, 4H), 1.83 (dd, J = 12.9, 5.1 Hz, 1H), 1.42 (s,
3H), 1.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 171.3, 140.7,
139.1, 137.1, 128.5, 128.0, 127.9, 125.7, 120.4, 119.6, 109.9, 109.2, 73.1,
69.7, 65.5, 64.3, 54.5, 54.5, 48.8, 43.4, 36.7, 32.8, 29.3, 27.8, 24.8, 21.4;
Exact mass calcd for C30H32ClN3O3Na [M + Na]+, 540.2024, found
540.2017.
17c: (colorless solid) mp 224.2−225.6 °C; TLC (5% MeOH in
CHCl3), Rf 0.50 (CAM); IR (KBr pellet) 3199, 1691, 1475, 1455, 1199,
1098, 1058, 883, 811, 733, 697 cm−1; 1H NMR (400 MHz, DMSO) 8.76
(s, 1H), 7.57 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.37−7.28 (m, 5H), 7.10
(dd, J = 8.6, 2.0 Hz, 1H), 5.69 (d, J = 10.9 Hz, 1H), 5.64 (d, J = 10.9 Hz,
1H), 4.59 (s, 2H), 3.44 (d, J = 15.6 Hz, 1H), 3.35 (s, 1H), 3.33−3.23 (m,
1H), 2.72 (d, J = 16.0 Hz, 1H), 2.55−2.50 (m, 2H), 2.12−1.81 (m, 5H),
1.36 (s, 3H), 1.09 (s, 3H); 13C NMR (100 MHz, DMSO) δ 173.0, 168.2,
141.5, 138.6, 137.5, 128.3, 127.7, 127.7, 126.8, 125.0, 120.0, 119.1, 109.8,
107.2, 73.1, 69.0, 66.1, 58.9, 50.2, 43.6, 35.8, 30.5, 28.6, 27.1, 24.0, 23.6,
25
(CAM); [α]D = −2.7 (c 0.48, MeOH); IR (KBr pellet) 1721, 1690,
1495, 1474, 1453, 1406, 1370, 1311, 1241, 1204, 1109, 1071, 929, 914,
881 cm−1; 1H NMR (400 MHz, CDCl3) 7.38−7.31 (m, 11H), 7.18 (d, J
= 1.6 Hz, 1H), 7.08 (dd, J = 8.2, 2.0 Hz, 1H), 6.42 (s, 1H), 6.22 (s, 1H),
5.55 (d, J = 10.9 Hz, 1H), 5.52 (d, J = 11.3 Hz, 1H), 4.77 (d, J = 9.4 Hz,
1H), 4.58 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.14 (d, J = 9.8
Hz, 1H), 3.78 (d, J = 15.6 Hz, 1H), 2.68 (t, J = 7.4 Hz, 1H), 2.66 (d, J =
15.6 Hz, 1H), 2.34 (m, J = 7.8 Hz, 2H), 1.49 (s, 3H), 1.32 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.5, 166.1, 140.5, 139.1, 136.3, 129.4,
128.6, 128.6, 128.2, 127.9, 126.5, 125.0, 120.8, 119.2, 109.6, 107.2, 89.3,
73.0, 70.0, 68.4, 65.1, 60.8, 50.6, 36.4, 29.9, 27.8, 25.0, 21.0; Exact mass
calcd for C34H32ClN3O4Na [M + Na]+, 604.1973, found 604.1967.
Aldehyde 22. To a solution of compound 21b (63 mg, 0.11 mmol)
in toluene (1 mL) at 0 °C was added dibal-H (2.10 mL, 1.0 M solution in
toluene). The reaction was stirred for 0.5 h at 0 °C, and then EtOAc (2
mL), potassium sodium tartrate tetrahydrate (100 mg), and water (2
mL) were successively added. The biphasic mixture was stirred rapidly
for 1 h, and the organic layer was removed. The aqueous layer was
extracted with additional EtOAc (3 × 10 mL). The organic layers were
combined, dried (Na2SO4), and concentrated in vacuo. The unpurified
product was a single diastereomer as judged by 1H NMR. The residue
was purified by flash chromatography on silica gel (elution: 45−65%
EtOAc in hexane) to afford the derived intermediate aminoalcohol (not
shown) (49 mg, 80% yield) as a yellow oil. Spectral data were in
agreement with published data.15 A portion of this aminoalcohol
material (43 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) at 0 °C was added
DMSO (55 μL) and iPr2NEt (100 μL, 0.57 mmol). To this solution was
added SO3·pyridine (0.5 M, 450 μL). The solution was stirred for 30
min at 0 °C and extracted with EtOAc (3 × 10 mL). The organic layers
were combined, washed with brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by flash chromatography on silica gel
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The Journal of Organic Chemistry
Article
(elution: 35−100% EtOAc in hexane) to afford product 22 (39 mg, 92%
yield) as a yellow oil: TLC (50% EtOAc in hexane) Rf 0.25 (CAM); [α]D
= +20.9 (c 1.0, CH2Cl2); IR (film) 1733, 1669, 1475, 1454, 1360,
The solution was sparged with H2. After 5 min, the H2 was stopped and
Ar was bubbled through the solution. The suspension was filtered
through Celite and concentrated in vacuo to afford a mixture containing
predominantly product 3 (4.0 mg, 65% yield): TLC (80% EtOAc in
hexane) Rf 0.25 (CAM). Spectral data for 3 were in agreement with
published data.18,23
25
1318, 1266, 1240, 1202, 1132, 1065, 882, 805, 738 cm−1; 1H NMR (400
MHz, CDCl3) 10.23 (s, 1H), 7.43−7.18 (m, 11H), 7.06 (d, J = 8.2 Hz,
2H), 6.44 (s, 1H), 5.53 (s, 2H), 4.57 (s, 2H), 4.28 (d, J = 12.9 Hz, 1H),
3.31 (d, J = 12.9 Hz, 1H), 3.23 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 15.6 Hz,
1H), 2.80 (d, J = 15.2 Hz, 1H), 2.29−2.01 (m, 4H), 1.54 (s, 3H), 1.45 (s,
3H) 13C NMR (100 MHz, CDCl3) δ 198.9, 171.7, 141.2, 138.8, 137.7,
136.7, 128.6, 128.4, 128.4, 128.3 128.2, 127.9, 127.3, 125.0, 120.8, 118.8,
109.7, 106.6, 77.2, 73.0, 70.1, 66.5, 59.4, 59.2, 55.1, 47.3, 35.2, 30.1, 29.5,
28.8, 22.5; Exact mass calcd for C34H34ClN3O3Na [M + Na]+, 590.2181,
found 590.2184.
Saturated Alcohol 29. To a solution of compound 26 (36 mg,
0.059 mmol) in THF (1.0 mL) at 0 °C was added NaBH4 (24 mg, 0.64
mmol) and LiI (76 mg, 0.57 mmol). The solution was warmed to rt, and
additional NaBH4 and LiI (10 equivalents each) were added in three
portions after successive 12 h increments. After 48 h, sat. aqueous
NH4Cl (1 mL) was added. The aqueous layer was separated and
extracted with EtOAc (3 × 10 mL). The organic layers were combined,
washed with brine, dried (Na2SO4), and concentrated in vacuo to give a
1:3 mixture of alcohols 28 and 29 as shown by 1H NMR. The residue
was purified by flash chromatography on silica gel (elution: 50−100%
EtOAc in hexanes) to afford product 29 (20. mg, 58% yield) as a white
solid: mp 92.7−94.2 °C; TLC (60% EtOAc in hexane), Rf 0.15 (CAM);
[α]D 25 = +1.4 (c 0.85, CH2Cl2); IR (film) 1740, 1672, 1473, 1453, 1359,
Weinreb Amide 25. To a solution of compound 22 (39 mg, 0.069
mmol) in acetonitrile (3.8 mL) was added phosphonamide 23 (34 mg,
0.14 mmol), LiCl (23 mg, 0.54 mmol), and DBU (0.026 mL, 0.17
mmol). The solution was stirred at rt for 1 h, and then H2O (2 mL) was
added. The aqueous layer was separated and extracted with EtOAc (3 ×
10 mL). The organic layers were combined, washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (elution: 60−80% EtOAc in hexane) to
afford product 25 (27 mg, 60% yield) as a yellow oil: TLC (60% EtOAc
in hexane) Rf 0.20 (CAM); [α]D25 = +8.9 (c = 0.09, CH2Cl2); IR (film)
1682, 1629, 1472, 1455, 1418, 1374, 1313, 1241, 1204, 1131, 1061, 999,
882, 800, 753 cm−1; 1H NMR (400 MHz, CDCl3) 7.52−7.13 (m, 14H),
7.05 (dd, J = 8.4, 1.8 Hz, 1H), 6.33 (s, 1H), 5.55 (s, 2H), 4.57 (d, J = 0.8
Hz, 2H), 4.28 (d, J = 13.7 Hz, 1H), 3.68 (s, 3H), 3.27 (s, 3H), 3.27 (d, J =
10.9 Hz, 1H), 3.13 (d, J = 13.3 Hz, 1H), 2.83 (q, J = 15.2 Hz, 2H), 2.30−
2.25 (m, 2H), 2.10−2.04 (m, 2H), 1.58 (s, 3H), 1.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.0, 143.2, 141.5, 138.9, 138.5, 136.8, 128.6,
128.4, 128.3, 128.2, 128.1, 128.0, 127.0, 125.1, 122.0, 120.8, 118.7, 109.8,
106.8, 73.1, 70.2, 62.0, 61.9, 60.1, 59.3, 54.9, 47.8, 35.1, 35.0, 30.3, 30.2,
22.5; Exact mass calcd for C38H41ClN4O4Na [M + Na]+, 675.2709,
found 675.2702.
1
1318, 1240, 1205, 1059, 882, 802, 746 cm−1; H NMR (400 MHz,
CDCl3) 7.40−7.13 (m, 12H), 7.04 (d, J = 8.2 Hz, 1H), 6.56 (s, 1H), 5.54
(s, 2H), 4.56 (s, 2H), 4.27 (d, J = 12.9 Hz, 1H), 3.78−3.72 (m, 2H), 3.11
(d, J = 10.9 Hz, 1H), 3.06 (d, J = 12.5 Hz, 1H), 2.81 (d, J = 15.6, 1H),
2.76 (d, J = 15.2, 1H), 2.48 (s, 1H), 2.27 (dd, J1 = 13.3, J2 = 4.3 Hz, 1H),
2.20 (d, J = 11.3 Hz, 1H), 2.07−1.98 (m, 2H), 1.93 (d, J = 11.7, 2H),
1.88−1.83 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.4, 141.6, 138.8, 138.5, 136.8, 128.6, 128.4, 128.3, 128.2,
127.9, 127.0, 125.1, 120.8, 118.7, 109.7, 106.8, 77.2, 73.1, 70.1, 62.7,
60.2, 59.6, 57.3, 54.5, 47.3, 35.1, 30.4, 30.2, 30.1, 26.9, 26.4, 22.3; Exact
mass calcd for C36H40ClN3O3Na [M + Na]+, 620.2650, found 620.2643.
Alcohol 29 can also be prepared from 28 as follows. To a solution of
compound 28 (6.0 mg, 0.0092 mmol) in EtOH (0.4 mL) at rt was added
4-methylbenzene sulfonhydrazide (2 mg, 0.010 mmol) and NaOAc (1
mg, 0.010 mmol). The solution was heated to reflux, and additional
portions (0.010 mmol) of sulfonhydrazide and NaOAc were added after
2 h. After 6.5 h at reflux, heat was removed, and the solution was
concentrated in vacuo. Sat. aqueous Na2CO3 (2 mL) and EtOAc (2 mL)
were added to the residue, and the aqueous layer was separated and
extracted with additional EtOAc (3 × 5 mL). The organic layers were
combined, washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash chromatography according to
the above procedure to afford 29 (3.3 mg, 60% yield) as a white solid.
Malbrancheamide B (2). To a solution of compound 29 (24 mg,
0.040 mmol) in CH2Cl2 (0.4 mL) at 0 °C was added pyridine (6.3 μL,
0.079 mmol) and MsCl (3.4 μL, 0.043 mmol). The solution was allowed
to warm to rt with stirring, and additional portions of MsCl (3.4 μL,
0.043 mmol) were added every 3 h. After a total of 12 h, sat. aq.
NaHCO3 (2 mL) was added. The aqueous layer was separated and
extracted with EtOAc (3 × 10 mL). The organic layers were combined,
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
resulting residue (22 mg) was dissolved in toluene (2 mL) and heated to
125 °C in a sealed tube with stirring. After 10 h, heat was removed, and
the solution was concentrated in vacuo. To a solution of the unpurified
residue (18 mg) in toluene (1.5 mL) was added KI (6.0 mg, 0.035
mmol) and NEt3 (0.15 mL) in a sealed tube. The solution was heated to
125 °C and stirred for 20 h. After 20 h, heat was removed, and the
solution was concentrated in vacuo. To a solution of the unpurified
residue (13 mg) in CH2Cl2 (2.6 mL) was added TsOH·H2O (15.8 mg,
0.083 mmol) at 0 °C. The solution was allowed to warm to rt with
stirring, and an additional portion of TsOH·H2O (14 mg, 0.072 mmol)
was added after 2 h. After a total of 4 h, NaHCO3 (2 mL) was added. The
aqueous layer was separated and extracted with EtOAc (4 × 10 mL).
The organic layers were combined, washed with brine, dried (Na2SO4),
and concentrated in vacuo. The product was purified by flash
chromatography on silica gel (elution: 0−10% MeOH in CHCl3) to
afford product 2 (6.0 mg, 40% yield) as an amorphous colorless solid:
Methyl Ester 26. To a solution of compound 22 (110 mg, 0.19
mmol) in acetonitrile (10 mL) was added trimethyl phosphonoacetate
24 (0.065 mL, 0.40 mmol), LiCl (67 mg, 1.60 mmol), and DBU (0.075
mL, 0.50 mmol). The solution was stirred at rt for 1 h, and then H2O (2
mL) was added. The aqueous layer was separated and extracted with
EtOAc (3 × 10 mL). The organic layers were combined, washed with
brine, dried (Na2SO4), and concentrated in vacuo to give a 3:1 mixture
of E and Z isomers of 26 as shown by 1H NMR. The residue was purified
by flash chromatography on silica gel (elution: 40−100% EtOAc in
hexane) to afford product 26 (110 mg, 91% yield) as a yellow oil: TLC
(40% EtOAc in hexane) Rf 0.40 (CAM); [α]D25 = +7.9 (c 2.4, CH2Cl2);
IR (film) 1724, 1685, 1608, 1562, 1495, 1475, 1454, 1359, 1308, 1241,
1
1202, 1174, 1131, 1062, 882, 803, 740 cm−1; H NMR (400 MHz,
CDCl3) 7.51 (d, J = 16.4 Hz, 1H), 7.38−7.18 (m, 12H), 7.05 (d, J = 8.2,
1H), 6.63 (d, J = 16.4 Hz, 1H), 5.55 (s, 2H), 4.60−4.54 (m, 2H), 4.25 (d,
J = 12.9 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 1H), 3.26 (d, J = 10.9 Hz, 1H),
3.13 (d, J = 13.3 Hz, 1H), 2.89−2.81 (m, 2H), 2.25−2.05 (m, 4H), 1.58
(s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 166.8,
145.2, 141.3, 138.8, 138.3, 136.8, 128.6, 128.4, 128.3, 128.3, 128.2, 128.1,
128.0, 127.9, 127.1, 125.0, 124.1, 120.8, 120.7, 118.8, 109.7, 106.8, 77.2,
73.0, 70.1, 61.6, 59.8, 59.3, 54.9, 51.7, 47.8, 35.1, 34.6, 30.3, 30.0, 24.3,
22.4; Exact mass calcd for C37H38ClN3O4Na [M + Na]+, 646.2443,
found 646.2436.
Premalbrancheamide (3). To a solution of compound 25 (26 mg,
0.39 mmol) in PhMe (1 mL) at −78 °C was added a solution of dibal-H
(1.0 M in PhMe, 0.20 mL). The solution was stirred for 1 h, and then
MeOH (1 mL), HCl (1 mL), EtOAc (1 mL), and potassium sodium
tartrate·4H2O (50 mg) was added. After an additional 1 h of stirring, the
aqueous layer was separated and extracted with EtOAc (3 × 10 mL).
The organic layers were combined, dried (Na2SO4), and concentrated in
vacuo. The residue was quickly purified by flash chromatography on
silica gel (elution: 40−100% EtOAc in hexanes) to afford product 27
(15.5 mg, 67% yield) as a light yellow oil. Aldehyde 27 was unstable and
prone to decomposition; accordingly, the product was used immediately
in the following reduction sequence. To a solution of compound 27 (7.0
mg, 0.015 mmol) in MeOH (1.0 mL) was added Pd/C (17 mg) at rt.
25
TLC (5% MeOH in CHCl3), Rf 0.50 (CAM); [α]D = +25 (c 0.4,
MeOH), Lit.16 [α]D = +50 (c 1, MeOH), Lit.22 (−)-2, [α]D = −36 (c
0.81, MeOH), Lit.17 [α]D = +28 (c 0.5, MeOH); HPLC trace and UV
signature identical for both synthetic and an authentic natural sample of
2427
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Article
2; Mobile phase, gradient mixture of H2O + 0.1% TFA/MeCN, 1.0 mL/
min; 0−10 min 20% MeCN, 10.01−20 min 20−50% MeCN);
Phenomenex C18 Luna (250 mm × 4.6 mm × 5 μm), retention time
15.17 min; UV λ 230, 283 nm; IR (film) 1653, 1465, 1361, 1319, 1291,
1253, 1227, 1198, 1131, 1099, 1059, 1024, 904, 797 cm−1; Exact mass
calcd for C21H24ClN3O [M + H]+, 370.1681, found 370.1677. 1H and
13C NMR spectral data for synthetic material both match the data for the
authentic sample and are in agreement with published data.21,22,16b
Sherman, D. H. Med. Chem. Commun. 2012, 3, 987−996. (b) Li, S. Y.;
Finefield, J. M.; Sunderhaus, J. D.; McAfoos, T. J.; Williams, R. M.;
Sherman, D. H. J. Am. Chem. Soc. 2012, 134, 788−791. (c) Sunderhaus,
J. D.; Sherman, D. H.; Williams, R. M. Isr. J. Chem. 2011, 51, 442−452.
(d) Ding, Y. S.; de Wet, J. R.; Cavalcoli, J.; Li, S. Y.; Greshock, T. J.;
Miller, K. A.; Finefield, J. M.; Sunderhaus, J. D.; McAfoos, T. J.;
Tsukamoto, S.; Williams, R. M.; Sherman, D. H. J. Am. Chem. Soc. 2010,
132, 12733−12740.
(12) (a) Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711−740.
(b) Williams, R. M.; Stocking, E. M.; Sanz- Cervera, J. F. Top. Curr.
Chem. 2000, 209, 97−173.
ASSOCIATED CONTENT
* Supporting Information
■
S
(13) Additional strategies not encompassed in the review: (a) Frebault,
F. C.; Simpkins, N. S. Tetrahedron 2010, 66, 6585−6596. (b) Frebault,
F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc. 2009, 131, 4214−
4215. (c) Crick, P. J.; Simpkins, N. S.; Highton, A. Org. Lett. 2011, 13,
6472−6475. (d) Simpkins, N.; Pavlakos, I.; Male, L. Chem. Commun.
2012, 48, 1958−1960.
(14) Morris, E. N.; Nenninger, E. K.; Pike, R. D.; Scheerer, J. R. Org.
Lett. 2011, 13, 4430−4433.
(15) Margrey, K. A.; Chinn, A. J.; Laws, S. W.; Pike, R. D.; Scheerer, J.
R. Org. Lett. 2012, 43, 2458−2461.
(16) (a) Martinez-Luis, S.; Rodriguez, R.; Acevedo, L.; Gonzalez, M.
C.; Lira-Rocha, A.; Mata, R. Tetrahedron 2006, 62, 1817−1822.
(b) Figueroa, M.; Gonzalez, M. D. C.; Mata, R. Nat. Prod. Res. 2008,
22, 709−714.
(17) Watts, K. R.; Loveridge, S. T.; Tenney, K.; Media, J.; Valeriote, F.
A.; Crews, P. J. Org. Chem. 2011, 76, 6201−6208.
(18) Miller, K. A.; Figueroa, M.; Valente, M. W. N.; Greshock, T. J.;
Mata, R.; Williams, R. M. Bioorg. Med. Chem. Lett. 2008, 18, 6479−6481.
(19) Several selective PDE1 are currently used in the clinic, including
sildenafil and Zaprinast. For reviews on PDE inhibition and the
therapeutic effects and potential application, see: (a) Bender, A. T.;
Beavo, J. A. Pharmacol. Rev. 2006, 58, 488−520. (b) Menniti, F. S.;
Faraci, W. S.; Schmidt, C. J. Nat. Rev. Drug Discovery 2006, 5, 660−670.
(c) Sharma, R. K.; Das, S. B.; Lakshmikuttyamma, A.; Selvakumar, P.;
Shrivastav, A. Int. J. Mol. Med. 2006, 18, 95−105.
(20) (a) Schmidt, C. J. Curr. Top. Med. Chem. 2010, 10, 222−230.
(b) Monti, B.; Contestabile, A. Mini-Rev. Med. Chem. 2009, 9, 769−781.
(21) (a) Miller, K. A.; Welch, T. R.; Greshock, T. J.; Ding, Y. S.;
Sherman, D. H.; Williams, R. M. J. Org. Chem. 2008, 73, 3116−3119.
(b) Valente, M. W. N.; Williams, R. M. Heterocycles 2006, 70, 249−259.
(22) (a) Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc.
2009, 131, 4214−4215. (b) Frebault, F. C.; Simpkins, N. S. Tetrahedron
2010, 66, 6585−6596.
(23) (a) Ding, Y. S.; Greshock, T. J.; Miller, K. A.; Sherman, D. H.;
Williams, R. M. Org. Lett. 2008, 10, 4863−4866. (b) Ding, Y. S.;
Williams, R. M.; Sherman, D. H. J. Biol. Chem. 2008, 283, 16068−16076.
(24) Tietze, L. F. Chem. Rev. 1996, 96, 115−136.
(25) The BOM indole N-protecting group was necessary to effect the
domino reaction sequence. Reaction with the unprotected indole did
not afford any desired product; rather, deformylation of the indole was
observed.
Spectroscopic data and experimental details for the preparation
of all new compounds as well as 1H NMR and 13C NMR spectra.
This information is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jrscheerer@wm.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Donors of the ACS Petroleum
Research Fund and the Research Corporation for Scientific
Advancement. We acknowledge Professor David Sherman (Life
Sciences Institute and Departments of Medicinal Chemistry,
Chemistry, Microbiology & Immunology at the University of
Michigan) and Professor Robert Williams (Colorado State
University, Department of Chemistry) for an authentic sample of
malbrancheamide B.
REFERENCES
■
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Article
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lectivity nor stereochemistry was clearly established on this material.
Rather, this intermediate was directly subjected to N-dealkylation
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