A rapid and convergent synthesis of the integrastatin core

Article abstract of DOI:10.1039/c1ob05725a

The tetracyclic core of the integrastatin natural products has been prepared in a convergent and rapid manner. Our strategy relies upon a palladium(ii)-catalyzed oxidative cyclization to form the central [3.3.1]-dioxabicycle of the natural product core. Overall, the core has been completed in only 4 linear steps from known compounds.

Full text of DOI:10.1039/c1ob05725a

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A rapid and convergent synthesis of the integrastatin core†
Pamela M. Tadross, Pradeep Bugga and Brian M. Stoltz*
Received 8th May 2011, Accepted 26th May 2011
DOI: 10.1039/c1ob05725a
The tetracyclic core of the integrastatin natural products has
been prepared in a convergent and rapid manner. Our strategy
relies upon a palladium(II)-catalyzed oxidative cyclization to
form the central [3.3.1]-dioxabicycle of the natural product
core. Overall, the core has been completed in only 4 linear
steps from known compounds.
As part of our research program aimed at the total synthesis
of natural products by oxidative catalysis,5 we have targeted the
polycyclic [3.3.1]-dioxabicyclic core of the integrastatin natural
products. To achieve this, we retrosynthetically disconnected the
central [3.3.1]-dioxabicycle (3) along the two C–O bonds of the
acetal and removed the oxidation at C(9), leading back to diol 4
(Scheme 1). Diol 4 could be prepared in turn from two aromatic
fragments (5 and 6) of similar complexity by a Grignard addition.
Since its discovery in 1981, the United Nations and World Health
Organization have estimated that HIV/AIDS has claimed more
than 25 million lives, placing it among the most destructive
pandemics in history.1 The urgency of the matter is emphasized by
the explosion of research over the past 30 years geared toward the
development of new therapies aimed at disabling viral replicative
processes. One target that holds particular promise for inhibiting
viral replication is the enzyme HIV integrase.2 Because of the
potential that integrase inhibitors hold for the advancement of
HIV therapy, these compounds are attractive targets for total
synthesis and medicinal chemistry.
In particular, the naturally occurring integrastatins A (1) and
B (2) display inhibitory activity against HIV-1 integrase at mi-
cromolar concentrations and have thus been attractive targets for
therapeutic development (Fig. 1). The integrastatins were initially
isolated as racemic compounds in 2002 from an unidentified
fungus found in herbivore dung in New Mexico.3 Both compounds
displayed potent inhibition of the strand transfer reaction of
recombinant HIV-1 integrase at micromolar concentrations. IC50
values for integrastatins A and B are 1.1 mM and 2.5 mM,
respectively. Although there have been no reports of the total
synthesis of these natural products, two groups have reported
syntheses of the tetracyclic core of the integrastatins.4
Scheme 1 Retrosynthetic analysis of tetracycle 3.
In the forward sense, we began with the synthesis of benzylic
bromide 6 from commercially available 2-carboxybenzaldehyde
(7) (Scheme 2). Wittig olefination of benzaldehyde 7 produced
styrene8,6 whichwas subsequently reducedtothe primarybenzylic
alcohol (10) through an intermediate mixed anhydride (9).7,8
Moving forward, a number of conditions were examined for the
conversion of primary alcohol 10 to the benzylic bromide (6);
ultimately we found that use of NBS with triphenylphosphine
accomplished the transformation in high yield. With benzylic
bromide 6 in hand, ketone 5 was prepared in one step from
Fig. 1 Integrastatins A (1) and B (2).
The Warren and Katharine Schlinger Laboratory for Chemistry and Chem-
ical Engineering, California Institute of Technology, Division of Chemistry
and Chemical Engineering, Mail Code 101-20, Pasadena, CA, 91125, USA.
E-mail: stoltz@caltech.edu; Fax: +1-626-395-8436; Tel: +1-626-395-6064
† Electronic supplementary information (ESI) available: Characterization
data, NMR and IR spectra. See DOI: 10.1039/c1ob05725a
Scheme 2 Preparation of benzylic bromide 6.
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commercially available 2-hydroxyacetophenone (11) by protection
Experimental
of the phenol as a silyl ether (Scheme 3).9
Materials and methods
Unless stated otherwise, reactions were performed in flame-dried
glassware under an argon or nitrogen atmosphere using dry,
deoxygenated solvents (distilled or passed over a column of
activated alumina). Commercially obtained reagents were used
as received. Styrene 8 was prepared according to the method
of Seijas, et al.6 Benzylic alcohol 10 was prepared according
to the method of Bonnaud, et al.7 Ketone 5 was prepared
according to the method of Murata, et al.9 Reaction temperatures
were controlled by an IKAmag temperature modulator. Thin-
layer chromatography (TLC) was performed using E. Merck
silica gel 60 F254 precoated plates (0.25 mm) and visualized by
UV fluorescence quenching, potassium permanganate, or CAM
staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–
0.063 mm) was used for flash chromatography. 1H and 13C NMR
spectra were recorded on a Varian Inova 500 (at 500 MHz and
125 MHz, respectively) and are reported relative to Me4Si (d 0.0).
Data for 1H NMR spectra are reported as follows: chemical shift
(d (ppm)) (multiplicity, coupling constant (Hz), integration). Data
for 13C spectra are reported in terms of chemical shift relative
to Me4Si (d 0.0). IR spectra were recorded on a Perkin Elmer
Paragon 1000 Spectrometer and are reported in frequency of
absorption (cm-1). HRMS were acquired either using an Agilent
6200 Series TOF with an Agilent G1978A Multimode source
in electrospray ionization (ESI), atmospheric pressure chemical
ionization (APCI) or mixed (MM) ionization mode or from the
Caltech Mass Spectral Facility.
Scheme 3 Preparation of ketone 5.
We next turned our attention toward coupling of benzylic
bromide 6 and ketone 5 and construction of an appropriate
Wacker cyclization substrate. To this end, Grignard addition of the
organomagnesium reagent derived from benzylic bromide 6 into
ketone 5 furnished tertiary alcohol 12, which was subsequently
desilylated under standard conditions to yield diol 4 (Scheme 4).
Treatment of diol 4 with catalytic quantities of PdCl2 and CuCl2
under an oxygen atmosphere resulted in cyclization of both the
phenol and tertiary alcohol of diol 4 onto the styrenyl olefin
to generate the [3.3.1]-dioxabicycle central to the integrastatin
core (14).10 This key cyclization reaction likely proceeds first
through palladium-catalyzed formation of a 6-membered ring
enol ether (13). At this point, the pendant phenol can cyclize
onto the enol ether, furnishing the acetal moiety. Importantly,
Taylor and co-workers have shown that tetracycle 14 can undergo
benzylic oxidation when treated with PDC, Celite, and t-BuOOH
to produce benzylic ketone 3 in good yield.4a
Benzylic bromide 6
A solution of benzylic alcohol 10 (736 mg, 5.49 mmol) in CH2Cl2
◦
(27 mL) was cooled to 0 C in an ice bath. Triphenylphosphine
(1.67 g, 6.36 mmol) was added as a solid in one portion and the
resulting solution was maintained at 0 ◦C for 10 min with stirring.
Following this period, N-bromosuccinimide (1.13 g, 6.36 mmol)
was added portion-wise as a solid over 5 min. The reaction was
then maintained with stirring at 0 ◦C for 20 min or until benzylic
alcohol 10 was consumed by TLC analysis. The reaction was
concentrated under vacuum and purified by flash chromatography
(10 : 1 hexanes : ethyl acetate eluent) to yield benzylic bromide 6
1
(932 mg, 85% yield): Rf 0.56 (10 : 1 hexanes : ethyl acetate); H
NMR (500 MHz, CDCl3) d 7.56–7.51 (m, 1H), 7.35–7.29 (m, 2H),
7.28–7.23 (m, 1H), 7.11 (dd, J = 17.3, 11.0 Hz, 1H), 5.76 (dd, J =
17.3, 1.2 Hz, 1H), 5.45 (dd, J = 11.0, 1.2 Hz, 1H), 4.58 (s, 2H);
13C NMR (125 MHz, CDCl3) d 137.25, 134.56, 133.36, 130.23,
129.13, 128.11, 126.43, 117.08, 31.63; IR (NaCl/film) 3066, 1847,
1627, 1569, 1486, 1453, 1416, 1223, 1210, 1184, 987, 917, 772, 758
cm-1; HRMS (EI+) m/z calc’d for C9H979Br [M]+: 195.9888, found
195.9897.
Scheme 4 Coupling of benzylic bromide 6 and ketone 5, and completion
of the integrastatin core.
In summary, we have prepared the tetracyclic core (14) of the
integrastatin natural products (1 and 2) in 30% overall yield and
in only 4 linear steps from known compounds. The central [3.3.1]-
dioxabicycle was directly generated by a palladium-catalyzed
oxidative cyclization of diol 4 to complete the tetracycle synthesis.
Efforts are currently underway to apply this transformation to a
rapid synthesis of integrastatins A and B and analogs thereof.
Tertiary alcohol 12
A flame-dried reaction flask was charged with Mg turnings
(141 mg, 5.79 mmol). The flask was evacuated and backfilled
with nitrogen. Diethyl ether (5 mL) was added, followed by 1,2-
dibromoethane (20 mL). The suspension was stirred for 15 min
and then concentrated under vacuum. Next, benzylic bromide 6
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(457 mg, 2.32 mmol) was added as a solution in diethyl ether
(23 mL), and the resulting suspension was maintained at room
temperature with stirring for 2 h. Following this time, ketone 5
(870 mg, 3.47 mmol) was added to the reaction as a solution in
diethyl ether (5 mL). The reaction was maintained for 1 h with
stirring at room temperature and then quenched by the addition
of saturated aqueous NH4Cl solution (5 mL). Water (10 mL)
was added and the biphasic solution was extracted with diethyl
ether (25 mL). The organic phase was washed sequentially with
saturated aqueous NaHCO3 (25 mL) and brine (25 mL), dried
with MgSO4, and concentrated under vacuum. The crude isolate
was purified by flash chromatography (30 : 1 petroleum ether : ethyl
ether eluent) to yield tertiary alcohol 12 (556 mg, 65% yield): Rf
a short column of MgSO4, concentrated under vacuum, and
purified by flash chromatography (50 : 1 → 25 : 1 hexanes : ethyl
acetate eluent) to yield tetracycle 14 (30.4 mg, 61% yield): Rf 0.41
(10 : 1 hexanes : ethyl acetate); 1H NMR (500 MHz, CDCl3) d 7.45
(dd, J = 7.7, 1.3 Hz, 1H), 7.23–7.12 (m, 2H), 7.11–7.02 (m, 2H),
7.02–6.97 (m, 1H), 6.85 (td, J = 7.5, 1.2 Hz, 1H), 6.71 (dd, J =
8.2, 1.1 Hz, 1H), 3.29 (d, J = 16.0 Hz, 1H), 2.95 (d, J = 16.1 Hz,
1H), 1.98 (s, 3H), 1.76 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 151.06, 135.87, 133.19, 128.20, 128.18, 128.06, 127.42, 126.75,
125.72, 124.58, 120.71, 116.81, 97.66, 73.08, 43.09, 27.62, 26.67;
IR (NaCl/film) 2994, 2932, 1607, 1585, 1484, 1452, 1382, 1299,
1275, 1249, 1115, 1081, 978, 899, 879, 760 cm-1; HRMS (MM:
ESI-APCI) m/z calc’d for C17H17O2 [M+H]+: 253.1223, found
253.1211.
1
0.38 (10 : 1 hexanes : ethyl acetate); H NMR (500 MHz, CDCl3)
d 7.45 (dd, J = 7.8, 1.1 Hz, 1H), 7.18–7.11 (m, 2H), 7.08–7.00 (m,
2H), 6.93 (dd, J = 17.3, 10.9 Hz, 1H), 6.88–6.81 (m, 2H), 6.78 (dd,
J = 7.7, 1.1 Hz, 1H), 5.51 (dd, J = 17.3, 1.4 Hz, 1H), 5.13 (dd,
J = 10.9, 1.4 Hz, 1H), 4.42 (s, 1H), 3.37 (d, J = 13.4 Hz, 1H), 3.31
(d, J = 13.4 Hz, 1H), 1.56 (s, 3H), 1.08 (s, 9H), 0.42 (s, 3H), 0.39
(s, 3H); 13C NMR (125 MHz, CDCl3) d 153.22, 138.25, 135.68,
135.53, 135.46, 132.02, 128.16, 127.97, 127.22, 126.77, 125.89,
121.24, 118.46, 115.23, 76.45, 44.79, 27.07, 26.30, 18.70, –3.36,
–3.64; IR (NaCl/film) 3532, 2931, 2859, 1598, 1577, 1485, 1445,
1255, 1234, 1052, 906, 838, 781, 753 cm-1; HRMS (FAB+) m/z
calc’d for C23H33O2Si [M+H]+: 369.2250, found 369.2260.
Acknowledgements
This publication is based on work supported by Award No.
KUS-11-006-02, made by King Abdullah University of Science
and Technology (KAUST). Financial support from Caltech, the
Rose Hills Foundation (undergraduate fellowship to P.B.), and the
California HIV/AIDS Research Program (graduate fellowship to
P.M.T.) is also gratefully acknowledged.
Notes and references
1 Joint United Nations Programme on HIV/AIDS; World Health
Organization. AIDS epidemic update: Special report on HIV/AIDS;
December 2006; Geneva, Switzerland, 2006.
Diol 4
To a solution of silyl ether 12 (475 mg, 1.29 mmol) in THF (3 mL)
was added TBAF (1 M solution in THF, 1.41 mL, 1.42 mmol).
The resulting solution was then maintained with stirring at room
temperature until silyl ether 12 was consumed by TLC analysis
(about 1 h). The reaction was diluted with water (10 mL) and
then extracted with diethyl ether (25 mL). The organic phase was
washed with water (3 ¥ 10 mL) and brine (10 mL), dried with
MgSO4, and concentrated under vacuum. The crude product was
purified by flash chromatography (12 : 1 → 10 : 1 hexanes : ethyl
acetate eluent) to yield diol 4 (291 mg, 89% yield): Rf 0.22 (10 : 1
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hexanes : ethyl acetate); H NMR (500 MHz, CDCl3) d 9.11 (s,
1H), 7.55 (dd, J = 7.7, 1.3 Hz, 1H), 7.33–7.25 (m, 1H), 7.25–7.14
(m, 2H), 7.12–6.96 (m, 3H), 6.89 (dd, J = 8.1, 1.3 Hz, 1H), 6.87–
6.79 (m, 1H), 5.63 (dd, J = 17.3, 1.3 Hz, 1H), 5.29 (dd, J = 10.9,
1.3 Hz, 1H), 3.36 (d, J = 13.9 Hz, 1H), 3.20 (d, J = 13.9 Hz,
1H), 2.51 (s, 1H), 1.59 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 155.81, 138.43, 135.12, 133.51, 132.13, 129.72, 129.09, 127.53,
127.46, 126.37, 126.12, 119.54, 117.76, 116.21, 79.13, 44.54, 28.12;
IR (NaCl/film) 3306, 1618, 1582, 1491, 1453, 1374, 1293, 1237,
1154, 1095, 1036, 989, 914, 865, 752 cm-1; HRMS (FAB+) m/z
calc’d for C17H17O [M+H]+–H2O: 237.1279, found 237.1268.
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Tetracycle 14
8 All attempts to reduce the acid directly (e.g., with LiAlH4) resulted in
significant quantities of the fully reduced product (15), lacking the key
terminal olefin.
A flame-dried reaction flask was charged with PdCl2 (6.9 mg,
0.0393 mmol) and CuCl2 (5.3 mg, 0.0393 mmol). THF (1.5 mL)
was added followed by diol 4 (50 mg, 0.197 mmol) as a solution
in THF (500 mL). The reaction was placed under an oxygen
atmosphere (1 atm) and maintained at room temperature with
vigorous stirring until diol 4 was consumed by TLC analysis (about
24 h). Upon completion, the reaction solution was passed through
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