Total synthesis of indotertine A and drimentines A, F, and G

Article abstract of DOI:10.1002/anie.201303334

Oh my darling, Drimentine: The first total synthesis of the pyrroloindoline alkaloids drimentinesA, F, and G, and their congener, indotertineA, is reported. An intermolecular radical conjugate addition was key in the synthesis of the drimentine alkaloids, and a biologically inspired iminium-olefin cyclization converted drimentineF into indotertineA. Copyright

Full text of DOI:10.1002/anie.201303334

Angewandte
Chemie
Communications
Natural Product Synthesis
Oh my darling, Drimentine: The first total
synthesis of the pyrroloindoline alkaloids
drimentines A, F, and G, and their con-
gener, indotertine A, is reported. An
intermolecular radical conjugate addition
was key in the synthesis of the drimentine
alkaloids, and a biologically inspired
iminium–olefin cyclization converted dri-
mentine F into indotertine A.
Y. Sun, R. Li, W. Zhang,
A. Li*
&&&& — &&&&
Total Synthesis of Indotertine A and
Drimentines A, F, and G
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DOI: 10.1002/anie.201303334
Natural Product Synthesis
Total Synthesis of Indotertine A and Drimentines A, F, and G**
Yu Sun, Ruofan Li, Wenhao Zhang, and Ang Li*
Dedicated to Professor Guo-Qiang Lin on the occasion of his 70th birthday
The pyrroloindoline alkaloids attract wide interest from the
fields of chemistry, biosynthesis, and biology.[1] From a struc-
tural perspective, they can be divided into several classes that
vary in the substituent on C3a of the pyrroloindoline core,
including heteroatoms, arenes, aliphatic groups, and another
pyrroloindoline motif. Accordingly, a series of strategies have
been developed for the synthesis of the above pyrroloindoline
classes.[2–6] Notably, a structurally complex aliphatic side chain
linked to the C3a position is rather rare. The drimentine
alkaloids (1–4, Scheme 1), which exhibit anticancer, antibac-
terial, antifungal, and anthelmintic properties, possess the
latter substitution mode.[7] A stereocontrolled method to form
the C10b–C12 bond of the drimentine scaffold is highly
desired for the synthesis of these compounds. Indotertine A
(5, Scheme 1) with an unprecedented, but biosynthetically
relevant, skeleton was recently discovered.[7b] The biosyn-
thetic relationship between 3 and 5 is postulated in Scheme 1.
Acidic activation of the germinal diamine moiety of 3 may
generate an iminium species 6, which could undergo an
iminium–olefin cyclization[8,9] followed by a proton elimina-
tion of the cationic intermediate 7. Herein, we report the first
total synthesis of drimentines A, G, and F (1–3), exploiting
a photocatalyzed radical conjugate addition to address the
problem of the C10b–C12 bond formation; a synthesis of
indotertine A (5), guided by the above biosynthetic hypoth-
esis, is also described.
We first undertook a retrosynthetic analysis of drimenti-
ne G (Scheme 2). Disassembly of the diketopiperazine motif
=
at the amide bonds followed by cleavage of the exocyclic C C
bond simplifies this molecule to core structure 8. Disconnec-
tion of the C10b–C12 bond leads to a pair of precursors (9 and
10) for an intermolecular radical conjugate addition. The
former is readily available from bis(Boc-l-tryptophan)
methyl ester (Boc = tert-butoxycarbonyl), whereas the latter
could be derived from commercially available (+)-sclareolide
(11).
Scheme 1. Representative drimentine alkaloids and the postulated
biosynthetic relationship between drimentine F and indotertine A.
[*] Y. Sun,[+] R. Li,[+] W. Zhang, Prof. Dr. A. Li
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032 (China)
E-mail: ali@sioc.ac.cn
[+] These authors contributed equally to this work.
[**] We thank Dr. D. J. Edmonds for helpful discussions. Financial
support was provided by Ministry of Science and Technology
(2013CB836900), the National Natural Science Foundation of China
(21290180, 21172235, and 21222202), and Chinese Academy of
Sciences.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303334.
Scheme 2. Retrosynthetic analysis of drimentine G.
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Table 1: Investigation of conditions for the radical conjugate addition.
The intermolecular radical C C bond formation is
a powerful tool in organic synthesis,[10] and recent advances
in this field are encouraging.[11] A C3a-bromopyrroloindoline,
such as 9 (Scheme 2), can readily generate benzylic radicals
with retention of the original stereochemistry. These have
found good use in some intermolecular transformations,[5a,b,6a]
including conjugate additions,[5a,b] albeit with rather limited
scope of acceptors. Visible-light photoredox catalysis, pio-
neered by the groups of MacMillan, Yoon, and Stephenson,
has emerged as a powerful, yet controllable, method to
promote radical reactions.[12,13] In an inspiring synthesis of
gliocladin C, Stephenson et al. developed the direct coupling
of a pyrroloindoline radical with a substituted indole, employ-
ing [Ru(bpy)3Cl2] (bpy = bipyridine) as a photocatalyst.[14]
The conjugate addition of functionalized radicals (such as a-
amino and a-alkoxy alkyl radicals) by photoredox catalysis
has attracted remarkable attention,[15] whereas similar types
of reactions with non-functionalized radicals remain rather
rare in the literature, despite the seminal report by Okada
et al. two decades ago.[16,17]
Entry
Conditions
Yield [%][f]
1
2
3
4
5
6
7
8
AIBN, Bu3SnH, or (TMS)3SiH, toluene[a,b]
Et3B, O2, Bu3SnH, THF[a,c]
0
0
0
58
51
12
[Co(PPh3)Cl], acetone[a,c]
Bu3SnH (syringe pump), benzene[b,d]
[Ru(bpy)3Cl2]·6H2O (2.5%), blue LED, Et3N[a,c,e]
blue LED, Et3N[a,c,e]
[Ir(ppy)2(dtbbpy)]PF6 (2.5%), blue LED, Et3N[a,c,e]
[Ir(ppy)2(dtbbpy)]PF6 (2.5%), blue LED, Et3N
10/9=1:1.5[c,e]
89 (87)[h]
91 (86)[g,h]
[a] 4.0 equiv of 10. [b] 808C. [c] 228C. [d] 10.0 equiv of 10. [e] 2.0 equiv of
Et3N in DMF (0.5m in 9 or 10). [f] Based on 9. [g] Based on 10. [h] Yields
in parentheses obtained from gram-scale reactions. AIBN=azobisiso-
butyronitrile, bpy=bipyridine, dtbbpy=4,4’-di-tert-butyl-2,2’-bipyridine,
ppy=2-phenylpyridine, TMS=trimethylsilyl.
With the above retrosynthetic analysis and literature
precedents in mind, we started the synthesis of drimentine G
by preparing precursors 9 and 10 (Scheme 3). Sclareolide (11)
was converted into iodoformate 12 using the two-step method
a large excess of enone 10 (4.0 equiv) was employed to
accelerate the desired intermolecular reaction. The conven-
tional radical conditions (AIBN, Bu3SnH or (TMS)3SiH) led
to rapid and complete debromination of 9 (entry 1), as did
alternative initiation conditions, such as Et3B/O2 (entry 2).
The reductive initiator [Co(PPh3)3Cl] merely resulted in
instantaneous homodimerization of the radical (entry 3),
despite the high concentration of 10 (ca. 1.0m). In all of the
above cases, 10 was fully recovered. As these results illustrate,
the pyrroloindoline radical was readily generated under
various conditions; however, side reactions rapidly quenched
the radical species before the desired conjugate addition
occurred. At this point, we carefully examined the method
employed by Crich et al. (slowly adding Bu3SnH).[5a]
Although the reported conditions only gave debromo-9, we
were pleased to find that, with a much higher dilution (ca.
0.005m in benzene) and a slower addition rate (syringe pump,
8 h) of Bu3SnH, and in the presence of larger excess of 10
(10 equiv), the desired product 8 was obtained in 58% yield
(entry 4). However, the use of a large excess of toxic Bu3SnH
and the synthetically more precious 10 makes this reaction
less satisfactory. Thus, we moved on to photoredox catalysis.
Upon visible-light irradiation (blue LED, lmax = 454 nm),
treatment with the photocatalyst [Ru(bpy)3Cl2] at 228C for
16 h produced 8 in 51% yield (entry 5). A control experiment
in the absence of the photocatalyst provided only a small
amount of 8 (entry 6). The efficiency of the conjugate
addition was significantly improved by replacing [Ru-
(bpy)3Cl2] with [Ir(ppy)2(dtbbpy)PF6][20,13b–e] (89% yield,
entry 7). Reactions with a reversed ratio of the two substrates
were also investigated (entry 8). As shown, 1.5 equiv of 9
ensured optimal efficiency (91% yield), and the reaction
scaled reliably (entries 7 and 8). The structure of 8 was
Scheme 3. Multigram synthesis of the precursors for the radical
conjugate addition. Reagents and conditions: a) DIBAL-H (1.2 equiv),
CH2Cl2, À788C, 1 h; b) I2 (1.2 equiv), PIDA (1.4 equiv), hn, benzene,
908C, 5 min; c) K2CO3 (1.5 equiv), MeOH, 228C, 2 h, 78% for the 3
steps; d) SOCl2 (1.5 equiv), Et3N (3.0 equiv), CH2Cl2, À908C, 5 min,
86%; e) O3, CH2Cl2, À788C, 5 min, then Et3N (20 equiv), 608C, 2 h,
82%; f) NBS (1.0 equiv), PPTS (1.0 equiv), CH2Cl2, 228C, 15 min,
96%. DIBAL-H=diisobutylaluminum hydride, NBS=N-bromosuccini-
mide, PIDA=phenyliodonium diacetate, PPTS=pyridinium p-toluene-
sulfonate.
developed by Baran et al. (DIBAL-H reduction followed by
Suꢀrez cleavage).[18] Compound 11 was then further hydro-
lyzed to give alcohol 13 (78% yield from 11). Treatment of 13
with SOCl2/Et3N furnished exocyclic olefin 14 in 86% yield,
=
the C C bond of which was cleaved by ozonolysis. The
resulting iodoenone smoothly underwent b-elimination pro-
moted by Et3N to give 10 on a multigram scale. Meanwhile, 9
was obtained through bromocyclization of l-tryptophan
derivative 15 in 96% yield on a decagram scale.[19]
Having prepared a large quantity of both substrates, we
investigated the radical conjugate addition (Table 1). Initially,
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confirmed by X-ray crystallographic analysis (m.p. 210–
2128C, EtOAc/petroleum ether 1:1).[21]
The postulated mechanism for this conjugate addition
reaction is as follows: The pyrroloindoline radical can be
generated through IrII reduction of the indoline moiety (a
À
SET process) followed by mesolytic cleavage of the C Br
bond. It then attacks 10 to form an a-carbonyl radical, which
is quenched by hydrogen transfer from a Et3N radical
cation[22] or an electron transfer from the IrII species[15c–e] (to
generate an enolate), followed by protolysis. The success of
this reaction is presumably due to the low concentration of
the reductive species and the slow rate of side reactions such
as the formation of debromo-9.[23] Interestingly, 9 plays
a protecting role for 10 in the reaction, by preferentially
reacting with the IrII species. We observed significant
reductive dimerization and hetero [4+2] cycloaddition reac-
tions of 10 in the absence of 9.[22,24]
With 8 in hand, we entered the final stage of drimentine G
(2) synthesis (Scheme 4). Boc deprotection with trifluoro-
acetic acid (TFA) gave diamine 16 in 98% yield, which was
mono-aminoacylated with Boc-l-valine 17a to afford amide
18a. Treatment of 18a with TFA followed by basification with
NH3·H2O furnished diketopiperazine 19a in 86% yield over
the three steps. A variety of ketone methylenation methods,
such as Wittig, Julia, Tebbe, Petasis, Nysted, and Peterson (or
ceric Peterson) reactions, failed to convert 19a into 2,
presumably due to the sterically hindered nature of 19a. To
our delight, tertiary alcohol 20a could be obtained as a single
diastereomer on a 500 mg scale through the use of a methyl
ceric reagent (generated in situ from anhydrous CeCl3 and
MeMgBr).[25] Conventional tertiary alcohol dehydration con-
ditions (MsCl/Et3N, Martin sulfurane, or Burgess reagent) did
not provide any characterizable product; BF3·OEt2 treatment
instantaneously gave the thermodynamically more-favored
trisubstituted olefin, the D14,15 isomer of 2. The optimized
conditions for dehydrating tertiary alcohol 13 (SOCl2/Et3N)
unfortunately led to a 6:1 mixture of the D14,15 and D13,14
isomers of 2. Finally, 20a was subjected to SOCl2 and pyridine
at À908C,[26] producing drimentine G (2, 43% yield) together
with its D14,15 and D13,14 isomers (ca. 5:5:1 ratio). Drimenti-
nes A and F were also synthesized through similar routes
from 16 and the corresponding Boc-l-leucine 17b and Boc-N-
Me-l-valine 17c (Scheme 4). Tertiary alcohols 20b and 20c
were obtained in four steps (68% and 43% overall yield)
through intermediates 18b/19b and 18c/19c, respectively.
Dehydration reactions under the same conditions mentioned
above furnished drimentine A (1, 35% yield) and drimenti-
ne F (3, 28% yield), respectively. The ratio of 1 and its D14,15
and D13,14 isomers was ca. 3:4:1, whereas, in the case of the
elimination of 20c, the D14,15 isomer was favored over 3 (ca.
2.4:1).
Scheme 4. Completion of the total synthesis of drimentines A, F, and
G. Reagents and conditions: a) TFA/CH2Cl2 (1:3), 228C, 2 h, 98%;
b) 17a/b (1.5 equiv), 2,4,6-collidine (3.0 equiv), HATU (1.5 equiv),
CH2Cl2, 228C, 5 h; 17c (2.0 equiv), iPr2NEt (3.0 eq), HATU (1.5 equiv),
DMF, 228C, 8 h; c) TFA/CH2Cl2 (1:3), 228C, 2 h; then aq NH3·H2O
(28 wt%)/MeOH (1:20), 228C, 10 min, 86% for 19a, 93% for 19b,
68% for 19c, over the 3 steps, respectively; d) MeMgBr (4.0 equiv),
CeCl3 (5.0 equiv), THF, 08C, 30 min; then 228C, 30 min, 73% for 20a;
73% for 20b, 63% for 20c; e) SOCl2 (5.0 equiv), pyridine (10.0 equiv),
CH2Cl2, À908C, 5 min, 43% for 2, 35% for 1, 28% for 3. DMF=dime-
thylformamide, HATU=o-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetrame-
thyluronium hexafluorophosphate, TFA=trifluoroacetic acid.
As shown in Scheme 5, treatment of drimentine F (3) with
[27]
Bi(OTf)3/KPF6 smoothly rendered indotertine A (5, 78%
Scheme 5. Conversion of drimentine F into indotertine A. Reagents
and conditions: a) Bi(OTf)3 (1.0 equiv), KPF6 (1.0 equiv), 228C, 2 h,
78%. Tf=trifluoromethanesulfonate.
yield), presumably through the path depicted in Scheme 1.
The spectral and physical properties of the synthetic drimen-
tines A, F, and G, and indotertine A were identical to those
reported for the natural samples, which also verified their
absolute configuration.[7b]
In conclusion, we have developed a concise route to
accomplish the first total synthesis of drimentines A, F, and G,
and indotertine A. The key intermediate for this synthesis was
4
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assembled by an intermolecular radical conjugate addition.
Photoredox catalysis played a determining role in the success
of this transformation. A biologically inspired iminium–olefin
cyclization was exploited to convert drimentine F into indo-
tertine A. This synthesis is expected to facilitate the biological
studies on these naturally scarce compounds.
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Received: April 19, 2013
Revised: June 20, 2013
Published online: && &&, &&&&
Keywords: conjugate addition · iminium-olefin cyclization ·
.
photoredox catalysis · pyrroloindoline alkaloids · total synthesis
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[11] For selected examples, see: a) D. A. Nagib, D. W. C. MacMillan,
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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