Concise Total Synthesis of Herqulines B and C

Article abstract of DOI:10.1021/jacs.8b13029

A simple total synthesis of herqulines B and C is reported, modeled on the reductive biosynthesis reported previously by other researchers. Commencing from tyrosine, these alkaloids were fashioned through a dimerization, macrocyclization, and four consecu

Full text of DOI:10.1021/jacs.8b13029

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Communication
Concise Total Synthesis of Herqulines B and C
Chi He, Thomas P Stratton, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Dec 2018
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Concise Total Synthesis of Herqulines B and C
Chi He,§ Thomas P. Stratton,§ and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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Supporting Information Placeholder
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cycle or linear precursor (Figure 1B). Such knowledge
influenced our first forays and thus numerous pathways
were explored before returning to the current approach
outlined herein. From a tactical standpoint, it is worth men-
tioning that, in accordance with most total synthesis en-
deavors,11 puzzling stability features of each intermediate
dictated a specific sequence of events leading to the final
route.
ABSTRACT: A simple total synthesis of herqulines B and
C is reported, modeled on the reductive biosynthesis re-
ported by Tang and co-workers. Commencing from tyro-
sine, these alkaloids were fashioned through a dimeriza-
tion, macrocyclization, and four consecutive reductions.
Emerging from these studies are strategic insights on the
synthesis of these strained alkaloids, as well as mild condi-
tions for the exhaustive reduction of diketopiperizines.
A. Strained tyrosine-derived natural products
HO
O
HO
HO
From morphine to vancomycin, tyrosine-based natural
products comprise some of the most fascinating and bio-
logically significant structures ever isolated.1 As a particu-
larly redox-active amino acid, most biosyntheses of iso-
lates originating from tyrosine involve key oxidative ma-
nipulations of the phenol moiety, leading to remarkable
diversity.2 Early studies from Barton3 cemented the logic
of how oxidized phenols prefer to react, and decades of
biosynthetic studies have revealed the enzymatic machin-
ery responsible for initiating such events.2 Our own studies
in the area of tyrosine-based natural products have focused
on peculiar frameworks notable for their strained cyclo-
phane cores (Figure 1A), such as haouamine (1) and ary-
lomycin (2). In both instances, strain was introduced
through oxidative events; the former relying on a late-stage
unsaturation4 and the latter on a specific Cu-based oxi-
dant.5 The herquline family, first isolated by Ōmura in
1979 from Penicillium herquei,6 of which herquline B (3)
is a representative member,7 was of particular appeal due
to its extensively reduced framework. A landmark study by
the Tang group8 recently revealed its unusual reductive
biosynthesis, while the Wood group demystified the stere-
ochemistry of 3 in their elegant synthesis.9 The difficulty
of assembling such structures is well documented and is
described in detail below. This Communication outlines a
concise entry into the herquline family that strategically
mirrors the biosynthesis by employing a carefully choreo-
graphed sequence of chemical reductions from a simple
tyrosine-based starting material.
H
HO
[-H2]
HO
N
N
ref. 4
H
H
Strain induced
through [O]
HO
haouamine (1)
HO
Δ-1
R
R
Me
N
Me
N
[-H2]
OH
OH
OH
OH
O
O
ref. 5
NH
NH
Me
Me
NH
O
NH
O
HO2C
arylomycin (2)
HO2C
Δ-2
OMe
Strain relieved
through [H]
O
O
OMe
H
4 x [+H2]
H
O
H
N
H
N
this work
H
H
N
H
N
Me
4
H
Me
herquline B (3)
O
B. High level summary of documented failures:
O
OMe
O
O
OMe
O
I I
Despite the apparent simplicity of its 2-D depiction and
the direct nature of the approach described below, the jour-
ney towards the herqulines was far from straightforward.
Indeed, this small, strained alkaloid has confounded sever-
al others as documented by the impressive collection of
approaches found in the dissertation literature.10 Structural-
ly, the herqulines contain an unsymmetrical basic diamine
wrapped within a bowl-shaped macrocycle containing two
b,g-unsaturated enones. From a strategic standpoint, sever-
al others10 have recounted efforts to these structures based
on unsuccessful phenol-oxidative coupling, iodoenone-
reductive coupling, and Birch reduction of a biaryl macro-
X
H
O
X
H
N
H
N
N
H
N
H
H
H
N
H
H
N
H
Me
X
closure not viable
Me
O
X
phenol coupling and
Birch fail
Figure 1. (A) Strained tyrosine-derived natural products
are generally prepared through oxidation events with
herquline as a notable outlier; (B) Summary of selected
failed routes.
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Scheme 1. Total Synthesis of Herqulines B (3) and C (9).a
OMe
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1
2
3
I
MeO
I
OMe
OMe
4
5
6
7
8
9
OMe
I
O
CO2Me
O
3. Pd(0),
B2Pin2
1. HATU,
DIPEA
2. a. HCO2H
b. 105 ℃
NH
O
MeN
O
CO2R
H
N
MeN
[>30 gram
scale]
[gram scale]
60 %
NHR’
BocHN
H
70 % over
2 steps
N
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
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23
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O
4: R = H, R’ = Boc
5: R = R’ = Me
I
6
7
8
OMe
4. Li (0), NH3
TFE
I
77%
OMe
OMe
OMe
H
OMe
OMe
OMe
O
OMe
O
H
O
H
O
H
5. [Ir(COE)Cl]2
Et2SiH2
7. Li (0), NH3
t-BuOH
6. H+,
O
H
N
H
N
H
N
86%
OH
H
N
HO
H
H
H
N
Me
N
Me
H
H
N
Me
H
H
N
Me
H
O
12 (used crude)
13
10
9
oxalic acid
MeOH:H2O
(3:1)
1N HCl
O
O
O
OMe
O
O
H
H
then
DBU,toluene
30 min
H
H
H
H
N
H
N
H
N
28% from 10
H
H
N
Me
H
H
N
Me
H
N
Me
H
11
11
herquline C (14)
(+)–herquline B (3)
aReagents and conditions: (1) HATU (1.2 eq), DIPEA (1.5 eq), DMF, rt, overnight. (2) Formic acid, then sBuOH:PhMe (3:1), 105 ºC
(70% yield over 2 steps). (3) Pd(dppf)Cl2 (20 mol%), B2Pin2 (4.0 eq), K2CO3 (6.0 eq), DMSO:H2O (100:1, 20 mM), 90 ºC, overnight
(60% yield). (4) Li(0) (15 eq), NH3, F3CCH2OH (8.0 eq), THF, -78 ºC, 1 h (77% yield). (5) [Ir(COE)2Cl]2 (20 mol%), Et2SiH2 (10 eq),
PhMe, 2 h reflux (86% yield). (6) PTSA (0.5 eq), ethylene glycol (15 eq), benzene, Dean-Stark trap, reflux. (7) Li(0) (15 eq), NH3,
tBuOH:THF (1:10), -78 ºC, 2 h; THF/MeOH:1N HCl (3:1); DBU, PhMe, 30 min, rt (28% over 3 steps). HATU = 1-[Bis-
(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = N,N-diisopropylethylamine; DMF
= N,N-dimethylformamide; PhMe = toluene; dppf = 1,1’-Bis(diphenylphosphino)ferrocene; DMSO = dimethylsulfoxide; sBuOH = sec-
butyl alcohol; THF = tetrahydrofuran; COE = cyclooctene; PTSA = p-toluenesulfonic acid; DBU = 1,8-Diazobicyclo(5.4.0)undec-7-ene.
The synthesis of 3 commenced (Scheme 1) from known
tyrosine-derived building blocks 4 and 5.12 Amide bond
formation mediated by HATU delivered dipeptide 6 which
was subjected to standard diketopiperazine (DKP) ring-
forming conditions (HCO2H followed by heat)13 to furnish
7 in 70% overall yield from 4/5. The ensuing Pd-catalyzed
macrocyclization to 8 was accomplished by adopting a pro-
cedure initially reported by Hutton14 and further improved
by Schindler.15 In order to increase the yield further and
perform the reaction on a larger scale (4.6 gram), increas-
ing the concentration (20 mM) proved helpful.
function of intermediate stability and reactivity. The first
reduction was achieved using a venerable Birch reduction16
to deliver enol ether 9 in 77% yield. The proton source
(TFE) was essential to deliver the regiochemical outcome
observed to deliver the 1,2/4,5 unsaturation (vs. the isomer-
ic 3,4/1,6 diene that was observed when employing a range
of other alcoholic proton sources). At this juncture the
mechanistic basis of this empirical observation is unclear.
The substituents on the DKP also appear to play a role in
governing selectivity as the N,N-dimethyl congener deliv-
ered exclusively the wrong selectivity. The next two reduc-
tions required chemoselective excision of the DKP ox-
ygens, a maneuver historically accomplished using DIBAL
or LAH.17 Exposure of 9 to either of these strong reducing
agents led to monoreduction of the tertiary amide or de-
To convert 8 to the herquline core, no less than four re-
ductions needed to be achieved. The precise order of events
that appears in Scheme 1 was thus dictated empirically as a
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composition, respectively. Ultimately, Brookhart’s Ir-based
Author Contributions
reduction protocol18 provided a mild and reliable means to
accomplish both reductions, thereby delivering 10 in 86%
yield. To the best of our knowledge, this is the first use of
such conditions to achieve exhaustive DKP reduction and
will likely be useful in other contexts. The complete stereo-
chemistry and structural assignments thus far were con-
firmed by X-ray crystallography of enone 11 after mild
acidic hydrolysis.
§These authors contributed equally to this paper and are
1
2
3
4
5
6
7
8
listed alphabetically.
ACKNOWLEDGMENTS
We are grateful to Professor John L. Wood for sharing a
copy of ref. 9 prior to publication. Financial support for this
work was provided by NIH (GM-118176). We thank Dr.
D.-H. Huang and Dr. L. Pasternack for NMR spectroscopic
assistance, Prof. A. L. Rheingold and Dr. C. E. Moore for
X-ray crystallographic analysis, and Dr. Jason Chen for
helpful discussions.
The final reduction of 10 to access the herqulines proved
extremely challenging, in accord with reports from others.
All Birch reduction conditions screened on this substrate
either cleanly returned 10 or led to reduction of the homo-
benzylic positions (4,5 and/or 1,2) before reducing the final
aromatic ring. Such a result is not surprising given that
Birch reductions of biaryls16 without overreduction of one
of the arenes is rare. It was reasoned that introducing two
additional sp3 carbon centers would both alleviate strain
and prevent overreduction from occurring. Thus, exposure
to ethylene glycol in the presence of PTSA led to clean
conversion to ketal 12 which was taken forward in crude
form to a final Birch reduction. Again, the proton source
(TFE provided no observed product, whereas tBuOH was
clean) proved pivotal in delivering reduced macrocycle 13.
This ketal-enol ether containing structure was then hydro-
lyzed with 1N HCl to deliver herquline C (14) and B (3) as
an isolated 5:1 mixture. It should be noted that the crude
reaction mixture was enriched in 14 but over time we no-
ticed that it slowly converted to (–)-3.19 To complete the
synthesis of 3, the mixture of isomers was simply treated
with DBU in toluene for 30 minutes (28% overall yield
from 10). In contrast to prior reports,8,9 3 appears to be
thermodynamically stable when using the above conditions
as no change was observed even at 90 °C with excess DBU
after 10 h. It is worth emphasizing that our initial target
was 3 (not 14) and that Wood’s inaugural synthesis9 al-
lowed for rapid assignment of the 3/14 mixture.
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(3) Barton, D. H. R., Some Recollections of Gap Jumping;
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kubo, T.; Tomosawa, K.; Iwai, Y.; Ōmura, S. Herquline B, a
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Soc. 2016, 138, 13529–13532.
(9) Cox, J. B.; Kimishima, A.; Wood, J. L. Total Synthesis of
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(10)(a) Kim, G. T. Ph.D. Thesis, Korea Advanced Institute of
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(11) (a) Sierra, M. A.; de la Torre, M. C. Dead Ends and Detours:
Direct Ways to Successful Total Synthesis; Wiley-VCH: Zur-
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More Dead Ends and Detours: En Route to Successful Total
Synthesis; Wiley-VCH: Zurich, 2013.
A number of strategic and tactical challenges needed to
be overcome to access the strained, reduced cyclophane
architecture of the herqulines. The peculiar selectivity of
late-stage Birch reductions in highly complex settings as a
function of subtle structural changes and differing proton
sources is notable. The chemoselective complete reduction
of DKPs using an Ir/silane system is a useful observation
that enabled this route. The syntheses reported here are
another reminder of the role of careful experimentation to
overcome tactical hurdles in the pursuit of a strategically
concise (7-8 steps from iodotyrosine building blocks)
pathway.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, ana-
lytical data (1H and 13C NMR, MS) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
(12) See supporting information for preparation of known build-
E-mail: pbaran@scripps.edu (P.S.B.).
Notes
The authors declare no competing financial interest.
ing blocks.
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(15) Zhu, X.; McAtee, C. C.; Schindler, C. S. Scalable Synthesis
of Mycocyclosin. Org. Lett. 2018, 20, 2862–2866.
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Compounds. In Organic Reactions, Denmark, S. E., Ed.;
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(17) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Design and
Synthesis of Novel C2-Symmetric Chiral Piperazines and an
Application to Asymmetric Acylation of ∂-Symmetric 1,2-
Diols. Org. Lett. 2006, 8, 6139–6142.
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(18) Cheng, C.; Brookhart, M. Iridium-Catalyzed Reduction of
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ethylsilane. J. Am. Chem. Soc. 2012, 134, 11304–11307.
[seven steps] [strain-relieving reductions] [mild DKP deoxygenation]
OMe
OMe
O
OMe
O
H
I
H
O
H
N
H
N
4 x [+H2]
H2N
H
H
herquline B
N
Me
N
Me
H
H
CO2H
O
The herqulines: a decades-old challenge for synthesis
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