Total syntheses of indolactam alkaloids (-)-indolactam V, (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2

Article abstract of DOI:10.1039/c4sc00256c

We report the total syntheses of (-)-indolactam V and the C7-substituted indolactam alkaloids (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2. The strategy for preparing indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish the C4-N linkage, in addition to an intramolecular conjugate addition to build the conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage sp²-sp³ cross-couplings on an indolactam V derivative are used to introduce the key C7 substituents and the necessary quaternary carbons. These challenging couplings, in addition to other delicate manipulations, all proceed in the presence of a basic tertiary amine, an unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform for probing complexity-generating and chemoselective transformations in the context of alkaloid total synthesis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00256c

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DOI: 10.1039/C4SC00256C
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Total syntheses of indolactam alkaloids (–)-
indolactam V, (–)-pendolmycin, (–)-lyngbyatoxin A,
and (–)-teleocidin A-2
Cite this: DOI: 10.1039/x0xx00000x
Noah F. Fine Nathel,† Tejas K. Shah,† Sarah M. Bronner, and Neil. K. Garg*
Received 00th January 2014,
Accepted 00th January 2014
We report the total syntheses of (–)-indolactam V and the C7-substituted indolactam alkaloids
(–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The strategy for preparing
indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish
the C4–N linkage, in addition to an intramolecular conjugate addition to build the
conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets
the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage
sp2–sp3 cross-couplings on an indolactam V derivative are used to introduce the key C7
substituents and the necessary quaternary carbons. These challenging couplings, in addition to
other delicate manipulations, all proceed in the presence of a basic tertiary amine, an
unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables
the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform
for probing complexity-generating and chemoselective transformations in the context of
DOI: 10.1039/x0xx00000x
www.rsc.org/
alkaloid total synthesis
.
of the C7-linked quaternary carbon, followed by assembly of
the indole core.11,12
Introduction
Natural products belonging to the family of indolactam
alkaloids1 (e.g., 1–4, Figure 1) have been widely studied for
their pharmacological properties. The most well-known of these
compounds is indolactam V (1), which was first isolated in
1984.2 Indolactam V (1) functions as an efficient tumor
promoter as a result of its ability to bind to protein kinase C
(PKC). Accordingly, 1 has been used in a variety of studies to
better understand mammalian tumor growth.3,4 Similarly, C7-
substituted indolactams 2–4 have been valued for their tumor-
promoting abilities. It should be noted that each of 1–4 and
their derivatives exhibit biological functions which range from
stem-cell differentiation5 to anti-bacterial,6 anti-malarial7 and
anti-cancer8 activities.
Me
N
Me
OH
Me
Me
O
H
OH
Me
N
H
N
Me
N
O
4
3
N
H
7
N
H
Me
Me
(–)-indolactamV (1)
(tumor promoter;
stem cell differentiator)
(–)-pendolmycin (2)
(tumor promoter)
Me
N
Me
O
Me
N
Me
O
OH
OH
H
N
H
N
Me
Me
The attractive biological profiles of indolactam alkaloids
have prompted numerous synthetic investigations. These efforts
have led to several total syntheses of 1,9,10 as well as completed
syntheses of 2–4.11,12 A central challenge to accessing each of
these alkaloids involves assembly of the parent 3,4-
disubstituted indole framework possessing a conformationally-
flexible13 9-membered lactam. To this end, most strategies to
access the medium-sized ring have involved amide bond
formation as the key step.9 With regard to 2–4, introduction of
the C7 sp2–sp3 linkage presents an additional challenge. The
few successful approaches to 2–4 all involve early introduction
N
H
Me
N
H
Me
7
7
Me
Me
Me
Me
(–)-lyngbyatoxin A (3)
(skin tumor promoter;
stem cell differentiator;
(–)-teleocidin A-2 (4)
(tumor promoter)
cervical carcinoma cytotoxicity)
Fig. 1 Indolactam alkaloids 1–4.
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DOI: 10.1039/C4SC00256C
We envisioned a strategically distinct approach to indolactam V
(1) and related C7-substituted alkaloids 2–4, which is
summarized in Scheme 1. Specifically, the 9-membered ring
would be introduced through two key steps from an appropriate
indole building block: namely, intermolecular assembly of the
C4–N bond and ring closure at C3. This would be implemented
in practice by accessing an indolyne in situ,14,15,16 which would
undergo selective C4-trapping by an amine nucleophile (5→6).
Elaboration of adduct 6 to ester 7 would be followed by a
challenging conjugate addition at C3 to forge the 9-membered
ring en route to 1. We hypothesized that 1 could be used as a
precursor to the C7-substituted indolactam alkaloids, without
the use of N-protecting groups. Our unique divergent strategy
would require the use of efficient cross-couplings to build the
sp2–sp3 C–C linkages and introduce the quaternary carbons
(1→8→2–4). Achieving alkylative cross-couplings at C7 of
indoles can be difficult, and only a few such examples are
known in the presence of unprotected indole nitrogens.17
Moreover, to our knowledge, there are no examples of sp2–sp3
cross-couplings to introduce quaternary C7 substituents on
indole substrates in the literature.
Results and discussion
Optimization of the total synthesis of indolactam V (1)
Although our previous studies toward 1 validated our approach,
we sought to improve several key steps of our formal
synthesis10 and render the route suitable for scale-up (Scheme
2). We first optimized the synthesis of indolyne precursor 9,
which can now be obtained in 7 steps from commercially
available materials in 62% overall yield (previously 27% yield,
over 7 steps).18 Next, treatment of silyltriflate 9 with peptide 10
in the presence of CsF in acetonitrile efficiently furnished
indolyne adduct 11 and established the key C4–N linkage.19,20
The regioselectivity in the indolyne trapping is governed by
aryne distortion,15a,b which arises from the presence of the
inductively-withdrawing C6 bromide substituent.10 After
elaborating 11 to α,β-unsaturated ester 7, ZrCl4-mediated
cyclization21 provided 12 as a single diastereomer in 90%
yield.22 As 12 possesses the undesired stereochemical
configuration at C9, we developed optimal conditions to
facilitate its epimerization based on the protocol reported by
Nakatsuka.9c Treatment of 12 with NaHCO3 in MeOH at 40 °C
delivered a separable mixture of recovered 12 and the desired
epimer 13. Reduction of 13 delivered indolactam V (1), which
was subsequently protected to give silyl ether 14 in 90% yield
over two steps. Using our optimized route, we have prepared
over 500 mg of 14 for use in subsequent functionalization
efforts.
Me
N
Me
O
Me
R
Me
R
H
N
N
H
N
Me
CO2Me
4
4
3
5
N
H
X
N
H
X
N
H
5
6
7
Me
N
Me
O
OR'''
Me
N
Me
O
H
N
OH
Me
H
pendolmycin (2)
Me
N
lyngbyatoxin A (3)
teleocidin A-2 (4)
3
N
H
7
N
H
R'
R''
Me
indolactam V (1)
8
Synthetic Challenges
• Regioselective indolyne trapping to forge C4–N bond
• Cyclization at C3 to build 9-membered ring
• Late-stage introduction of C7 substituent
(sp2–sp3 C–C bond, quaternary carbon)
• Late-stage manipulations with free NHs and tertiary amine
Scheme 1 Synthetic strategy toward 1 and C7 substituted indolactam alkaloids
2–4.
We herein describe the enantiospecific total syntheses of
indolactam alkaloids 1–4. As we have previously reported a
formal total synthesis of 1,10 aside from a brief discussion of
optimization of key steps, this manuscript focuses on C7
functionalization studies and the divergent total syntheses of the
less well-studied targets 2–4. This study not only leads to the
generation of several natural products enantiospecifically, but
also serves as an exercise aimed at probing complexity-
generating and chemoselective transformations in alkaloid total
synthesis.
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DOI: 10.1039/C4SC00256C
Me
Me
O
O
substrate 15 (entry 5). By simply increasing the catalyst loading
to 5 mol%, full conversion to product 16b was observed (entry
6). Zinc enolate 22, which was generated in situ from the
corresponding α-bromoamide, was also evaluated as a potential
coupling partner using Hartwig’s methodology.27 Although no
reaction was observed using literature conditions (entry 7), we
found that the desired product 16c could be obtained under
more forcing conditions (i.e., 15 mol% Pd and 80 °C) (entry 8).
It should be noted that desbromo compound 17 and dimer 18
were also formed in minor quantities. To our knowledge, the
successful formation of 16b and 16c represents the first
simultaneous formation of an sp2–sp3 bond and quaternary
center at the C7 position of an indole with an unprotected
nitrogen.
H
N
Me
Me
N
Me
O
N
H
OMe
O
H
N
TMS
4
Me
OH
3 Steps
OMe
TfO
Br
10
5
6
4
CsF, CH3CN
0 ! 23 °C
OH
N
H
N
H
6
Br
(75% yield)
9
(7 steps,
62% yield)
11
Me
N
Me
Me
N
Me
O
H
N
H
N
Me
Me
9
CO2Me
OMe
ZrCl4
O
3
O
3
CH2Cl2, 34 °C
(90% yield)
N
H
N
H
7
12
Table 1 C7 sp2–sp3 cross-coupling on model substrate 15.
Me
Me
O
O
H
N
9
NaHCO3
MeOH, 40 °C
Me
LiBH4
THF, 0 ! 23 °C
Me
N
OMe
Me
Me
Me
19, 20,
21 or 22
+
+
N
H
(50% yield and
45% recovered12)
N
H
N
H
Pd
catalysis
N
H
N
H
7
O
Me
Me
Br
13
2
X
15
17
18
Me
Me
O
16a; X = H
16b; X = OMe
16c; X = morpholine
Me
N
Me
O
OTBS
OH
H
N
H
N
Me
TBSCl, TBAI
imidazole
Me
N
ratiob
15:16:17:18
cross-coupling
partner
conditionsa
entry
DMF, 23 °C
c
2 mol% Pd(OAc)2, Ligand 23
(90% yield, 2 steps)
N
H
Me
1
3.7 : 0 : 1 : 0
19
H
N
H
7
Cs2CO3, dioxane, 80 °C
Me
indolactam V (1)
Scheme 2 Optimized synthesis of indolactam V (1) and 14.
14
c
2 mol% Pd(OAc)2, Ligand 23
2
1 : 0 : 0 : 0
O
LiNCy2, dioxane, 80 °C
1 mol% Pd(dba)2, P(t-Bu)3
LiNCy2, toluene, 23 °C
Cross-coupling to introduce the C7 sp2–sp3 linkage and the key
quaternary carbon
20
Me
3
4
1 : 0 : 0 : 0
1 : 0 : 0 : 0
MeO
Me
Me
5 mol% Pd(dba)2, P(t-Bu)3
LiNCy2, toluene, 23 °C
O
With access to late-stage compound 14, we turned our attention
to the previously unexplored divergent approach to alkaloids 2–
4. One of the most challenging aspects of this strategy involves
functionalization of C7. Importantly, the methodology would
have to build a new sp2–sp3 C–C linkage, containing a
quaternary center, on an unprotected indole. In general, sp2–sp3
couplings are far less common compared to their sp2–sp2
counterparts and, as mentioned previously, no examples of such
couplings to introduce quaternary carbons at C7 of indoles are
available.
Me
1 mol% Pd(dba)2, P(t-Bu)3
ZnF2, DMF, 80 °C
21
5
6
1 : 3 : 0 : 0
0 : 1 : 0 : 0
MeO
5 mol% Pd(dba)2, P(t-Bu)3
ZnF2, DMF, 80 °C
OTMS
2.5 mol% [P(t-Bu)3PdBr]2
toluene, 23 °C
O
Me
7
8
1 : 0 : 0 : 0
N
Me
15 mol% [P(t-Bu)3PdBr]2
toluene, 80 °C
0 : 11.3 : 2.1 : 1
22
OZnX
We tested the viability of our alkylative coupling strategy
using readily available unprotected bromoindole substrate 15
(Table 1). Enolate precursors 19–22 were examined, as the
carbonyls in the presumed products could plausibly be
elaborated to the olefins present in 2–4. Unfortunately, attempts
to use isobutyraldehyde (19) as the coupling partner23 led
predominantly to the recovery of starting material 15 with or
without formation of desbromo indole 17 (entries 124 and 2,
respectively). We also tested ester 20 as a coupling partner,25
but only observed recovered substrate 15 (entries 3 and 4).
Next, silylketene acetal 21 was employed in the desired
coupling.26 To our delight, using 1 mol% Pd(dba)2, some of the
desired product 16b was formed, albeit with recovered
a
b
For detailed reaction conditions, see the ESI. Ratios determined by 1H
NMR analysis of the crude reaction mixtures. c Ligand 23 = diisopropyl[2’-
methoxy-1,1’-binaphthalen]-2-yl.
Total synthesis of (–)-pendolmycin (2)
Our promising results for the cross-coupling on the model
system prompted us to shift our efforts to the complex
indolactam scaffold (Scheme 3). Treatment of 14 with NBS led
to C7 bromination to furnish 24.28 Next, the critical coupling
reactions using the aforementioned conditions (see Table 1,
entries 6 and 8) were tested. Despite our previous success in
coupling silylketene acetal 21, attempts to effect the
corresponding coupling on indolylbromide 24 led to no
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Total synthesis of lyngbyatoxin A and teleocidin A-2
reaction. However, the coupling of bromide 24 with zinc
enolate 22 delivered cross-coupled product 25 in 61% yield. As
this complexity-generating transformation proceeds on an
advanced late-stage intermediate in the presence of two free
NHs and a tertiary amine to introduce an sp2–sp3 linkage with a
quaternary carbon, its success demonstrates the exceptional
tolerance and utility of Hartwig’s parent methodology.27
Although structurally similar to pendolmycin (2), lyngbyatoxin
A (3) and teleocidin A-2 (4) present additional degrees of
complexity. Specifically, the sidechains appended to C7 of the
indole each contain a quaternary stereocenter, in addition to an
electron-rich olefin. We envisioned that both natural products 3
and 4 could be obtained from bromoindole 24 (see Scheme 3)
and a prochiral cross-coupling partner.
Me
MeO
Me
To enable this approach, we prepared amide 29 and tested
the key cross-coupling reaction (Figure 2). Ester 28, which was
obtained from commercial sources, first underwent α-
bromination under standard conditions.31 Subsequent
saponification,32 followed by CDI-mediated coupling with
morpholine, afforded amide 29.33 Reaction of amide 29 with Zn
metal resulted in conversion to the corresponding zinc enolate
30. Gratifyingly, treatment of bromoindole 24 with in situ-
generated enolate 30 under Pd-catalyzed coupling conditions
gave the desired diastereomeric products 31 and 32 in 75%
21
OTMS
no reaction
Me
N
Me
O
Pd(dba)2 (5 mol%)
ZnF2, P(t-Bu)3
DMF, 80 °C
OTBS
H
N
Me
Me
N
Me
O
OTBS
H
N
Me
O
Me
N
N
H
Me
X
22
OZnX
N
H
Me
[P(t-Bu)3PdBr]2
(15 mol%), 80 °C
toluene
NBS, THF
–78 !
–15 °C
O
14 (X = H)
24 (X = Br)
25
Me
1
combined yield (d.r. = 1:1 by H NMR analysis).34 Isomers 31
N
O
(87% yield)
(61% yield)
and 32 were separable by silica gel chromatography.35 The
formation of 31 and 32 represents the first implementation of
Hartwig’s amide enolate coupling methodology in the assembly
of stereogenic quaternary carbons.27
Scheme 3 C7 functionalization of 14 and introduction of key sp2–sp3 linkage with
a quaternary carbon substituent.
Having installed the necessary C7 substituent and the key
quaternary carbon, we were able to complete the total synthesis
of pendolmycin (2), as shown in Scheme 4. The morpholine
amide of 25, which neighbors the sterically-congested
quaternary carbon, was selectively reduced with the Schwartz
reagent (i.e., Cp2Zr(H)Cl)29 to furnish aldehyde 26. Of note,
competitive reduction of the secondary amide was not
observed.30 Subsequent Wittig olefination of 26 provided the
penultimate compound 27. Finally, exposure of 27 to TBAF in
THF revealed the primary alcohol to deliver (–)-pendolmycin
(2). This three-step sequence provides a concise means to
convert amide 25 to the natural product (2), without the use of
N-protecting groups.
Me
Me
O
Me
Br Me
1. LDA, TMSCl, THF;
NBS, –78 ! 23 °C
MeO
N
Me
Me
2. LiOH, THF
H2O, 0 °C
3. CDI, morpholine
CH2Cl2, 23 °C
O
O
28
29
(71% yield, 3 steps)
Me
N
Me
OTBS
H
N
Me
Me
Me
OTBS
Me
O
Me
Me
H
N
Me
O
N
N
OZnX
30
O
N
H
Me
[P(t-Bu)3PdBr]2 (15 mol%)
LiBr (1 equiv)
O
N
H
Me
THF/toluene, 80 °C
Me
Br
N
O
24
31 + 32
(dr: 1:1)
(75% yield)
Me
N
Me
OTBS
Me
N
Me
O
H
N
OTBS
Me
H
N
Fig.
2
Synthesis of morpholine amide 29 and cross-coupling to access
diastereomeric adducts 31 and 32 possessing the necessary all-carbon
quaternary stereocenters.
Me
O
BrPPh3CH3
t-BuOK
Cp2Zr(H)Cl
THF, 60 °C
N
H
Me
THF, 0 ! 23 °C
N
H
O
With coupled products 31 and 32 in hand, we completed the
total syntheses of (–)-lyngbyatoxin A (3) and (–)-teleocidin A-2
(4), respectively (Schemes 5 and 6). Amide 31 was reduced to
aldehyde 33, which in turn, underwent Wittig homologation to
give 34 (Scheme 5). To complete the total synthesis of (–)-
lyngbyatoxin (3), it was necessary to deprotect the primary
alcohol in 34. Although attempts to employ TBAF led to
decomposition, we found that exposure of 34 to LiBF4 and
camphorsulfonic acid (CSA) in THF at ambient temperature
afforded natural product 3.28,36 We were delighted to find that
the analogous 3-step reaction sequence facilitated the
conversion of diastereomer 32 to (–)-teleocidin A-2 (4) as
O
(52% yield, 2 steps)
Me
Me
Me
N
O
H
25
26
Me
Me
O
Me
N
Me
OH
H
OTBS
H
N
Me
Me
N
N
TBAF
THF
O
N
H
N
H
(70% yield)
Me
Me
Me
Me
(–)-pendolmycin (2)
27
Scheme 4 Total synthesis of (–)-pendolmycin (2).
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DOI: 10.1039/C4SC00256C
summarized in Scheme 6. Spectral data for our synthetic
samples of natural products 2–4 matched literature reports.11,12
Acknowledgements
The authors are grateful to the NIH-NIGMS (R01 GM090007),
Boehringer Ingelheim, DuPont, Eli Lilly, Amgen, AstraZeneca,
Roche, Bristol–Myers Squibb, the A. P. Sloan Foundation, the
Dreyfus Foundation, the S.T. Li Foundation, and the University
of California, Los Angeles, for financial support. N.F.F.N.
acknowledges the NIH for a predoctoral fellowship (F31
GM101951-02) and S.M.B. thanks the Foote Family and the
Stauffer Charitable Trust for their generous support. We thank
the Garcia–Garibay laboratory (UCLA) for access to
instrumentation and Dr. John Greaves (UC Irvine) for mass
spectra. These studies were supported by shared
instrumentation grants from the NSF (CHE-1048804) and the
National Center for Research Resources (S10RR025631).
Me
N
Me
O
OTBS
H
N
Me
N
Me
O
Me
OTBS
H
N
Me
BrPPh3CH3
t-BuOK
Cp2Zr(H)Cl
N
H
Me
THF, 50 °C
THF, 0 ! 23 °C
O
N
H
Me
Me
(64% yield,
2 steps)
Me
O
N
O
Me
Me
H
31
33
Me
Me
Me
N
Me
OTBS
OH
H
N
H
N
Me
Me
N
LiBF4, CSA
THF, 23 °C
(63% yield)
O
O
Notes and references
N
H
Me
N
H
Me
Department of Chemistry and Biochemistry, University of California, 607
Charles Young Drive East, Box 951569, Los Angeles, CA 90095, USA.
E-mail: neilgarg@chem.ucla.edu
Me
Me
Me
Me
34
(–)-lyngbyatoxin A (3)
Scheme 5 Total synthesis of (–)-lyngbyatoxin A (3).
†
Authors contributed equally to this work.
Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/b000000x/
Me
N
Me
O
OTBS
H
N
Me
N
Me
O
Me
OH
H
N
Me
3 steps
N
H
Me
(46% yield)
O
N
H
Me
Me
Me
N
O
Me
Me
(–)-teleocidin A-2 (4)
32
Scheme 6 Total synthesis of (–)-teleocidin A-2 (4).
Conclusions
1
For pertinent reviews on (–)-indolactam V isolation, tumor-
promoting activity, and derivatives, see: (a) K. Irie and K.
Koshimizu, Mem. Coll. Agric. Kyoto Univ., 1988, 132, 1–59.
(b) K. Irie and K. Koshimizu, Comments Agric. Food Chem.,
1993, 3, 1–25. (c) K. Irie Nippon Nogei Kagaku Kaishi, 1994,
68, 1289–1296. (d) K. Irie, Y. Nakagawa and H. Ohigashi,
Curr. Pharm. Des., 2004, 10, 1371–1385. (e) K. Irie, Y.
Nakagawa and H. Ohigashi, Chem. Rec., 2005, 5, 185–195.
K. Irie, M. Hirota, N. Hagiwara, K. Koshimizu, H. Hayashi, S.
Murao, H. Tokuda and Y. Ito, Agric. Biol. Chem., 1984, 48,
1269–1274.
We have completed the total syntheses of four indolactam
alkaloids: (–)-indolactam V, (–)-pendolmycin, (–)-lyngbyatoxin
A, and (–)-teleocidin A-2. Our approach to these alkaloids
features a number of key features, including: a) a distortion-
controlled indolyne functionalization reaction to assemble a key
C–N bond; b) a Lewis acid-mediated cyclization to assemble
the nine-membered lactam; and specifically, for the divergent
syntheses of 2–4: c) late-stage sp2–sp3 cross-couplings to
introduce the C7 sidechains and the challenging quaternary
2
3
carbons; and d)
a series of delicate functional group
For pioneering studies of (–)-indolactam V’s ability to bind
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4
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34 The addition of LiBr helped to suppress the competitive
formation of des-bromo compound 14.
18 The transformations used to prepare 9 are identical to those
previously developed in our laboratory, but with modified
procedures to improve the yields. See the ESI for details.
19 Our previously reported yield for the formation of 11 from 9
and 10 was 62%; see reference 10.
35 The stereochemical configurations at the newly formed
quaternary centers of 31 and 32 were assigned after conversion
to the natural products 3 and 4.
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29 For reactions involving the Schwartz Reagent, see: e-EROS
Encyclopedia of Reagents for Organic Synthesis,
Chlorobis(cyclopentadienyl)hydridozirconium.
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