Synthesis of (+)-Pancratistatins via Catalytic Desymmetrization of Benzene

Article abstract of DOI:10.1021/jacs.7b10351

A concise synthesis of (+)-pancratistatin and (+)-7-deoxypancratistatin from benzene using an enantioselective, dearomative carboamination strategy has been achieved. This approach, in combination with the judicious choice of subsequent olefin-type difunctionalization reactions, permits rapid and controlled access to a hexasubstituted core. Finally, minimal use of intermediary steps as well as direct, late stage C-7 hydroxylation provides both natural products in six and seven operations.

Full text of DOI:10.1021/jacs.7b10351

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Synthesis of (+)-pancratistatins via catalytic desymmetrization of benzene
Lucas W. Hernandez, Jola Pospech, Ulrich Kloeckner, Tanner W. Bingham, and David Sarlah
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Oct 2017
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Synthesis of (+)-pancratistatins via catalytic desymmetrization of
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Lucas W. Hernandez, Jola Pospech, Ulrich Klöckner, Tanner W. Bingham, David Sarlah*
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA
Supporting Information Placeholder
With the foregoing analysis in mind, we recognized that the
development of a dearomatization process9 that would also result
in desymmetrization of benzene10 was critical to our synthetic
plan. We hypothesized that the application of visibleꢀlightꢀ
promoted paraꢀcycloaddition of the N–N arenophile MTAD (4),11
in combination with an aryl nucleophile (ArM) and transition
metal catalysis (TM cat.), could provide transꢀcarboaminated
product 6 (Figure 2). Specifically, the intermediate MTADꢀ
benzene cycloadduct 5 could serve as a viable substrate for
ABSTRACT: A concise synthesis of (+)ꢀpancratistatin and (+)ꢀ
7ꢀdeoxypancratistatin from benzene using an enantioselective,
dearomative carboamination strategy has been achieved. This
approach, in combination with the judicious choice of subsequent
olefinꢀtype difunctionalization reactions, permits rapid and conꢀ
trolled access to a hexasubstituted core. Finally, minimal use of
intermediary steps as well as direct, late stage Cꢀ7 hydroxylation
provides both natural products in six and seven operations.
Me
O
TM cat.
ArM
visible
O
light
N
N
O
+
N
The plantꢀderived metabolites (+)ꢀpancratistatin (1)1 and (+)ꢀ7ꢀ
NMe
N
N
Ar
deoxypancratistatin (2)2 belong to
a family of densely
NRR'
O
3
4
benzene ( ) MTAD ( )
6
functionalized and stereochemically complex Amaryllidaceae
alkaloids that are well known for their potent anticancer activity
(Figure 1).3 For example, pancratistatin (1) showed substantial in
vivo activity against murine Pꢀ388 lymphocytic leukemia and
murine Mꢀ5076 ovary sarcoma, and reduced growth of
subcutaneous colon HTꢀ29 tumors.4 Moreover, experiments
examining pancratistatinꢀinduced apoptosis revealed noticeably
reduced death in nonꢀcancerous cells relative to cancer cell lines,
making these compounds appealing clinical lead candidates.5
Finally, pancratistatins also showed significant antiviral activities,
including in vivo models for Japanese encephalitis,6 a disease for
which no other known smallꢀmolecule antiꢀinfective agent exists.
benzene-MTAD
[arenophile]
5
cycloadduct ( )
mechanistic rationale:
LnTMn
decomplexation
complexation
LnTMn
LnTMn
M
N
O
N
O
N
H
N
Ar
N
NMe
O
NMe
N
O
IV
I
Ar
NMe
O
O
6
reductive
elimination
oxidative
addition
LnTMn+2
Ar
M
LnTMn+2
N
N
N
O
N
O
NMe
II
III
NMe
O
O
transmetalation
ArM
Figure 2. Design of dearomative transꢀcarboamination sequence.
Figure 1. Structures of pancratistatin (1) and 7ꢀ
deoxypancratistatin (2) and their retrosynthetic analysis.
oxidative addition due to its bisꢀallylic bridgehead positions
bearing an electronꢀdeficient urazole.12 Mechanistically, we
envisioned this catalytic process as commencing with πꢀ
coordination of the diene to the metal complex anti to the
arenophile moiety (5→I). Subsequent oxidative addition should
give cyclohexadienyl intermediate II, which should undergo
transmetalation with an aryl metal reagent to form species III.
This symmetric η5ꢀcomplex can then undergo reductive
These promising biological properties made pancratistatins
exceptionally attractive targets for chemical synthesis.7,8
Nevertheless, despite numerous impressive efforts, only milligram
quantities of pancratistatins have been prepared to date. Herein,
we report a scalable and concise synthesis of (+)ꢀpancratistatin (1)
and (+)ꢀ7ꢀdeoxypancratistatin (2) from benzene (3) using a
dearomative functionalization approach. Using this strategy,
benzene can be seen as a surrogate for the hypothetical 1,3,5ꢀ
cyclohexatriene that could readily undergo three olefinꢀtype
functionalizations and enable key retrosynthetic simplifications
(Figure 1).
elimination to deliver diene complex IV.
Finally, diene
decomplexation yields the product and regenerates the metal
catalyst. The central feature of this design is the generation and
capture of η5ꢀcyclohexadienyl reactive intermediate; the desired
1,2ꢀsiteꢀselectivity of the carboamination process would be
favored because of the greater positive charge localized on the
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termini of the η5ꢀsystem.13 Though no catalytic processes
protocol involving epoxidation with mCPBA and subsequent
1
2
3
4
5
6
7
8
involving cyclohexadienyl complexes exist to date, such
outcomes are well precedented in cases wherein cationic
cyclohexadienylmetal complexes react with nucleophiles in a
stoichiometric fashion.14 Importantly, because of the symmetrical
nature of the η5ꢀintermediate III, a suitable chiral ligand bound to
the metal center could enable enantiodiscrimination that involves
the differentiation of the enantiotopic termini of the
cyclohexadienyl system, forming the desired product in an
enantioselective fashion.
epoxide hydrolysis in the presence of pTsOH and a large excess
of water.16 In addition, the use of hexafluoroisopropanol (HFIP)
as the solvent was essential to obtain diol product 11 in 74%
yield.17 Exposure of the remaining alkene in 11 to Upjohn
dihydroxylation conditions18 provided tetraol 12 in 91% yield and
as a single stereoisomer. Importantly, this step completes the
trifold olefin difunctionalization sequence that transforms benzene
into the fully decorated pancratistatin core, establishes all six
contiguous stereocenters, and sets the stage for lactam
construction. To this end, deprotection of urazole 12 to free amine
14 using conditions to effect hydrolysis and N–N bond cleavage
proved challenging, as aggressively acidic or basic conditions led
to complete decomposition of starting material. Therefore, we
explored hydrideꢀbased reducing agents and found that treatment
of 12 with LiAlH4 could reduce the urazole; however, the
resulting cyclic hydrazine hemiaminal 13 proved unstable,
complicating its isolation and the overall reproducibility of this
step. To overcome this hurdle, we decided to developed a oneꢀpot
protocol that directly reduced urazole 12 to amine 14 without
handling the sensitive intermediate 13. Thus, LiAlH4 reduction,
followed by aqueous quench and subsequent addition of Raney®ꢀ
cobalt19 under a hydrogen atmosphere, gave the best results and
provided free amine 14 in 60% yield. Noteworthy, using this
sequence, we were able to prepare several grams of aminotetraol
precursor 14 in a single pass.
9
On the basis of this design, we began our investigations into the
dearomative carboamination. Accordingly, we found that nickelꢀ
based catalysts with bidentate ligands, in combination with aryl
Grignard reagents, gave the best results (Figure 3). Specifically,
we identified that conducting the MTADꢀbenzene cycloaddition
reaction in dichloromethane, followed by the addition of a Niꢀ
catalyst ([Ni(cod)2]/dppf (8) = 10/20 mol%) and aryl Grignard
reagent 7 delivered the desired dearomatized product 6 in 74%
yield as a single constitutional and diastereoisomer. In addition,
we performed a comprehensive evaluation of chiral bidentate
ligands,15 and discovered that the PHOXꢀtype ligand (R,Rp)ꢀiPrꢀ
Phosferrox (9) afforded desired product 6 in 75% yield and with
high enantioselectivity (98:2 er).
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12
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The final step, needed to complete isocarbostyril framework of
the pancratistatins, namely the installation of the carbonyl group,
was achieved in two steps comprising halogenation and
intramolecular aminocarbonylation. To increase step economy
and the overall efficiency of the synthesis20 we probed reactions
that could function on the unprotected aminotetraol 14. After
extensive investigation, this task was effectively accomplished
using bromination (Br2 in AcOH),21 followed by NaCo(CO)4ꢀ
catalyzed carbonylation under a CO atmosphere and UV light
irradiation22 to give the corresponding (+)ꢀ7ꢀdeoxypancratistatin
(2) in 72% yield over the two steps. Moreover, we were able to
conduct both transformations in a single reaction vessel, without
the need of isolation and purification of the bromide intermediate,
making this formal carbonyl insertion operation more practical on
a gram scale.
Figure 3. MTADꢀmediated, Niꢀcatalyzed dearomative transꢀ1,2ꢀ
carboamination of benzene.
The enantioselective, dearomative transꢀcarboamination of
benzene serves as the key strategic maneuver as it installs the first
two vicinal stereocenters and drastically simplifies synthetic entry
to the pancratistatin core (Figure 4). Early on, we found that
masking the acidic urazole hydrazyl group (pKa = 5.8 in water) is
crucial for the precise orchestration of subsequent stereoselective
manipulations. Therefore, we selected the methyl group as it
could be introduced simply by quenching the dearomatization
Though more than a dozen chemical syntheses of (+)ꢀ7ꢀ
deoxypancratistatin (2) exist, its conversion to (+)ꢀpancratistatin
(1) through lateꢀstage Cꢀ7 arene hydroxylation has never been
established. We undertook this task by exploring directed ortho
metalations and found that hydroxylation of position Cꢀ7 could be
effected using a cupration/oxidation sequence23; however, only
when (+)ꢀ7ꢀdeoxypancratistatin (2) was persilylated with
hexamethyldisilazane (HMDS).24 According to control
experiments (see Supplementary materials), this direct arene
hydroxylation is likely to proceed through the intermediacy of
tetraꢀOꢀsilylatedꢀ(+)ꢀ7ꢀdeoxypancratistatin (15), which undergoes
Cꢀ7 cupration with (TMP)2Cu(CN)Li2. Subsequent in situ
oxidation with tBuOOH and acidic workup furnished (+)ꢀ
pancratistatin (1) in 62% yield.
reaction with dimethyl sulfate (3→10). Moreover, on
a
preparative scale, we were able to lower the catalyst and ligand
loadings to 5 and 10 mol% without significant erosion in yield or
selectivity (65% yield, 98:2 er, after methylation quench). Thus,
by simply executing this reaction in a oneꢀliter media bottle with
commercialꢀgrade visibleꢀlight diodes we were able to
conveniently prepare dearomatized compound 10 on a decagram
scale. It is worth noting that using this protocol, we have prepared
>300 g of this carboaminated product in total.
In summary, we have completed the syntheses of (+)ꢀ7ꢀ
deoxypancratistatin (2) and (+)ꢀpancratistatin (1) in six and seven
operations in 19% and 12% overall yield. Importantly, using this
synthetic blueprint, we have prepared several grams of natural
products 1 and 2 to date. The synthetic efficiency of our approach
originates from the development of an enantioselective, catalytic,
dearomative transꢀcarboamination of benzene for which no
chemical or biological equivalent exists. This transformation
permits access to the key diene 10 and greatly simplifies the
synthetic approach to the aminocyclitol core. Finally, by
With the key diene intermediate 10 in hand, the focus then
shifted to the next two olefin difunctionalization operations,
which would introduce the remaining four hydroxy substituents in
a stereoselective manner and complete the pancratistatin core.
Because of the electronꢀwithdrawing effect of the urazole
nitrogen, the alkene distal to this moiety reacted preferentially
with electrophilic reagents. Thus, a chemoꢀ and diastereoselective
preparation of transꢀdiol 11 was accomplished using a oneꢀpot
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OH
OH
1
2
3
4
HO
HO
OH
OH
[1.] MTAD (4),
visible light;
[2.] mCPBA,
TsOH, H2O
[3.] OsO4,
NMO
O
O
O
O
9
then [Ni(cod)2/ ],
74%
91%
NUR
NUR
NUR
O
7
ArMgBr ( ),
O
Me2SO4 (quench)
5
6
7
8
benzene (3)
10
11
12
65%, 98:2 er
[>10g scale]
[4.] LiAlH4;
then H2,
60%
Raney-Co
OH
OH
NH
9
OH
HO
OH
OH
HO
OH
OH
HO
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
[5.] Br2, AcOH
[7.] HMDS;
O
O
O
O
O
[6.] NaCo(CO)4, CO,
UV light (365 nm)
72% overall
then (TMP)2Cu(CN)Li2,
NH
O
t
BuOOH
NH2
7
62%
OH
O
O
14
(+)-pancratistatin (1)
(+)-7-deoxypancratistatin (2)
OTMS
OH
TMSO
OTMS
O
NMe
HO
OH
O
MgBr
O
O
N
MeN
ArMgBr
=
=
NUR
O
O
O
O
OTMS
7
NH
HN
O
N
Me
O
13
15
Figure 4. Synthesis of (+)ꢀpancratistatins (1 and 2) from benzene (3). Reagents and conditions: [1.] benzene (3), MTAD (4), CH2Cl2,
visible light, –78 °C; then [Ni(cod)2] (5 mol%), (R,Rp)ꢀiPrꢀPhosferrox (9, 10 mol%), arylmagnesium bromide 7, CH2Cl2, THF, –78 °C to
rt; quench with Me2SO4, K2CO3, 65% (98:2 er). [2.] mCPBA, TsOH, CH2Cl2, HFIP, H2O, 50 °C, 74%. [3.] NMO, OsO4 (5 mol%),
tBuOH:H2O, rt, 91%. [4.] LiAlH4, THF, reflux; quench with Rochelle salt; then Raney®ꢀCo, H2 (1 atm), 60 °C, 60%. [5.] Br2, AcOH, rt.
[6.] NaCo(CO)4 (30 mol%), nBu4NBr, CO (1 atm), NaHCO3, H2O, 1,4ꢀdioxane, 365 nm light, 60 °C, 72% over two steps. [7.] HMDS, I2
(1 mol%), MeCN, 80 °C; then solvent removal and (TMP)2Cu(CN)Li2, THF, –78 °C→0 °C; then tBuOOH, THF, –78 °C, 62%.
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providing
a
chemical
connection
between
(+)ꢀ7ꢀ
cal Sciences (GM122891). D. S. is an Alfred P. Sloan Fellow. L.
H. acknowledges the National Institute of General Medical Sciꢀ
ences (NIGMS)ꢀNIH ChemistryꢀBiology Interface Training Grant
and J. P. and U. K. thanks the German Research Foundation
(DFG) for postdoctoral fellowships. We thank Profs. S. E. Denꢀ
mark and P. J. Hergenrother (University of Illinois) for critical
proofreading of this manuscript and W. R. Grace and Co. for a
gift of Raney®ꢀcobalt. We also thank Dr. D. Olson and Dr. L.
Zhu for NMR spectroscopic assistance, Dr. D. L. Gray for Xꢀray
crystallographic analysis assistance, and F. Sun for mass spectroꢀ
metric assistance.
deoxypancratistatin (2) and (+)ꢀpancratistatin (1), this work also
presents a notable departure from previous syntheses of the
pancratistatins, in which each member required de novo synthesis
using the properly Cꢀ7 functionalized aromatic starting material.
We believe that the myriad opportunities in alkene
functionalization should render the dearomative carboamination
strategy amenable to the preparation of other natural products, as
well as a diverse set of congeners.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
sarlah@illinois.edu
Notes
The University of Illinois has filed a provisional patent on this
work.
ACKNOWLEDGMENT
Financial support for this work was provided by the University of
Illinois, the National Science Foundation (CAREER Award No.
CHEꢀ1654110), and the NIH/National Institute of General Mediꢀ
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For selected work, see: (e) Panteleev, J.; Menard, F.; Lautens, M. Adv.
Synth. Catal. 2008, 350, 2893. (f) Lautens, M.; Ma, S. J. Org. Chem.
1996, 61, 7246.
(13)Davies, S. G.; Green, M. L. H.; Mingos, D. M. P. Tetrahedron 1978,
34, 3047.
(14)Pearson, A. J. Acc. Chem. Res. 1980, 13, 463.
(15)See the Supporting Information for details regarding ligand
examination.
(16)For a review on the siteꢀselective opening of vinylepoxides, see:
Olofsson, B.; Somfai, P. in Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Eds.; WileyꢀVCH: Weinheim, Germany,
2006; p 315.
(17)For the beneficial role of HFIP in epoxidation and epoxide opening
reactions, see: (a) Berkessel, A.; Adrio, J. A. J. Am. Chem. Soc. 2006,
128, 13412. (b) Byers, J. A.; Jamison, T. F. Proc. Natl. Acad. Sci. U.
S. A. 2013, 110, 16724.
(18)VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17,
1973.
(19)Banwell, M. G.; Jones, M. T.; Reekie, T. A.; Schwartz, B. D.; Tan, S.
H.; White, L. V. Org. Biomol. Chem. 2014, 12, 7433.
(20)Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009,
38, 3010.
(21)Crude 1HꢀNMR revealed an 8:1 ratio of constitutional isomers.
(22)Brunet, J.ꢀJ.; Sidot, C.; Caubere, P. J. Org. Chem. 1983, 48, 1166.
(23)Tezuka, N.; Shimojo, K.; Hirano, K.; Komagawa, S.; Yoshida, K.;
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2
OH
3
4
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6
7
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9
HO
OH
OH
3
olefin-like
difunctionalization
O
O
NH
trans
-dihydroxylation
cis-dihydroxylation
benzene
R
O
trans-carboamination
(+)-pancratistatin (R = OH)
(+)-7-deoxypancratistatin (R = H)
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