Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and (+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A

Article abstract of DOI:10.1021/jacs.5b12392

The concise, enantioselective total syntheses of (+)-asperazine (1), (+)-iso-pestalazine A (2), and (+)-pestalazine A (3) have been achieved by the development of a late-stage C3-C8′ Friedel-Crafts union of polycyclic diketopiperazines. Our modular strategy enables the union of complex polycyclic diketopiperazines in virtually their final forms, thus providing rapid and highly convergent assembly at the challenging quaternary stereocenter of these dimeric alkaloids. The significance of this carbon-carbon bond formation can be gauged by the manifold constraints that were efficiently overcome, namely the substantial steric crowding at both reactive sites, the nucleophilic addition of C8′ over N1′ to the C3 carbocation, and the multitude of reactivity posed by the use of complex diketopiperazine fragments in the coupling event. The success of the indoline π-nucleophile that evolved through our studies is notable given the paucity of competing reaction pathways observed in the presence of the highly reactive C3 carbocation generated. This first total synthesis of (+)-pestalazine A also allowed us to revise the molecular structure for this natural alkaloid.

Full text of DOI:10.1021/jacs.5b12392

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Article
Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and
(+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A.
Richard P. Loach, Owen S. Fenton, and Mohammad Movassaghi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12392 • Publication Date (Web): 04 Jan 2016
Downloaded from http://pubs.acs.org on January 4, 2016
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Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine
A, and (+)-iso-Pestalazine A. Structure Revision of (+)-
Pestalazine A.
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Richard P. Loach, Owen S. Fenton, and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: The concise, enantioselective total syntheses of
H
Me
Me
H
O
O
(+)-asperazine (1), (+)-iso-pestalazine A (2), and (+)-pestalazine
A (3) have been achieved by the development of a late-stage
C3–C8' Friedel-Crafts union of polycyclic diketopiperazines.
Our modular strategy enables the union of complex polycyclic
diketopiperazines in virtually their final forms, thus providing
rapid and highly convergent assembly at the challenging quater-
nary stereocenter of these dimeric alkaloids. The significance of
this carbon–carbon bond formation can be gauged by the mani-
fold constraints that were efficiently overcome, namely the sub-
stantial steric crowding at both reactive sites, the nucleophilic
addition of C8' over N1' to the C3 carbocation, and the multi-
tude of reactivity posed by the use of complex diketopiperazine
fragments in the coupling event. The success of the indoline π-
nucleophile that evolved through our studies is notable given the
paucity of competing reaction pathways observed in the pres-
ence of the highly reactive C3 carbocation generated. This first
total synthesis of (+)-pestalazine A also allowed us to revise the
molecular structure for this natural alkaloid.
N
N
H
H
H
H
N
H
N
H
O
O
NH
H
NH
H
O
O
8'
8'
NH
NH
3
3
N
N
H
H
N
H
N
H
H
H
O
O
(+)-asperazine (1)
(+)-iso-pestalazine A (2)
isolation report (ref. 4)
O
H
O
NH
H
N
R'
H
H
O
H
HN
N1'
N
O
H
O
H
The hexahydropyrroloindoles comprise a structurally and
biologically fascinating class of alkaloid natural products.1 The
dimeric diketopiperazine incarnations of these metabolites are
replete with the sort of molecular complexity that regularly
nourishes the advancement of new synthetic methodologies.2
Undeniably, the greatest obstacle for researchers seeking to gain
efficient access to these structures has been the stereocontrolled
introduction of the quaternary stereocenter and the carbon–
carbon bond at the heart of these alkaloids. (+)-Asperazine (1)3
and its more recently isolated congener (+)-pestalazine A4 pre-
sent an exemplary challenge for chemical synthesis by pos-
sessing heterodimeric diketopiperazines with a unique quater-
nary C3sp3–C8'sp2 juncture (Figure 1). While outstanding ad-
vances have been achieved in the synthesis of C3-aryl pyr-
roloindolines,5,6,7 Overman’s elegant synthesis of (+)-asperazine
(1),8 predicated on early introduction of the C3-quaternary ste-
reocenter by an intramolecular Heck reaction9 followed by for-
mation of the diketopiperazines, stands as the only solution to
alkaloid (+)-1. Our highly convergent synthesis of the C3–C7'
fused (+)-naseseazine alkaloids (Figure 1),10 prompted us to
investigate the possibility of a complementary Friedel-Crafts
based approach11 to alkaloids (+)-1-2, involving late-stage di-
rected union of complex diketopiperazines, to secure the chal-
lenging C3sp3–C8'sp2 linkage.12 Herein, we report the develop-
ment and implementation of this ambitious strategy to the highly
expedient synthesis of (+)-asperazine (1), and the first total syn-
thesis (+)-iso-pestalazine A (2) and (+)-pestalazine A (3). The
culmination of our study was the revision and subsequent syn-
thesis of the corrected structure of (+)-pestalazine A (3).
NH
H R
NH
O
3
H
N
8'
NH
N
H
3
O
H
N
H
Me
Me
N
H
H
(–)-asperazine A (4a)
(R, R'=Ph)
O
(+)-pestalazine B (4b)
(R=i-Pr, R'=Ph)
(+)-pestalazine A (3)
revised structure (this report)
Me
N
N
H
O
H
O
N
MeN
NMe
H
H
H
NH
O
O
HN
H
N
8'
7'
R1
R2
N
H
3
3
NMe
N
H
H
H
N
H
(–)-idiospermuline (7)
(+)-naseseazine A (5, R1=H, R2=Me)
(+)-naseseazine B (6, R1/R2=(CH2)3)
Figure 1. Representative heterodimeric diketopiperazines.
In recent years, various innovative methodologies have been
13,14,15,16
formulated to address the synthesis of C3sp3–C3'sp3
,
C3sp3–N1'17 and C3sp3–arene5–9,11,12 bound pyrroloindolines. Our
group has a long-standing interest in developing mild, versatile
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chemistries that can rapidly generate these complex, acutely
(Scheme 2) for heterodimers (+)-1 and (+)-2 strived to achieve
the same levels of regiocontrol by employing C8'-
1
2
3
4
5
6
7
8
sterically-congested C3 linkages in stereo- and regioselective
fashion.2c While many of the existing approaches to C3-aryl
pyrroloindolines rely on alkylation of oxindoles,6 or rearrange-
ment chemistry,7b,d,f,g,k alternative methodologies have also been
reported.7a,e,h–j Since our first report on diazene directed frag-
ment assembly as a viable strategy for C3 arylation,16a,b much
progress has also been made in the synthesis of C3-diazenyl
pyrroloindolines.18 Recent advances in transition metal-
catalyzed coupling methodologies have also provided exciting
opportunities for the development of new routes to C3-aryl pyr-
roloindolines.5,19 The Overman group’s Heck cyclization based
strategy has proven especially successful in this arena,8,9 provid-
ing enantiomerically enriched C3-aryl oxindoles that paved the
way for their landmark syntheses of C3-aryl pyrroloindoline
alkaloids including (+)-asperazine (1), which was accomplished
in 22 steps and 1.0% overall yield.8
a
trifluoroborate 12, which could intercept tetracyclic carbocation
13. Bromide 15 would stem from diastereoselective bromocy-
clization of indole 16, procurable in decagram quantities from
amino acid condensations of L-tryptophan. Our newly devel-
oped one pot protocol for the boronation of L-tryptophans also
prompted us to consider C8'-boroindole derivatives 12 and 14.26
O
O
H
H
9
N
NH
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
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38
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40
41
42
43
44
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46
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60
HN
6'
H
H
2'
O
O
AgSbF6
EtNO2
NCbz
N
Cbz
7'
R
O
O
(–)-8, R=H
(–)-9, R=BF3K
6'
H
R=H, 27%
(+20% isomer)
R=BF3K, 50%
7'
N
H
+
Our group has sought a different inroad into these heterodi-
mers, based on a maximally convergent late-stage C3–arene
coupling of advanced diketopiperazine intermediates. This tactic
draws inspiration from biogenetic hypotheses on the origins of
3
O
O
N
H
Br
N
Cbz
N
3
N
(–)-11
these natural products,20 21 but unlike the oxidative radical di-
,
H
N
H
merizations,7i we found ionic unification pathways22 could bet-
ter dictate regiocontrol at the C3–aryl juncture.12 Specifically,
we developed a mild Friedel‒Crafts-based method for the ste-
reo- and regioselective addition of a wide range of nucleophiles
to the C3 carbocation.23 Indolic interceptions at this benzylic
cation, arising from mild silver activation of a bromide precur-
sor, were instrumental in our expedient syntheses of the bi-
onectins, gliocladins, and luteoalbusins.11 The ultimate demon-
stration of our late-stage heterodimerization paradigm came in
our total syntheses of the C7'-linked (+)-naseseazines (i.e. 5 and
6, Figure 1).12 We now report our development of a powerful
and enabling ortho-indoline-based Friedel-Crafts strategy that
has led to a highly convergent, concise, regio- and stereocon-
trolled total synthesis of (+)-asperazine (1), (+)-iso-pestalazine
A (2) and (+)-pestalazine A (3). This amplifies our group’s rep-
ertoire of heterodimerization modes to now include late-stage
C3sp3–C8'sp2 bond formation. A key feature of our routes to these
targets is a newly-developed regioselective reductive ring-
opening reaction, which allowed the transposition of a more π-
nucleophilic and regioselective indoline onto the eventual indole
moiety, whilst simultaneously thwarting N1' and C2' nucleo-
philic attack.
[H2]
Cbz
(+)-10
(+)-naseseazine B (6)
Scheme 1. Concise Synthesis of the Naseseazines.
The pronounced challenges that met our plan to switch from
C7' to C8' indole for C3 addition were borne out by our initial
studies into directing π-nucleophilicity to this position. From the
outset, unlike the naseseazines, the unfeasibility of using N1-
protected indoles for C8'-directed Friedel-Crafts coupling pre-
sented added complications.27 Notably, attempts at Miyaura
boronation of N1-protected 8-bromotryptophans failed to pro-
vide the corresponding C8-boronotryptophan.28 Conversely, N1-
functionalization post-C8 boronation of tryptophans proved
equally ineffective. With facile access to trifluoroborate (+)-17a
on a multigram scale from the pinacol precursor,26 we were able
to explore Friedel-Crafts conditions for its reaction with bro-
mide (+)-18a. This bromide was itself readily attained in one
step through bromocyclization of the corresponding diketop-
iperazine (vide infra) in a manner akin to our previous synthetic
campaigns.11,12,14 Thus, by employing silver(I) hexafluoroanti-
monate in conjunction with 18-crown-6 and 2,6-di-tert-butyl-4-
methylpyridine (DTBMP),29 we were able to obtain 6% yield of
the desired product, C8'-linked indole (+)-19a, but this was
compounded by the presence of the C7'- and C2'-linked regioi-
somers in similar quantities (Scheme 3).29,30 We next considered
blocking these two undesired positions by introducing reduc-
tively removable substituents,11a in the form of 6-bromo-2-
chloroindole (+)-17b.29 The reaction of trifluoroborate (+)-17b
with bromide (+)-18a gave fewer side products, with 22% yield
of adduct (+)-19b.31 This low yield of the desired C8'-linked
indole indicated that the underlying problem of poor π-
nucleophilicity at C8' had persisted despite the use of a directing
trifluoroborate.12,25c In spite of this, dimer (+)-19 could be car-
ried forward (Scheme 3) to (+)-asperazine (1) via indoline (+)-
20.29 Importantly, this unoptimized first-generation synthesis
allowed us to establish the critical heterodimeric C8'–C3 bond.29
The parity of our data with that of Overman’s previous synthe-
sis8 also retrospectively confirmed the regio- and stereochemical
outcome of our first generation solution for securing the quater-
nary stereocenter and the challenging C3sp3–C8'sp2 bond.
As well as its initial discovery in minute quantities from a
Caribbean sponge-derived culture of Aspergillus niger, (+)-
asperazine (1) was also isolated in 2008 alongside (+)-
pestalazine A (3) and the C3sp3–N1' linked (+)-pestalazine B
(4b, Figure 1) from the plant pathogenic fungus Pestalotiopsis
theae.4 Interestingly, in a second exploration of extracts from
Aspergillus niger, the N1'-linked isomer of (+)-asperazine (1),
and congener of (+)-pestalazine B (4b), (–)-asperazine A (4a)
was also unearthed.24 Accordingly, considerations of the inter-
related biogenetic origins of these alkaloids added further impe-
tus to our desire for a synthesis (Scheme 1) that espoused late-
stage, convergent assembly. Such a route would endow us with
the utmost flexibility in rapidly accessing C3–C8'-bound struc-
tural variants of these fascinating natural products for future
studies.
In our synthesis of the naseseazine alkaloids (Figure 1) the
desired C3–arene connectivity was secured by deployment of an
N1-protected C3-substituted indole (–)-8 (Scheme 1) that gar-
nered π-nucleophilicity at its C6'/C7' positions.12 Exclusive C7'
Friedel‒Crafts regioselection for product (–)-11 was ensured by
use of trifluoroborate (–)-9, whose anionic directing group could
facilitate tight ion pairing with the C3-derived cation from bro-
mide (+)-10 (Scheme 1).12,25 Our initial retrosynthetic outlook
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Scheme 2. Initial Retrosynthetic Analysis of Alkaloids (+)-1 and (+)-2 based on C8-Boronated Tryptophan Synthesis.
1
2
3
4
5
6
7
8
O
H
N
O
O
H
H
NH
H
R'
H
NH
H
O
H
HN
N
boronation
R'
O
late-stage
C8'-directed
Friedel-Crafts
HN
H
H
R'
NH
charge
pairing
O
O
N
H
10
14
8'
N
H
H
NH
HN
12
O
R/R'
Bpin
H
O
O
2
F3B
O
8'
O
H
N
H
NH
N
H
Br
3
NH
H
8'
NH
H
16
N
R
9
3
halo-
cyclization
R
N
H
R
H
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
O
N
H
N
H
O
H
(+)-1, R, R'=Bn
(+)-2, R=Bn, R'=i-Bu
13
15
reduction of alcohol 22. This alcohol would act as a stable sur-
rogate of dimer 21, and originate from ortho Friedel‒Crafts
coupling of indoline 23 to C3-bromide 24. In order to maximize
the propensity for C8' addition of indoline 23, it was crucial
from consideration of steric as well as electronic factors, to
forego any form of N1 protection. Critical to our plan’s success
was the notion that the N1 position of tetracycle 23 would be
too sterically encumbered to itself add efficiently to the C3 elec-
trophile.33 Again, both Friedel‒Crafts components 23 and 24
could be fashioned via halocyclization of the necessary indolic
diketopiperazines 16, thus preserving the expediency of our
previous route.
Scheme 3. First Generation Synthesis of (+)-Asperazine (1).a
CO2Me
NHBoc
MeO2C
R2
R1
NHBoc
R1
2'
7'
N
H
8'
2'
BF3K
a
NH
O
(+)-17a, R1=R2=H
(+)-17b, R1=Cl, R2=Br
R2
H
8'
7'
NH
H
+
3
O
H
N
Br
NH
H
H
N
Cbz
3
O
N
Scheme 4. Revised Retrosynthetic Analysis of Alkaloids
(+)-1 and (+)-2.
N
Cbz
H
(+)-19a, 6%
(+)-19b, 22%
O
(+)-18a
H
O
O
R'
N
NH
b or c
H
R'
H
H
H
H
N
O
N
H
MeO2C
N
X
O
H
H
O
C3' reduction/
ring-opening
3'
H
NHBoc
N
H
NH
O
NH
H
O
O
H
8'
d, e
8'
NH
H
NH
H
NH
NH
H
3
O
O
O
3
N
R
N
R
H
8'
8'
NH
H
NH
H
N
H
H
N
H
3
H
O
O
3
N
N
21, X=H
22, X=OH
(+)-1, R, R'=Bn
N
H
N
H
H
H
O
(+)-2, R=Bn, R'=i-Bu
(+)-20
(+)-asperazine (1)
Friedel-Crafts
C3 arylation
O
H
O
aReagents and conditions: (a) AgSbF6 (2.0 equiv), DTBMP (2.2 equiv),
18-crown-6 (2.0 equiv), EtNO2, 23 ˚C, 1 h. (b) (+)-19a, Pd/C (10%), H2,
EtOAc, 7 h, 23 ˚C, 81%. (c) (+)-19b, Pd/C (10%), NH4HCOO, EtOH,
70 ˚C, 7 h, 37%. (d) TFA, CH2Cl2, 23 ˚C, 2 h; EDC•HCl, HOBt, Boc-D-
Phe, 23 ˚C, 4 h. (e) TFA, CH2Cl2, 23 ˚C, 7 h; n-BuOH, 120 ˚C, 46 h,
13% (over 2 steps).
Br
C6 chlorination
C3 hydration
H
N
NH
6
HO
3
NH
H
N
R'
H
Cl
6
3
R'
N
H
H
O
8
N
H
H
O
O
8
25
halocyclization
O
23
These observations set the foundation for our development
of a second generation C3–C8' coupling strategy focused on
enhancing C8' reactivity and thereby suppress formation of re-
gioisomeric and oligomeric side products. Central to this new
approach was the utility of a reversible cyclization of trypto-
phan-derived diketopiperazines. Since tryptophan-derived
diketopiperazines are known to cyclize reversibly in acid to their
tetracyclic forms,32 our concerns could be addressed by tempo-
rarily locking this equilibrium at bis-indoline 21 (Scheme 4).
From a retrosynthetic perspective, this would allow us to har-
ness the superior π-nucleophilicity of an aniline moiety for
Friedel‒Crafts chemistry and simultaneously remove C2' nucle-
ophilicity. The subsequent unlocking of bis-indoline 21 could be
achieved post-C8'–C3 bond formation, by C3' ionization‒
H
H
NH
Br
R/R'
halocyclization
NH
H
10
HN
H
3
N
R
2
O
N
H
H
N
H
O
16
24
Knowledge from our prior synthetic campaigns pointed to
conditions for C3 bromide ionization being milder in the pres-
ence of a carboxybenzyl over a sulfonyl N1 substituent.11,12,14
The synthesis of the tetracyclic diketopiperazine intermediates
therefore began with readily available Nα-Boc-N-Cbz-L-
tryptophan methyl ester and its straightforward conversion to
diketopiperazines (+)-26a and (+)-26b, via dipeptide self-
condensation in 80% and 83%, respectively.29 Initial attempts to
3
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obtain tetracyclic bromide (+)-18a via diastereoselective bro-
locking in the cyclotryptamine substructure during the Lewis
acid-promoted Friedel-Crafts step, later to be ionized and re-
duced under Brønsted acidic conditions.
mocyclization of indole11b,12 (+)-26a were hampered by poor
solubility of these diketopiperazines in various organic solvents.
Exposure of diketopiperazine (+)-26a to our standard procedure
involving an equivalent of bromine in dichloromethane,12 ben-
zene,11b or acetonitrile,11c,d gave the desired bromide (+)-18a in
< 30% yield.34 This yield was substantially improved by addi-
tion of two equivalents of boron trifluoride to a slurry of precur-
sor (+)-26a in acetonitrile prior to bromonium ion formation. To
this end, the use of N-bromosuccinimide in place of bromine
was found to result in a superior endo/exo ratio, and we were
able to synthesize the versatile bromides (+)-18a and (+)-18b on
a gram scale in 63% and 66% yield, respectively. Scaling the
conditions to 15 g of diketopiperazine (+)-26a afforded bromide
(+)-18a in 59% yield (Scheme 5).
1
2
3
4
5
6
7
8
Having firmly established the route to our designed nucleo-
philic and electrophilic Friedel-Crafts components (Scheme 5)
for both alkaloid targets, now accessible in multigram quanti-
ties, we were well positioned to explore the key fragment-
coupling step. Initial forays involving exposure of bromide (+)-
18a to silver(I) hexafluoroantimonate, in the presence of indo-
line (+)-30a in nitroethane, led to 5–10% yield of C3–C8'-
coupled product. Importantly, we were pleased to observe virtu-
ally no N1'-linked heterodimeric products. However, as before,
mixtures of side products, largely attributable to competing
para-directed oligomerizations of precursor (+)-18a, were still
observed. Gratifyingly, replacement of tetracycle (+)-18a with
its 6-chlorinated counterpart (+)-27a resulted in excellent mass
balance, with the undesirable oligomerizations being mostly
suppressed. Under our optimal silver(I) activation conditions,29
the desired heterodimeric indoline (+)-31a was isolated in 41%
yield, along with 24% of recovered starting material (+)-30a,
and 30% of alcohol (+)-28a (Scheme 6), stemming from bro-
mide (+)-27a.
Notably, treatment of recovered alcohol (+)-28a with thionyl
bromide regenerated electrophile (+)-27a in near quantitative
yields (Scheme 5), meaning both Friedel-Crafts partners (+)-30a
and (+)-27a could be recycled to produce more of bis-indoline
(+)-31a. The degree of molecular complexity and congested
nature of the quaternary C3‒C8' bond being rapidly formed in a
single step, under mild conditions, make this Friedel-Crafts
reaction (Scheme 6) an exciting prospect for future applications
in related natural and designed complex molecule syntheses.
Two-dimensional NMR analysis provided decisive HMBC and
NOESY correlations in support of our structural assignment of
bis-indoline (+)-31a (Scheme 6). Nonetheless, our ability to
swiftly convert this dimer to alkaloid (+)-1 offered confirmation
of the C3–C8' dimeric linkage. We had originally envisaged
relying on the N1 protection of dimer (+)-31a as a means for
ensuring selective reopening of only the N1' free indoline to the
desired indole moiety. However, desilylation of ether (+)-31a
proved ineffective with all but nucleophilic fluorides, which
caused minor amounts of epimerization.37 We eventually found
that by first performing a combined hydrogenolysis and bis-
dehalogenation on substrate (+)-31a to provide silyl ether (+)-
32a in 79% yield (Scheme 6), the ensuing silyl cleavage could
proceed without incident. To this end, treatment of dimer (+)-
32a with tris(dimethylamino)sulfonium difluorotrimethylsilicate
(TASF) provided alcohol (+)-33a in 90% yield.38
With intermediate (+)-33a in hand, we were able to investi-
gate a range of conditions for the penultimate tandem C3' reduc-
tion‒ring opening step to arrive at alkaloid (+)-1 (Scheme 6).
After examining various conditions, the highest yield of (+)-
asperazine (1, 67%, Scheme 6) was attained by a combination of
triethylsilane with methanesulfonic acid. Based on our previous
thiolation studies for the syntheses of epipolythiodiketopipera-
zine alkaloids,11,14c-d, trifluoroacetic acid was originally chosen
for C3' ionization. However, when utilizing triethylsilane in
conjunction with this acid, only a modest yield (40%) of (+)-
asperazine (1) could be isolated, despite complete consumption
of alcohol (+)-33a after 24 h. Though we reasoned that a sub-
stantial Thorpe‒Ingold constraint should inhibit acid-catalyzed
opening of the southern tetracycle, the recovery of water-soluble
diketopiperazine side products from this experiment led us to
infer that such a destructive pathway was enhanced by pro-
longed exposure to acid, as well as silane reduction of the indole
moiety.39 This conclusion was corroborated when substitution
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Synthesis of Friedel-Crafts Components.a
O
O
H
NH
H
N
14
10
Br
R
NH
H
a
HN
3
H
R
O
N
H
N
O
Cbz
Cbz
(+)-26a, R=Bn
(+)-26b, R=i-Bu
(+)-18a, 59%
(+)-18b, 66%
b or c
O
O
H
H
N
HO
Br
NH
H
NH
H
d
6
Cl
6
Cl
3
3
N
R
R
N
H
N
Cbz
H
e
O
O
Cbz
(+)-28a, 96%
(+)-28b, 93%
(+)-27a, 94%
(+)-27b, 90%
f
O
O
H
N
H
N
TBSO
TBSO
NH
H
NH
6
Cl
6
g
Cl
3
3
R
R
1
N
H
H
N
H
H
O
O
Cbz
(+)-29a, 91%
(+)-29b, 87%
(+)-30a, R=Bn, 99%
(+)-30b, R=i-Bu, 90%
aReagents and conditions: (a) NBS, BF3•OEt2, MeCN, 0 ˚C, 40 min; (b)
(+)-27a: NCS, TFA, MeCN, 23 ˚C, 20 h; (c) (+)-27b: NCS, TiCl4,
MeCN, 23 ˚C, 15 h; (d) AgSbF6, H2O, EtNO2, 23 ˚C, 2 h; (e) SOBr2,
DTBMP, CH2Cl2, 0 ˚C, 40 min; (f) TBSOTf, 2,6-lutidine, CH2Cl2, 23
˚C, 35 h; (g) Pd(OAc)2, Et3SiH, NEt3, CH2Cl2, 23 ˚C, 4 h.
In order to induce ortho (C8) selectivity in the Friedel‒
Crafts coupling, the para position (C6) on the eventual nucleo-
phile 23 (Scheme 4) was temporarily blocked.11a After screening
various Lewis and Brønsted acids in combination with N-
chlorosuccinimide, the inclusion of trifluoroacetic acid35 for
bromide (+)-18a, or titanium(IV) tetrachloride in the case of
bromide (+)-18b, led to 94% and 90% yield, respectively, of the
corresponding C6-chlorinated tetracycles (+)-27a and (+)-27b
(Scheme 5). We were pleased to note that the presence of this
C6-chlorine had no deleterious effect on silver(I)-promoted C3
bromide ionization, as shown by the rapid conversion of in-
dolines (+)-27a and (+)-27b to hydrates (+)-28a and (+)-28b in
respective yields of 96% and 93%. Their conversion to silyl
ethers (+)-29a and (+)-29b on multigram scale was then fol-
lowed by efficient and mild palladium-catalyzed carboxybenzyl
removal,36 with no sign of dehalogenation,12 providing the de-
sired indolines (+)-30a and (+)-30b (Scheme 5). The C3-
hydroxyl could function as a stable placeholder, effectively
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Scheme 6. Friedel-Crafts Reaction and Ring-Opening: Synthesis of (+)-Asperazine (1) and (+)-iso-Pestalazine A (2).a
1
2
3
4
5
6
7
8
H
O
O
O
O
R
N
15'
H
NH
NH
H
H
TBSO
R
H
R
H
H
H
11'
14' NH
Cl
N
H
N
R
TBSO
N
R'O
N
O
1'
N
H
H
O
O
O
3'
3'
H
H
H
8'
6'
NH
NH
a
b
e
NH
H
O
O
O
O
Cl
Cl
(+)-30a, R=Bn
(+)-30b, R=i-Bu
H
H
8'
8'
8'
NH
H
NH
H
NH
6
11
3
3
3
+
15
N
Bn
N
Bn
O
H
N
9
H
N
Cbz
N
H
H
H
Br
N
H
H
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
O
Cl
3
R=Bn:
c
N
Bn
(+)-32a, R'=TBS, 79%
(+)-33a, R'=H, 90%
(+)-31a, R=Bn, 41%
(+)-31b, R=i-Bu, 48%
(+)-asperazine (1),
R=Bn, 67%
H
N
Cbz
H
O
R=i-Bu:
d
(+)-iso-pestalazine A (2),
R=i-Bu, 73%
(+)-32b, R'=TBS, 84%
(+)-33b, R'=H, 91%
(+)-27a
aReagents and conditions: (a) AgSbF6, DTBMP, EtNO2, 23 ˚C, 40 min; (b) Pd/C (10%), HCO2NH4, EtOH, 20 h, 70 ˚C; (c) TASF, DMF, 23 ˚C, 40 min; (d)
TBAF, THF, 23 ˚C, 1 h; (e) MsOH, Et3SiH, CH2Cl2, 23 ˚C, 4 h.
with methanesulfonic acid led to shorter reaction times and the
improved yield of (+)-asperazine (1, Scheme 6). We were
pleased to observe that all spectroscopic data for (+)-asperazine
(1), along with its optical rotation, were in complete accord29
with that of Overman’s synthetic (+)-asperazine,8 and the isolat-
ed metabolite.3
pestalazine A would be expected to share a similar biogenetic
origin to (+)-pestalazine B (4b), which had undergone structural
revision during its synthesis.17g Our hypothesis was further sub-
stantiated by the more recent discovery of (+)-asperazine (1)
along with its N1'-linked isomer (–)-asperazine A (4a).24 The
facility with which we could simply switch the top and bottom
monomers in our key Friedel-Crafts step (Scheme 7) proved
decisive in enabling us to rapidly elucidate the structure that
validated the data from the metabolite’s isolation report.
Having successfully employed this modular strategy to our
highly convergent synthesis of (+)-asperazine (1), the stage was
now set for us to tackle the first total synthesis of (+)-
pestalazine A (2). We began by replacing indoline (+)-30a with
its D-leucine counterpart (+)-30b, and under the same silver-
mediated conditions to ionize bromide (+)-27a, obtained the
corresponding heterodimer (+)-31b in 48% yield.29 The im-
proved yield in this reaction we attributed to the higher reaction
concentrations attained using substrate (+)-30b, which was more
soluble in nitroethane than indoline (+)-30a. The subjection of
bis-chlorinated dimer (+)-31b to hydrodehalogenation provided
silyl ether (+)-32b in 84% yield. The ensuing desilylation with
tetrabutylammonium fluoride also proceeded without incident to
furnish alcohol (+)-33b in 91% yield. Exposure of this interme-
diate to our optimal reduction–ring opening protocol, namely
methanesulfonic acid and triethylsilane, delivered indole (+)-2
in 73% yield (Scheme 6).
Scheme 7. Synthesis of (+)-Pestalazine A (3).a
O
O
H
H
NH
TBSO
NH
Cl
H
N
N
TBSO
1'
H
O
N
H
H
3'
8'
H
NH
H
O
O
8'
O
(+)-30a
Cl
Cl
+
a
NH
H
3
Br
N
NH
H
Cl
3
H
Me
N
Cbz
H
N
O
Me
Me
N
Cbz
H
O
(+)-31c, 32%
Me
Our completion of this synthesis allowed for conclusive
comparisons to be made between the structural data of alkaloid
(+)-2 and the isolation data originally reported by Che and
(+)-27b
b
O
H
N
O
1
NH
coworkers for natural (+)-pestalazine A.4 The H and 13C NMR
H
H
H
H
signals corresponding to the positions around the indole and
indoline portions of our molecule were in excellent agreement
with the isolation report (< 0.5 ppm difference between 13C
NMR signals),29 thereby confirming the crucial C3–C8' connec-
N
RO
N
H
O
O
3'
8'
H
NH
d
O
NH
H
H
O
1
tivity. However, the same could not be said of several key H
8'
NH
3
NH
H
signals corresponding to the diketopiperazine moieties, which
differed markedly from the values in the isolation report, specif-
ically the C11 (3.3729 vs. 4.684 ppm), C15 (4.1029 vs. 3.254
ppm), C11' (4.1629 vs. 3.464 ppm) and C15' (3.0329 vs. 3.804
ppm) positions (Scheme 6). Furthermore, indole (+)-2, which
we now came to regard as (+)-iso-pestalazine A, exhibited an
optical rotation of +99˚ (c 0.17, MeOH),29 as compared to Che’s
value of +203˚ (c 0.10, MeOH)4 for natural (+)-pestalazine A.
This propitious discovery would thus provide the ideal plat-
form to demonstrate the power of our modular Friedel‒Crafts
approach to C3–C8' coupling. Without any change to our syn-
thetic route, we pursued an alternative structural isomer of
dimer (+)-2, in which the northern and southern diketopipera-
zines were inverted (Figure 1). We believed this reversal of top
and bottom monomers to be highly plausible given that (+)-
N
3
N
H
Me
Me
N
H
H
O
Me
N
H
H
O
Me
(+)-32c, R=TBS, 69%
(+)-33c, R=H, 91%
c
(+)-pestalazine A (3), 71%
aReagents and conditions: (a) AgSbF6, DTBMP, EtNO2/CH2Cl2 (3:1), 23
˚C, 90 min; (b) Pd/C (10%), HCO2NH4, EtOH, 70 ˚C, 25 h; (c) TASF,
DMF, 23 ˚C, 1 h; (d) MsOH, Et3SiH, CH2Cl2, 23 ˚C, 4 h.
With the necessary Friedel‒Crafts components, indoline (+)-
30a and bromide (+)-27b, already in hand (Scheme 5), we were
able to direct the union of these tetracycles in formation of di-
mer (+)-31c in 32% yield (Scheme 7). In this case, we only
deviated from our established conditions by including dichloro-
methane as co-solvent during fragment assembly. This allowed
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us to work at higher reaction concentrations while maintaining
REFERENCES
1
2
3
4
5
6
7
8
the optimal reactivity that nitroethane had consistently provided.
The recovered starting material (+)-30a and the side product
alcohol (+)-28b could be recycled, the latter by its conversion
back to bromide (+)-27b in 98% yield by subjection to thionyl
bromide and 2,6-di-tert-butyl-4-methylpyridine (Scheme 5).29
Next, concomitant carboxybenzyl hydrogenolysis and bis-
dechlorination of dimeric substrate (+)-31c, followed by desi-
lylation of ether (+)-32c, proceeded in 69% and 91% yield, re-
spectively (Scheme 7). The final reduction and ring-opening of
alcohol (+)-33c furnished indole (+)-3 in 71% yield. To our
delight, all spectroscopic data for molecule (+)-3 were in excel-
lent agreement with those from Che’s isolation report of (+)-
pestalazine A,4 thereby confirming (+)-3 as the correct structure.
Furthermore, the optical rotation for (+)-3 was +211˚ (c 0.13,
MeOH)29 which was in good agreement with the reported value
for the natural isolate.4
In summary, we completed expedient and unified total syn-
theses of (+)-asperazine (1), (+)-iso-pestalazine (2), and (+)-
pestalazine A (3), in eleven steps from commercially available
N-Boc-L-tryptophan methyl ester, and respective overall yields
of 6.8%, 8.0% and 4.8%. Guided by our core ethos of retrobio-
synthetic2c,40 analysis, we developed a mild, regio‒ and stere-
ocontrolled, ortho-directed Friedel‒Crafts reaction for the for-
mation of the critical C3–C8' dimeric linkage in these mole-
cules. Our late-stage C3–C8' heterodimerization approach to
structures (+)-1, (+)-2 and (+)-3 benefits from its use of ad-
vanced diketopiperazine tetracycles as easily interconvertible
Friedel‒Crafts components. The successful implementation of
this new and convergent synthetic strategy for these dimeric
diketopiperazines required the application of the new tandem
C3' reduction‒ring opening transformation for the selective late-
stage unraveling of the tryptophan motif in these alkaloids. Ad-
ditionally, the generality of our three-step protocol from Friedel-
Crafts product (+)-31 to the final alkaloids was showcased by
our ability to employ the same sequence with all three natural
product targets. This paved the way for a modular, highly con-
vergent strategy that allowed for a facile inversion of the tetra-
cyclic fragments in (+)-iso-pestalazine (2) to (+)-pestalazine (3).
The first total synthesis of (+)-pestalazine A (3) led to a revision
of its structure from the originally reported polycyclic indole
(+)-2. Our biogenetically inspired synthetic strategy to these
fascinating alkaloids described here expands the range of heter-
odimeric diketopiperazines accessible by highly stereo- and
regioselective late-stage complex fragment assembly.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data, and copies of
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*Email: movassag@mit.edu
Notes
10. Raju, R.; Piggott, A. M.; Conte, M.; Aalbersberg, W. G. L.;
Feussner, K.; Capon, R. J. Org. Lett. 2009, 11, 3862.
The authors declare no competing financial interests.
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N.; Morrison, K. C.; Kim, J.; Hergenrother, P. J.; Movassaghi, M.
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ACKNOWLEDGMENT
We acknowledge financial support by NIH-NIGMS
(GM089732) and Amgen. R.P.L. thanks the Fonds de Recher-
che du Québec, Nature et Technologies for a postdoctoral fel-
lowship.
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.
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29. See Supporting Information for details.
30. The NMR analysis of the crude reaction mixture indicated ~10%
conversion to the C7'-linked regioisomer, and formation of a similar
amount of the C2'-linked regioisomer. HPLC purification was em-
ployed to separate the desired C8'-linked product (+)-19a from regi-
oisomers.
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34. Major side products were the corresponding C2,C3-diastereomeric
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group in dimer (+)-31a could be responsible for epimerization.
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(9 cm x 3-1/2 cm)
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H
Me
Me
H
H
O
O
O
N
N
N
H
H
H
H
H
H
N
H
N
H
N
H
O
O
O
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NH
H
NH
H
NH
H
O
O
O
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8'
8'
8'
NH
NH
NH
3
3
3
N
N
N
H
H
H
Me
Me
N
H
N
H
N
H
H
H
H
O
O
O
(+)-iso-pestalazine A
(+)-pestalazine A
(+)-asperazine
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