Ci-H bond arylation in the synthesis of aryltetralin lignans: A short total synthesis of podophyllotoxin

Article abstract of DOI:10.1002/anie.201311112

A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd-catalyzed C(sp³)-H arylation reaction enabled by a conformational biasing element to promote C-C reductive elimination over an alternative Ci-N bond-forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers. Testing a new tactic: In a concise synthesis of podophyllotoxin with a crucial palladium-catalyzed arylation step, subtle conformational effects govern reductive elimination pathways from the high-valent palladium center. This route to aryltetralin lignan derivatives may be of interest in drug discovery.

Full text of DOI:10.1002/anie.201311112

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DOI: 10.1002/anie.201311112
Total Synthesis
Hot Paper
ꢀ
C H Bond Arylation in the Synthesis of Aryltetralin Lignans: A Short
Total Synthesis of Podophyllotoxin**
Chi P. Ting and Thomas J. Maimone*
Abstract: A short total synthesis of podophyllotoxin, the
prototypical aryltetralin lignan natural product, is reported.
Key to the success of this synthetic pathway is a Pd-catalyzed
C(sp3)–H arylation reaction enabled by a conformational
biasing element to promote C–C reductive elimination over an
ꢀ
alternative C N bond-forming pathway. This strategy allows
for access to the natural product in five steps from commer-
cially available bromopiperonal, and sheds light on subtle
conformational effects governing reductive elimination path-
ways from high-valent palladium centers.
P
lant-derived aryltetralin lignans have found myriad use in
the treatment of disease owing to their potent antiviral,
antibacterial, and antineoplastic properties.[1] In the area of
cancer chemotherapy, they have proven particularly valuable
as the prototypical member, podophyllotoxin (1), serves as
starting material for the widely used type II topoisomerase
targeting drugs etoposide (VP-16) (2) and teniposide (VM-
26) (3) used for the treatment of lung and testicular cancer,
lymphoma, leukemia, and Kaposiꢀs sarcoma (Figure 1a).[2]
Owing to perceived future scarcity of 1, as well as the desire to
produce superior anticancer agents, there has been intense
interest in the synthesis of these compounds for 50 years.[3]
While numerous total syntheses of 1 and 4-epi 1 have been
reported to date, many of which utilize uniquely creative
synthetic strategies, the development of clinical candidates
superior to 2 has been exceedingly slow. Without question,
a lack of three-dimensional structural insight into the binding
of 2 to the cleavage complex formed between DNA and
type II topoisomerase (Top2) has been a significant impedi-
ment. Given the recently disclosed X-ray crystal structure of
a Top2/DNA/2 cleavage complex,[4] the sophistication of this
drug class is poised to undergo further advancement. A
synthesis of this family of compounds which can easily modify
the aromatic residues in a manner that is independent of their
electronic nature would be highly enabling from the vantage
point of diverse analogue preparation.[5] Herein we report
ꢀ
Figure 1. a) Podophyllotoxin and related anticancer agents. b) A C H
activation approach to the aryltetralin lignan class.
shed light on subtle conformational effects influencing
reductive elimination pathways from high-valent palladium
centers.
Our retrosynthetic analysis of the aryl tetralin lignan class
is shown (Figure 1b). We envisioned that a cyclopalladated
intermediate (5) could serve as a late-stage entry into the
aromatic-ring-modified substrates (4). The pioneering work
of Daugulis,[6] Yu,[7] Chen,[8] and others,[9] in the area of amide-
directed, Pd-catalyzed C(sp3)–H arylation and alkylation, as
well as several formidable applications in total synthesis,[10]
served as our inspiration for this work. Nevertheless, con-
ꢀ
struction of the highly hindered C C bond in 4 in the presence
of multiple electron-rich aryl rings and an epimerizeable
chiral center, and the opportunity for thermodynamically
favorable naphthalene formation, was of particular concern
to us in the context of the task at hand.
ꢀ
We began our studies by preparing C H arylation
ꢀ
a C H arylation approach to the aryltetralin lignans that is
precursor 8 bearing the extensively utilized 8-aminoquino-
line-derived directing group (Scheme 1).[6,11] Epoxidation of
6-bromopiperonal, benzocyclobutenol formation, and silyla-
tion afforded 6 in a scalable, three-step procedure.[12] Thermal
cycloaddition of 6, via an o-quinodimethane intermediate,
distinct from all other synthetic strategies. These studies have
[*] C. P. Ting, Prof. Dr. T. J. Maimone
Department of Chemistry, University of California, Berkeley
826 Latimer Hall, Berkeley, CA 94720 (USA)
E-mail: maimone@berkeley.edu
ꢀ
with fumarate-derived amide 7 afforded C H activation
precursor 8. While the yield and diastereoselectivity of this
reaction was poor, this process allowed for the preparation of
gram quantities of 8 and no optimization attempts were made
at this point. Attempted coupling of 8 with 3,4,5-trimethox-
[**] We thank UC-Berkeley for generous start-up funding and the NSF for
a predoctoral fellowship to C.P.T. (DGE-1106400). We thank Dr.
Antonio DiPasquale and Dr. Chris Canlas for X-ray crystallographic
and NMR spectroscopic assistance, respectively.
ꢀ
yiodobenzene under a variety of common catalytic C H
arylation conditions (Pd(OAc)2, base, solvent) surprisingly
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311112.
afforded b-lactam 9 as the major product along with
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Scheme 1. Initial C H arylation attempts. Reagents and conditions: a) 6-bromopiperonal (1 equiv), Me3SI (2.7 equiv), BnNEt3Cl (4 mol%), 1:1
DCM/19m NaOH (v/v), 08C!RT, 24 h; b) nBuLi (1.2 equiv), MgBr2 (2 equiv), 10:3 Et2O/THF (v/v), ꢀ788C!08C, 1 h, 50% over two steps;
c) TIPSCl (2.2 equiv), imidazole (3.0 equiv), DMF, RT, 12 h, 90%; d) 6 (3 equiv), 7 (1 equiv), PhH, 808C, 24 h, 40% (d.r. 2.6:1); e) Pd(OAc)2
(15 mol%), 3,4,5-trimethoxyiodobenzene (3 equiv), Ag2CO3 (3.0 equiv), tBuOH, 1108C, 24 h, 30% of 9 +30% 8; f) Pd(OAc)2 (1 equiv), MeCN,
608C, 1.5 h, 53%; g) 10 (1 equiv), 3,4,5-trimethoxyiodobenzene (3 equiv), K2CO3 (1 equiv), tBuOH, 808C, 3 h, 74%; h) LiAlH4 (2 equiv), THF,
ꢀ788C!08C, 1 h, 38%; i) 1. TBAF (2 equiv), THF, ꢀ788C!258C, 4 h; 2. p-TsOH (10 mol%), 5:3 2,2-dimethoxypropane/THF (v/v), RT, 12 h,
81%; j) Pd(OAc)2 (1 equiv), MeCN, 608C, 1.5 h, 38%; k) 12 (1 equiv), 3,4,5-trimethoxyiodobenzene (3 equiv), K2CO3 (1 equiv), tBuOH, 1108C,
50%. DCM=dichloromethane, DG=directing group, TIPS=triisopropylsilyl, TBS=tert-butyldimethylsilyl, TBAF=tetrabutylammonium fluoride.
substantial amounts of recovered starting material. An X-ray
crystal structure of the OTBS derivative of 9 confirmed the
structure of this unusual product. These results were similar
with and without silver additives, and in all cases the typically
cyclohexene-type ring (podophyllotoxin C-ring), however, is
unusual in 10; this ring adopts a twist-boat conformation,
presumably to accommodate the palladacycle and position
the bulky OTIPS group in an equatorial position. The
measured distances shown in Scheme 1 attest to the highly
crowded environment surrounding the underside of this ring.
ꢀ
observed arylated product was not formed. While direct C N
bond reductive elimination of the amide directing group
nitrogen has been documented,[6d,13] as has the formation of
four-membered azetidine[8d,9c] and b-lactam rings,[9f,13,14] these
results were particularly surprising given that the majority of
It has been proposed that PdIV species are involved in these
[6b]
ꢀ
amide-directed C H arylation reactions, and if such con-
formational constraints are present in an octahedral or
prior reports utilized conditions incapable of forming C C
square-pyramidal PdIV intermediate, C C reductive elimina-
ꢀ
ꢀ
bonds.[14] In an effort to better understand the origins of 9 in
our system, we prepared acetonitrile-bound, PdII complex 10
postulated to be an intermediate in these arylation reactions
(Scheme 1). Unlike previous reports involving similar palla-
dacycles,[6b] heating this complex in the presence of excess aryl
iodide (tBuOH, K2CO3, 808C) cleanly formed b-lactam 9 in
tion from a high-valent form of 10 would incur significant
ꢀ
strain as the axial C Caryl bond begins to form, and the
resulting amide-ligated PdII center is forced to rotate under-
neath this crowded ring.[16,17]
Taking this hypothesis in account, we then prepared
conformationally distinct substrate 11 by
a selective
ꢀ
75% yield, again without formation of the typical C C
ester reduction/desilylation/ketalization sequence from 8
(Scheme 1). In analogy to 8, treatment of this substrate with
stoichiometric Pd(OAc)2 in MeCN formed square-planar PdII
complex 12. An X-ray crystal structure of 12 revealed that the
bonding arrangement at the PdII center is nearly identical to
that in 10, yet the rigid cyclic acetonide locks the six-
membered C-ring into a half-chair-like conformation. This
coupled product. Small amounts of biaryl side product were
also detected in these experiments.[15]
Compared to similar cyclometalated species which have
been crystallographically characterized,[6b] the structure of 10
shows no abnormalities with respect to the bonding arrange-
ment around the palladium center. The conformation of the
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conformational controlling element forces the palladacycle
away from the underside of the six-membered ring relative to
the orientation in 10. When 12 was heated in the presence of
excess 3,4,5-trimethoxyiodobenzene and K2CO3 (tBuOH,
1108C), arylated product 13 was formed as the major product
(50%) along with small amounts of b-lactam (10% yield).
These results suggest that subtle conformational effects
ꢀ
ꢀ
dictate the mode of reductive elimination (C C vs. C N) in
the context of this rigid polycyclic system.
ꢀ
With confirmation that C C coupling is possible, we
ꢀ
began to examine catalytic conditions for the C H arylation
reaction (Table 1). In addition to 8-aminoquinoline-derived
substrate 11, amide 14, which contains the related 2-thiome-
thylaniline-based directing group, was also evaluated.[6] The
Table 1: Pd-catalyzed C-H arylation: selected optimization.[a–d]
Entry Substrate Base
Solvent
toluene
Additive
AgOAc
Yield[b]
1
2
3
4
5
6
11
11
14
14
14
16
CsOAc
Ag2CO3 t-AmOH none
K2CO3
K2CO3
K2CO3
K2CO3
5%
10%
35%
35%
t-AmOH none
t-AmOH 40% PivOH
t-AmOH 40%(BnO)2PO2H 45%
Scheme 2. Top: Short total syntheses of 1 and 4-epi-1. Bottom: Ana-
t-AmOH 40%(BnO)2PO2H 58%[c,d]
logues synthesized in two steps from 14. Reagents and conditions:
a) 16 (1 equiv), 15 (2 equiv), KHMDS (2.2 equiv), THF, ꢀ788C!
08C!ꢀ788C, 1 h, 1. then LiEt3BH (4 equiv), 30 min; 2. p-TsOH
(10 mol%), 2:1 2,2-dimethoxypropane/THF (v/v), RT, 12 h, 41% over-
all; b) see Table 1, entry 6, 58%; c) 1:1:1 TFA/THF/H2O (v/v/v), RT,
[a] Conditions: 11 or 14 (0.02 mmol), Pd(OAc)2 (20 mol%), base
(3.0 equiv), ArI (4 equiv), solvent (1 mL), 1108C, 24 h. [b] Yield deter-
mined by 1H NMR spectroscopy using 2-chloroquinoline as an internal
standard. [c] Yield of isolated product. [d] Pd(OAc)2 loading=15 mol%,
ArI (2 equiv), K2CO3 (1.5 equiv), [14]=0.1m, t=50 h, 15% recovered 14
also isolated. ArI=3,4,5-trimethoxyiodobenzene.
ꢀ
24 h, 43% yield of 1, 33% yield of 4-epi-1. [a] Yield of isolated C H
arylated product. [b] Yield of isolated cyclization products as C-4
diastereomers (crude d.r.ꢁ1.5:1 in all cases). [c] Yield determined by
1H NMR analysis. HMDS=hexamethyldisilazide, TFA=trifluoroacetic
acid.
ꢀ
optimization of the C H arylation reaction proved to be
a daunting challenge and was plagued by low yields, decom-
position pathways, and poor catalyst turnover. After we had
examined a variety of bases and solvents (selected examples
shown), results remained modest. While incorporation of
pivalic acid as an additive[10b] had little effect on the outcome
of superhydride directly to this mixture led to efficient in situ
ester reduction, and following workup and ketalization of the
crude material (dimethoxypropane, pTsOH), arylation pre-
cursor 14 was obtained in 41% overall yield as a single
diastereomer from 15 with only one chromatographic purifi-
ꢀ
of this C H arylation, the addition of substoichiometric
quantities of dibenzyl phosphate, recently utilized by the
Chen[8a,b] and Shi groups,[9d] improved the yield of coupling to
45% (Table 1, entry 5). After adjusting the concentration and
reaction time, we were able to achieve a synthetically useful
58% yield of arylated product using 2 equivalents of ArI and
15 mol% Pd(OAc)2 loading (Table 1, entry 6).
ꢀ
cation. Following C H arylation, we investigated conditions
for removal of the directing group—a task that has historically
proven quite challenging. After significant experimentation,
it was found that simply stirring the arylated product in
a mixture of TFA/THF/H2O at room temperature directly
affords podophyllotoxin (1) (43% yield of isolated product)
as well as C-4 epi-1 (33% yield of isolated product) which has
the same configuration as etoposide. Overall this constitutes
a five-step total synthesis of these compounds requiring only
three chromatographic purifications.
ꢀ
With suitable conditions for C H arylation in hand, we
returned to the total synthesis of 1 (Scheme 2, top). Depro-
tonation of free cyclobutanol 15 with potassium hexamethyl-
disilazide allowed for low-temperature o-quinodimethane
formation[18] and a subsequent highly diastereoselective
cycloaddition with 2-methylthioaniline-containing amide 16
(prepared in one step from monomethyl fumarate). Addition
To date, the vast majority of aryltetralin lignan derivatives
have come from semisynthetic modification of podophyllo-
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stable cis-lactone counterpart (picropodophyllotoxin) largely
limits the chemistry that can be employed during such
endeavors.[5] A C H arylation approach allows for the
ꢀ
preparation of novel arene-modified podophyllotoxins (see
17–20), including heteroaryl derivatives, in only two steps
from amide 14 (Scheme 2, bottom). Notably, these com-
pounds cannot be easily accessed from natural sources, and
would otherwise require more lengthy individual syntheses.
Given the outstanding track record of this natural product
class in drug discovery, we envision that this synthetic
pathway will greatly accelerate the pace at which new
aryltetralin lignans with improved and/or novel biological
activity are discovered.
In summary, we have developed a short total synthesis of
the therapeutically important plant natural product podo-
ꢀ
phyllotoxin (1) and 4-epi 1 enabled by a C H arylation
strategy for aryltetralin lignan construction. Synthetic meth-
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cally been complicated with mixtures of products resulting
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directing-group control as well as electronic modulation of
the aryl iodide.[9c,14] The studies reported herein imply that
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substantially altered by remote conformational effects and
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ꢀ
even the normally facile C C bond reductive elimination
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Received: December 23, 2013
Published online: February 12, 2014
Keywords: C–H activation · lignan · natural products ·
.
total synthesis
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[12] E. Akgꢅn, E. M. B. Glinski, K. L. Dhawan, T. Durst, J. Org.
[15] This experiment was also performed without K2CO3 as well as
with Ag2CO3. In all cases, 9 was formed exclusively.
[16] Ligand dissociation from an octahedral PdIV center typically
ꢀ
precedes C C reductive elimination, see: A. J. Canty, Acc.
Chem. Res. 1992, 25, 83.
[17] A ring flip would place the bulky OTIPS group in a pseudo-axial
position.
[18] W. Choy, H. Yang, J. Org. Chem. 1988, 53, 5796.
[19] For a discussion on this topic, see: K. M. Engle, T.-S. Mei, X.
Wang, J.-Q. Yu, Angew. Chem. 2011, 123, 1514; Angew. Chem.
Int. Ed. 2011, 50, 1478.
Chem. 1981, 46, 2730.
[13] For two-step b-lactam synthesis through based on C H func-
ꢀ
ꢀ
tionalization (i.e. C H halogenation/cyclization, see: M. Wasa,
J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 14058 – 14059.
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