Concise total synthesis and stereochemical revision of (+)-naseseazines A and B: Regioselective arylative dimerization of diketopiperazine alkaloids

Article abstract of DOI:10.1021/ja206743v

Concise and enantioselective total syntheses of (+)-naseseazines A and B are described. Our regioselective and directed dimerization of diketopiperazines provides their critical C3-Csp² linkages, an assembly with plausible biogenetic relevance. We revise the absolute stereochemistry of (+)-naseseazines A and B.

Full text of DOI:10.1021/ja206743v

COMMUNICATION
pubs.acs.org/JACS
Concise Total Synthesis and Stereochemical Revision
of (+)-Naseseazines A and B: Regioselective Arylative
Dimerization of Diketopiperazine Alkaloids
Justin Kim and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
ABSTRACT: Concise and enantioselective total syntheses
of (+)-naseseazines A and B are described. Our regioselec-
tive and directed dimerization of diketopiperazines provides
their critical C3ꢀCsp2 linkages, an assembly with plausible
biogenetic relevance. We revise the absolute stereochemis-
try of (+)-naseseazines A and B.
imeric diketopiperazine alkaloids, which constitute an im-
portant class of natural products, possess an expansive
repertoire of biological activities intimately mirroring their
structural diversity.1 An important source of diversity of great
strategic relevance to their synthesis is the nature of the dimeric
D
linkage. In recent years, much progress has been made in
2ꢀ4
regard to the rapid construction of the C3sp3ꢀC30sp3
and
5
C3sp3ꢀN10 bond connectivities. In this work, we aimed to
broaden the spectrum of dimerization modes that are predis-
posed for rapid disconnection. We describe herein a Friedelꢀ
Crafts-based method for the regioselective and directed C3
functionalization of advanced diketopiperazine intermediates
employing a range of π-nucleophiles. The concise nature and
broad relevance of this approach to the synthesis of C3-arylated
hexahydropyrroloindole alkaloids6 (Figure 1) are highlighted
through the first total syntheses of Fijian actinomycete Strepto-
myces sp. derived alkaloids (+)-naseseazine A (1) and B (2),7 an
endeavor culminating in their stereochemical revision.
Figure 1. Representative C3-arylated hexahydropyrroloindole alkaloids
and revised structures of (+)-naseseazine A (1) and B (2).
67 and 51% yield as single diastereomers (Scheme 2). In
possession of all the necessary components, we sought to validate
the feasibility of our planned FriedelꢀCrafts-based strategy for
C3-arylation at this juncture. Treating a solution of (ꢀ)-10
(1.5 equiv) and (+)-11 (1 equiv) with AgSbF6 in nitroethane
under the optimized conditions (see below) afforded a mixture of
regioisomeric dimers (ꢀ)-13 and (ꢀ)-15 in 53% combined yield
[(ꢀ)-13:(ꢀ)-15 = 1:1.4]. Similarly, (ꢀ)-10 could be coupled to
tetracyclic bromide (+)-12 to give regioisomeric dimers (ꢀ)-14
and (ꢀ)-16 in 47% combined yield [(ꢀ)-14:(ꢀ)-16 = 1:1.4].
Hydrogenolytic removal of the carboxybenzyl groups on com-
pounds 13ꢀ16 provided the first access to (+)-iso-naseseazine A
(17) and B (18) as well as our target alkaloids 1 and 2, respectively
(Scheme 2). Notably, selectivity in favor of the regioisomer with the
desired C3ꢀC70 bond connectivity was observed during the
coupling reaction.8 While we were pleased with the utility of this
new mode of heterodimerization, the low level of regioselectivity in
this unguided union prompted further refinement of our new
strategy to give a more selective and directed assembly of complex
diketopiperazine fragments.
In deference to our desire for a maximally convergent synth-
esis of 1 and 2 and consistent with a plausible hypothesis for
their biogenesis,8,9 our retrosynthetic analysis commenced with
the disconnection of the C3ꢀC70 bonds of 1 and 2,10 affording
two diketopiperazine fragments of comparable complexity
(Scheme 1). Tetracyclic bromide 6 could be obtained by
bromocyclization of diketopiperazine 8,3b whereas pinacolbor-
onate 5 could be prepared from the corresponding bromodike-
topiperazine 7. We envisioned that ionization of 6 would provide
the necessary C3-electrophile,11,12 while conversion of the pina-
colboronate function of 5 to the corresponding trifluoroborate13
would offer the necessary C70-nucleophilic partner for a directed
and regioselective sp3ꢀsp2 bond formation (Scheme 1).
In our first-generation approach, alanine and proline diketo-
piperazines (ꢀ)-9 and (ꢀ)-10, the requisite tetracyclic bromides
en route to the corresponding naseseazine alkaloids, were synthe-
sized in 89 and 71% yield, respectively, from readily available
Nα-Boc-Nin-Cbz-L-tryptophan methyl ester.14 Exposure of (ꢀ)-9
and (ꢀ)-10 to pyridinium tribromide in 2,2,2-trifluoroethanol
afforded the respective tetracyclic bromides (+)-11 and (+)-12 in
We anticipated that the regioselective arylation of tetracyclic
bromide (+)-11 could be achieved by installation of a directing
Received: July 19, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis for 1 and 2
Table 1. Lewis Acid-Promoted C3-Nucleophile Substitution
Scheme 2. First-Generation Syntheses of 1 and 2a
a Isolated yields; averages of two experiments; AgSbF6 (2.0 equiv) and
nucleophile (2.0 equiv). b Regioisomeric ratios determined by 1H NMR
analysis. The major regioisomer is shown. c 18-crown-6 (2.0 equiv).
d The minor regioisomer is the para adduct.
18-crown-6 in CH2Cl2 at 23 °C, we obtained the desired C3-arylated
product as a mixture of regioisomers favoring the desired C3 adduct
(19:20 = 1:1.3). Subambient temperatures were then examined
to enhance the regioselectivity for C3; however, the selectivity did
not improve noticeably at 0 °C in CH2Cl2, and conversion to the
product was not observed at lower temperatures. Thus, we turned to
higher-dielectric-constant media to facilitate the ionization event.
Nitrile-based solvents such as acetonitrile and benzonitrile
enabled ionization; however, tight solventꢀcarbocation interac-
tions significantly impeded the nucleophilic reaction, and
hydroxylation19 and Ritter reaction adducts20 formed in signifi-
cant amounts as principal byproducts. Similarly, the use of DMF
resulted exclusively in hydroxyl and formate addition products.21
Ultimately, we discovered that the use of nitroalkane solvents was
most effective for the desired transformation. The level of regio-
selection improved for the C3-thiophenyl adduct at ꢀ25 °C in
nitromethane (19:20 = 1:2.8). Under optimal conditions, treat-
ment of (+)-11 with 3-thiophenetrifluoroborate at ꢀ45 °C in
nitroethane provided the desired product with an excellent level
of regioselection (50% yield, 19:20 = 1:17; Table 1, entry 2).9
Encouraged by the efficiency and high regioselectivity ob-
served in the trifluoroborate-directed thiophenylation of (+)-11,
we sought to examine the generality of this chemistry with
respect to other π-nucleophiles. Table 1 demonstrates the
substrate scope for the nucleophilic addition at the C3-position
of (+)-11: allyltri-n-butylstannane (60%; entry 3), allyltrimethylsilane
a Conditions: (a) PyHBr3, 2,2,2-trifluoroethanol, 23 °C. (b) (ꢀ)-10,
AgSbF6, EtNO2, 23 °C; for (+)-11, 13:15 = 1:1.4, 53%; for (+)-12,
14:16 = 1:1.4, 47%. (c) H2, Pd/C, AcOH, 23 °C.
group at an appropriate position of the π-nucleophile.15,16
Importantly, we wished to increase the ratios of (ꢀ)-15 and
(ꢀ)-16 to (ꢀ)-13 and (ꢀ)-14, respectively. In the early stages of
our optimization studies, we selected thiophene, with its innate
preference for reaction at the 2-position (19:20 = 6.2:1; Table 1,
entry 1), as our model system. While 3-cuprate, 3-trimethylstan-
nyl, and 3-zinc chloride thiophene derivatives were ineffective
as directed nucleophiles in the C3-arylation of (+)-11, the use of
the corresponding potassium trifluoroborate derivative proved
promising.15,17 We expected that the use of 18-crown-6 as an
additive would confer multiple benefits: increased solubility of the
potassium trifluoroborate salt, enhanced nucleophilicity of the arene
via ion pairing with the electrophile, and facilitated trifluoroborate
elimination by further dissociation of the potassium aryltrifluoro-
borate ion pair.18 Indeed, when AgSbF6 was introduced into
a solution of (+)-11, potassium 3-thiophenetrifluoroborate, and
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Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Concise and Directed Syntheses of 1 and 2a
efficiently provided bromotryptophan derivative (+)-30 in 97%
yield and >99% ee.24 An expeditious two-step sequence afforded
bromocyclodipeptide (ꢀ)-31 in 75% yield from (+)-30 without
the need for chromatography. Our initial efforts to introduce the
pinacol boronic ester function via Pd-catalyzed cross-coupling with
pinacolborane25 were hindered by undesired carboxybenzyl depro-
tection as well as the formation of significant amounts of a
C70-reduction byproduct. After significant experimentation, we
recognized that employing Buchwald’s aminobiphenyl-(XPhos)PdCl
precatalyst (34, 5 mol %),26 XPhos (15 mol %), K3PO4 (3 equiv),
and bis(pinacolato)diboron (3 equiv) in DMSO at 60 °C effectively
afforded the desired pinacol boronate (ꢀ)-32 in 65% yield (Scheme 3).
Treatment of (ꢀ)-32 with aqueous potassium hydrogen difluoride
gave the key potassium trifluoroborate (ꢀ)-33 in 88% yield.13
Treatment of alanine-derived tetracyclic bromide (+)-11
(1 equiv) with tetracyclic potassium trifluoroborate (ꢀ)-33
(1.5 equiv) in the presence of AgSbF6 and 18-crown-6 in
nitroethane at 23 °C afforded the desired (ꢀ)-dicarboxybenzyl
naseseazine A (15) in 56% yield with complete regioselection
(Scheme 3). Under identical conditions, exposure of proline-
derived tetracyclic bromide (+)-12 (1 equiv) with (ꢀ)-33 (1.5
equiv) gave (ꢀ)-dicarboxybenzyl naseseazine B (16) in 50%
yield as a single regioisomer (Scheme 3). Excitingly, the ability to
override the innate nucleophilic tendencies of the indole sub-
structure through an appropriately positioned directing group
has broad implications for the synthesis of related congeners of
different regioisomeric constitutions about the C3sp3ꢀCsp2 di-
meric linkage, such as in (+)-asperazine27 and (+)-pestalazine28
as well as the entire superfamily of oligomeric cyclotryptamines,1
represented by (+)-caledonine (Figure 1).29
Hydrogenolytic removal of the benzyloxycarbonyl groups from
(ꢀ)-15 and (ꢀ)-16 with Pd/C in acetic acid provided (+)-
naseseazine A (1) {[α]D22 = +123 (c 0.12, CH3OH); lit. [α]2D3 = +139
(c 0.10, CH3OH)}7 and (+)-naseseazine B (2) {[α]2D2 = +101 (c
0.23, CH3OH); lit. [α]2D3 = +95 (c 0.08, CH3OH)},7 respectively,
each in 80% yield (Scheme 3). All of the spectroscopic data for 1and
2 matched those reported in the literature.7 The agreement between
the optical rotation signs for our synthetic samples of 1 and 2 and
those of the natural alkaloids stands in direct contrast to the
predicted absolute stereochemistry of 1 and 2 based on C3 Marfey’s
analysis30 of degradation products. In view of the use of L-amino acid
derivatives in our synthesis of 1 and 2, we revise the absolute
stereochemistry of these dimeric natural alkaloids (Figure 1).
We have developed a general approach to dimeric diketopi-
perazine alkaloids containing a C3sp3ꢀCsp2 linkage, with the solu-
tion yielding a concise nine-step total synthesis of (+)-naseseazine
A (1) and B (2). Our mild and highly regioselective FriedelꢀCrafts-
based coupling strategy, featuring the formation of quaternary
stereogenic centers, facilitated the late-stage union of advanced dike-
topiperazine structures in a convergent manner. Our total syntheses
of 1 and 2 have also enabled the revision of the absolute stereo-
chemistries of these natural products. This new fragment assembly
strategy, ideated from a close adherence to biogenetically relevant
intermediates and transformations, highlights the power of a stra-
tegic framework guided by retrobiosynthetic31 analysis.
a Conditions: (a) CbzCl, Et3N, DMAP, CH2Cl2, 100%. (b) Boc-α-
phosphonoglycine trimethylester, DBU, CH2Cl2, 97%. (c) H2 (80 psi),
(S,S)-Et-DUPHOS-Rh (1.8 mol %), CH2Cl2, MeOH, 97%, >99% ee.
(d) TFA, CH2Cl2; EDC HCl, HOBt, Et3N, Boc-L-Pro. (e) TFA,
3
CH2Cl2; NH4OH, MeOH, 75% (two steps). (f) 2-aminobiphenyl-
(XPhos)PdCl (5 mol %), XPhos (15 mol %), (BPin)2, K3PO4, DMSO,
60 °C, 65%. (g) KHF2(aq), MeOH, 88%. (h) AgSbF6, 18-crown-6,
EtNO2, 23 °C. (i) H2, Pd/C, AcOH, 23 °C.
(52%; entry 4), and (isopropenyloxy)trimethylsilane (91%;
entry 5) act as suitable nucleophiles. Notably, vicinal quaternary
stereocenters can also be installed efficiently, as demonstrated by
the addition of methyl trimethysilyl dimethylketene acetal (89%;
entry 6). Electron-rich arenes such as thiophene (77%; entry 1)
and electron-neutral arenes, best represented by toluene (50%;
entry 7), can also be incorporated efficiently. Toluene itself adds
with exclusive selectivity for the para position, a preference that
can be reversed using the trifluoroborate group.
The regioselectivity of aryltrifluoroborate addition, although
moderate, is eroded in the presence of ortho substituents, such as
in o-tolyltrifluoroborate (25:24 = 3.5:1; Table 1, entry 8) and
2-methoxyphenyltrifluoroborate (26:260 = 2.7:1; entry 9), likely
reflecting a sterically demanding transition state in the formation
of quaternary stereocenters. Unfortunately, electron-deficient
arenes, such as potassium 4-acetylphenyl-trifluoroborate, lead
to exclusive C3-fluorination via fluoride transfer from the aryltri-
fluoroborate. Nucleophiles without a competent electrofuge,
such as styrene, result in polymerization. This problem can be
circumvented through the use of a trifluoroborate group, which
likely is eliminated faster than a proton (59%; entry 10). In
general, the efficiency of the reactions appears to correlate well
with the relative nucleophilicity of the compounds.22 The mild-
ness of the reaction conditions is also of particular note. The
utility of the method in late-stage applications is highlighted by
the preservation of stereochemical integrity at C11 and C15,
epimerizable stereocenters3b,5e that are consequential for the
further derivatization of advanced intermediates.3c
Our planned strategy for the directed union of the advanced-
stage diketopiperazine fragments for the syntheses of (+)-
naseseazine A (1) and B (2) required the synthesis of tri-
fluoroborate (ꢀ)-33 (Scheme 3). Starting from commercially
available 6-bromo-3-carboxaldehyde (28), benzyloxycarbonyla-
tion followed by a HornerꢀWadsworthꢀEmmons reaction with
Boc-α-phosphonoglycine trimethyl ester afforded enamide 29 in
97% yield over the two steps.23 Catalytic asymmetric hydrogena-
tion of the olefin using (S,S)-Et-DUPHOS-Rh (1.8 mol %)
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
troscopic data, and copies of UVꢀvis and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
(10) For the systematic positional numbering system used through-
out this report, see page S3 in the SI.
(11) (a)Forelectrophilic activation of a C3-selenocyclotryptamine, see:
Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. (b) Iwaki, T.; Yamada,
F.; Funaki, S.; Somei, M. Heterocycles 2005, 65, 1811.
Corresponding Author
movassag@mit.edu
’ ACKNOWLEDGMENT
(12) For addition to C3 of oxindoles, see: (a) Nicolaou, K. C.; Chen, D.
Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004,
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Chem. 1995, 60, 3020.
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Nα-Boc-L-Trp-OMe, see: Kiso, Y.; Inai, M.; Kitagawa, K.; Akita, T.
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rates in FriedelꢀCrafts alkylation reactions, see: Lee, S.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
We acknowledge financial support by NIH-NIGMS (GM089732),
Amgen, and DuPont. M.M. is a Camille Dreyfus Teacherꢀ
Scholar. J.K. acknowledges a National Defense Science and
Engineering Graduate Fellowship. We thank Dr. Omar K.
Ahmad and Dr. Nicolas Boyer for helpful discussions and Prof.
R. J. Capon for a communication regarding the discrepancy
between our respective stereochemical assignments of 1 and 2.
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(8) We consider a biosynthetic hypothesis in which dimerization
occurs at an advanced stage using well-elaborated tryptophan systems
(e.g., cyclodipeptides) to be plausible; see Scheme S1 in the SI.
(9) See the SI for details.
14943
dx.doi.org/10.1021/ja206743v |J. Am. Chem. Soc. 2011, 133, 14940–14943