Synthetic studies toward providencin: Efficient construction of a furanyl-cyclobutanone fragment

Article abstract of DOI:10.1016/j.tet.2011.06.002

Described is the construction of a furanyl-cylcobutanone fragment suited for incorporation into a synthesis of the naturally occurring anti-cancer agent Providencin.

Full text of DOI:10.1016/j.tet.2011.06.002

Tetrahedron 67 (2011) 6479e6481
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies toward providencin: efficient construction of a
furanyl-cyclobutanone fragment
*
ꢀ
ꢀ
ꢀ
Sarah J. Stevens, Amelie Berube, John L. Wood
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2011
Received in revised form 31 May 2011
Accepted 2 June 2011
Described is the construction of a furanyl-cylcobutanone fragment suited for incorporation into a syn-
thesis of the naturally occurring anti-cancer agent Providencin.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 13 June 2011
Dedicated to Professor Satoshi Omura on
the occasion of his receiving the Tetrahe-
dron Prize
Keywords:
Providencin
Cyclobutanone
Furan
Bromo ketone
1. Introduction
2. Results and discussion
The gorgonians encompass approximately 500 species of sea fans,
sea plumes, and sea whips found in oceans throughout the world.1
These gorgonian octocorals have proven to be an abundant source
of secondary metabolites that possess a diverse range of structural
features and biological activities.2 In 2003 Rodriguez and co-workers
isolated Providencin (1) from the Caribbean sea plume Pseudopter-
ogorgia kallos.3 Providencindemonstrated anti-canceractivityagainst
human breast (MCF7), lung (NCI-H460), and CNS (SF-268) cancer cell
lines. The growth inhibition of treated cells compared to untreated
cells was 57, 39, and 94%, respectively.3 Unfortunately, the dearth of
naturally occurring 1 has prevented further biological testing.
The structure and relative stereochemistry of 1 were determined
through a combination of NMR spectroscopy and X-ray crystallo-
graphic analysis. These studies revealed 1 to be a highly oxygenated
diterpene containing an unprecedented [12.2.0]hexadecane ring
system. Some of the more intriguing structural features include the
trans-fused cyclobutanol moiety and the tri-substituted furan.3 The
unique structure and biological activity of 1 combine to make it an
attractive target for total synthesis. Although several reports have
appeared describing synthetic approaches to 1 a total synthesis has
remained elusive.4
As illustrated retrosynthetically in Scheme 1, we envisioned
incorporating a preassembled furanyl cyclobutane segment (2) that
would in turn derive from the coupling of 3-furoic acid (3) with
a suitably protected cyclobutane electrophile. In accord with this
plan we chose to initially focus on the preparation of 4 wherein
bromine would serve as the leaving group in the coupling event.
Scheme 1. Retrosynthetic analysis.
Synthesis of bromocyclobutanone 4 began with the [2þ2] cyclo-
addition of diethyl ketene acetal (5) and diethyl fumarate (6), which,
under the conditions developed by Brunner,5 furnished the cyclo-
adduct 7 in excellent yield (Scheme 2).6 Although our intention was
to go forward with racemic material we did note a report from
* Corresponding author. E-mail address: tetlett@colostate.edu (J.L. Wood).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.002

6480
S.J. Stevens et al. / Tetrahedron 67 (2011) 6479e6481
Bisacchi and co-workers demonstrating that 7 can be resolved via
conversion to diastereomeric bis-amide derivatives followed by
crystallization.7 Reduction of the racemic diester (7) using LAH fur-
nished the known diol 8,7 which was converted to the corresponding
bis-benzyl ether under standard conditions. Removal of the acetal
provided cyclobutanone 9 and set the stage for incorporation of
bromine. To this end, numerous approaches were explored and the
most efficient conversion was observed by first converting 9 to the
corresponding silyl enol ether 10. Subsequent treatment of 10 with
NBS provided the bromocyclobutanone 11, which was isolated as
a 6:1 mixture of diastereomers, with the major diastereomer having
the illustrated transetrans-relationship between the substituents.
Further optimization studies revealed that LiHMDS is the base of
choice for promoting the 1,2-shift. This latter observation coupled
with the noted lability of the intermediate alcohols led to the de-
velopment of optimized sequence wherein the dianion addition,
esterification, and 1,2-shift were carried out without isolation of
the intermediate alcohols 13 and 14 (Scheme 5). Under these
conditions the desired product 12 could be obtained in 60% yield as
a single diastereomer. NMR studies, including 1D NOE and 2D
ROESY experiments confirmed the illustrated transetrans-re-
lationship between substituents.
Scheme 5. Optimized coupling sequence.
3. Conclusion
A convergent and efficient synthesis of a furanyl-cylcobutanone
fragment (12) suited for incorporation into a synthesis of the nat-
urally occurring anti-cancer agent Providencin (1) has been ach-
ieved. Efforts to complete the synthesis utilizing this key fragment
are currently underway.
Scheme 2. Preparation of the bromocyclobutanone.
4. Experimental9
Having assembled the requisite bromocyclobutanone, we
turned to its coupling with 3. In the event, 3-furoic acid was cooled
to ꢀ78 ꢁC and treated sequentially with 2 equiv of LDA and then 11.
After warming to 0 ꢁC the reaction was quenched and the crude
extract was treated with diazomethane. The latter facilitated han-
dling and characterization of the desired product (12), which was
isolated as a single diastereomer in 20% yield (Scheme 3). NMR
studies, including 1D NOE and 2D ROESY experiments confirmed
the illustrated transetrans-relationship between substituents.
4.1. Cyclobutanone 9
To a solution of diol 8 (4.8 g, 23 mmol) in DMF (100 mL) was
added 95% NaH dispersion in mineral oil (1.1 g, 46 mmol) at 0 ꢁC.
After 30 min, benzyl bromide (5.5 mL, 46 mmol) and NaI (10 mg)
were added and the reaction mixture was allowed to warm to room
temperature. After 48 h the reaction was quenched at 0 ꢁC by slow
addition of saturated NH4Cl solution and diluted with ether. The
biphasic solution was separated and the aqueous phase was
extracted with ether. The combined organic phases were washed
with brine, dried over Na2SO4, filtered and concentrated in vacuo.
The derived mixture of desired material and two monobenzylated
products were separated by flash chromatography (gradient elu-
tion10 to 100% EtOAc/hexanes) and the mono protected products
were re-subjected to the protection conditions to furnish the de-
sired intermediate acetal (7.0 g, 80% combined yield). A portion of
the latter acetal (4.5 g, 12 mmol) was dissolved in CH3CN (120 mL)
cooled to 0 ꢁC and treated dropwise with H2SO4 (10 mL, 1 M
aqueous). The reaction mixture was warmed to room temperature
and after 30 min was diluted with EtOAc. The biphasic solution was
separated and the organic phase washed sequentially with water,
saturated NaHCO3 solution and brine, dried over Na2SO4, filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography (9:1 hexanes/EtOAc) to yield 9 (3.7 g, 95% yield) as
Scheme 3. Initial coupling reaction.
Gratified by the successful coupling, our efforts turned to im-
proving the yield; thus, we began varying the reaction conditions.
These studies revealed that quenching the coupling reaction at
ꢀ78 ꢁC prior to treatment with diazomethane results in the for-
mation of tertiary alcohol 14 (Scheme 4). In addition to gaining
mechanistic insight, we noted that both 14 and the intermediate
acid (13) are quite labile and difficult to isolate. Moreover, sub-
sequent studies demonstrated that exposure of 14 to base promotes
formation of 12 via a 1,2-shift and displacement of bromine.8
a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.36e7.24 (m, 10H), 4.55
(s, 2H), 4.50 (s, 2H), 3.72 (dd, J¼10.0, 5.0 Hz, 1H), 3.64 (d, J¼5.9 Hz,
2H), 3.59 (dd, J¼9.9, 4.3 Hz, 1H), 3.37e3.29 (m, 1H), 3.03 (ddd,
J¼17.6, 9.0, 2.4 Hz, 1H), 2.87 (ddd, J¼17.6, 6.9, 3.0 Hz, 1H), 2.78e2.70
(m, 1H); 13C NMR (100 MHz, CDCl3)
d 208.81, 138.56, 138.50, 130.20,
128.87, 128.80, 128.15, 128.02, 127.92, 73.53, 73.50, 72.64, 67.35,
63.19, 48.55, 28.47; IR (thin film, NaCl) 2859 (m), 1781 (sh, s), 1723
(m), 1495 (w), 1453 (m), 1346 (w), 1254 (w), 1112 (m), 1027(w)
cmꢀ1: HRMS (FAB) m/z found 327.16, calcd for C20H25O4 [MþH3O];
327.16.
Scheme 4. Low temperature quenching study.

S.J. Stevens et al. / Tetrahedron 67 (2011) 6479e6481
6481
4.2. Bromocyclobutanone 11
was added at ꢀ78 ꢁC. When the starting material was consumed as
evidenced by TLC the reaction was quenched with saturated NH4Cl
solution. The aqueous layer was extracted with Et2O. The combined
organics were washed with H2O and dried over MgSO4 and con-
centrated in vacuo. The crude material was dissolved in Et2O,
treated with excess diazomethane at room temperature, and
concentrated in vacuo. The crude material was flashed in
20:1e10:1e4:1 hexanes/EtOAc to furnish 14 (0.101 g, 20% yield).
Cyclobutanone 9 (0.134 g, 0.43 mmol) was dissolved in THF
(10 mL) and cooled to ꢀ78 ꢁC and TBS-OTf (0.29 mL, 1.29 mmol)
was added slowly. Then a 1 M solution of LiHMDS in THF (2.2 mL,
2.15 mmol) was added rapidly down the side of the flask. After 1 h
the reaction was carefully quenched with saturated NH4Cl solution.
The aqueous layer was extracted with Et2O. The combined organics
were washed with H2O and dried over MgSO4 and then concen-
trated in vacuo. The crude material was dissolved in THF (10 mL)
and cooled to 0 ꢁC. The resultant solution was treated with NBS
(0.084 g, 0.47 mmol, added in one portion) and allowed to warm to
room temperature and stir for 1 h. The reaction was quenched with
H2O and the aqueous layer was extracted with Et2O. The combined
organics were washed with brine, dried over MgSO4 and concen-
trated in vacuo. The crude material was flashed (10:1 hexanes/
EtOAc) to furnish 11 (0.065 g, 40% yield, two steps). Rf¼0.28, 4:1
Rf¼0.31, 4:1 hexanes/EtOAc; 1H NMR (400 MHz, CDCl3)
d 7.37e7.21
(m, 8H), 7.10e7.08 (m, 2H), 6.66 (d, J¼1.9 Hz, 1H), 6.13 (d, J¼0.7 Hz,
1H), 5.49 (d, J¼8.9 Hz, 1H), 4.58 (s, 2H), 4.14 (dd, J¼11.7, 8.7 Hz, 2H),
3.89 (d, J¼6.8 Hz, 2H), 3.78 (s, 3H), 3.35e3.28 (m, 2H), 2.95 (q,
J¼4.8 Hz, 1H), 2.83e2.76 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
165.7, 160.2, 140.9, 138.2, 138.0, 128.5, 128.3, 128.0, 127.7, 127.5,
114.6,111.5, 75.2, 73.5, 73.2, 72.3, 68.8, 52.3, 51.0, 49.0, 38.7; IR (NaCl
thin film): 3301 (w), 3030 (w), 2950 (w), 2857 (m), 1725 (m), 1693
(s),1312 (s),1209 (s),1073 (s), 740 (s), 698 (s); HRMS (ESIeAPCI) m/z
calcd for C26H28BrO6 [MþH]þ: 515.1064, found: 515.105.
hexanes/EtOAc; 1H NMR (400 MHz, CDCl3)
d 7.39e7.29 (m, 10H),
4.99 (dd, J¼7.7, 2.4 Hz, 1H), 4.64e4.56 (m, 2H), 4.56e4.50 (m, 2H),
3.83 (dt, J¼9.9, 3.9 Hz, 1H), 3.78e3.70 (m, 2H), 3.65e3.56 (m, 2H),
Acknowledgements
2.87e2.81 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 199.3, 137.9, 137.8,
128.6, 128.5, 128.0, 127.8, 127.7, 127.6, 73.3, 73.2, 67.9, 66.2, 58.4,
48.3, 41.0 IR (NaCl thin film): 3030 (w), 2857 (w), 1792 (s), 1113 (m),
737 (m), 697 (m); HRMS (ESIeAPCI) m/z calcd for C20H25BrNO3
[MþNH4]þ: 406.1012, found: 406.1011.
Funding from the NIH (1 RO1 CA 93591) and NSF (CHE-1058292)
are gratefully acknowledged. J.L.W. thanks Amgen, Merck, Bristol-
Myers Squibb for financial support. Dr. Chris Rithner, Don Heyse
and Don Dick are acknowledged for their assistance with NMR
analysis and instrumentation.
4.3. Furanyl cyclobutanone 12
Supplementary data
A solution of 3-furoic acid 3 (0.028 g, 0.249 mmol) in THF (3 mL)
was cooled to ꢀ78 ꢁC and treated with a 0.5 M solution of LDA in
(1 mL, 0.497 mmol). The reaction was stirred for 30 min at ꢀ78 ꢁC
Supplementary data (proton NMR, carbon NMR and IR spectra
for 11, 12 and 14; ROESY spectra for 11 and 12) associated with this
article can be found. Supplementary data associated with this ar-
ticle can be found, in the online version, at doi:10.1016/
j.tet.2011.06.002.
and then
a solution of bromocyclobutanone 11 (0.088 g,
0.226 mmol) in THF (1 mL) was added. When starting material was
consumed as evidenced by TLC the reaction was quenched with
saturated NH4Cl solution. The aqueous layer was extracted with
Et2O and the combined organic phases were washed with H2O,
dried over MgSO4 and concentrated in vacuo. The crude material
was stirred in Et2O at room temperature and excess diazomethane
was added. The reaction was filtered through MgSO4 and then
concentrated in vacuo. The crude cyclobutanol (0.098 g, 0.19 mmol)
was dissolved in THF (3 mL) and cooled to ꢀ78 ꢁC. The resultant
mixture was treated dropwise with a 1 M solution of LiHMDS in
THF (0.19 mL, 0.19 mmol). The reaction was warmed to room
temperature and when complete by as evidenced by TLC analysis, it
was diluted with EtOAc and washed with 1 M HCl. The aqueous
layer was extracted with EtOAc and the combined organic phases
were washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude material was flashed in 4:1e2:1 hexanes/EtOAc to
furnish cyclobutanone 12 (0.082 g, 60% yield, three steps). Rf¼0.17,
References and notes
1. http://www.ceoe.udel.edu/kiosk/seafan.html
2. Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901e5904.
3. Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G. Org. Lett. 2003, 5, 2551e2554.
4. (a) Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 3937e3939; (b) White, J.
D.; Jana, S. Org. Lett. 2009, 11, 1433e1436; (c) Schweizer, E.; Gaich, T.; Brecker, L.;
Mulzer, J. Synthesis 2007, 3807e3814; (d) Gaich, T.; Arion, V.; Mulzer, J. Het-
erocycles 2007, 74, 855e862; (e) Gaich, T.; Weinstabl, H.; Mulzer, J. Synlett 2009,
1357e1366.
5. Brunner, A. U.S. Patent 6,025,519, 2000.
ꢀ
ꢀ
6. Berube, A. Dissertation, Yale University, New Haven, CT 2006.
7. Bisacchi, G. S.; Braitman, A.; Cianci, C. W.; Clark, J. M.; Field, A. K.; Hagen, M. E.;
Hockstein, D. R.; Malley, M. F.; Mitt, T.; Slusarchyk, W. A.; Sundeen, J. E.; Terry, B.
J.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler, R. J. Med. Chem. 1991, 34,
1415e1421.
8. Mechanistically, one can envision a 1,2-shift of the furan moiety; however,
displacement of bromine to form an intermediate epoxide, followed by ring
opening and 1,2-shift of hydride is also plausible. Epimerization of any in-
tervening mixtures derived form either process could furnish the observed
isomer. To provide some further insight into this issue, we attempted to assign
the relative stereochemistry of 14 spectroscopically. Unfortunately these efforts
were not fruitful. We thank a referee for discussions of mechanistic possibilities.
9. Unless otherwise stated, reactions were magnetically stirred in flame-dried
glassware under an atmosphere of nitrogen. Triethylamine (Et3N) and metha-
nol were dried over calcium hydride. Benzene, tetrahydrofuran, dichloro-
methane, toluene, and diethyl ether were dried using a solvent purification
system manufactured by SG Water U.S.A., LLC. All other commercially available
reagents were used as received.
All reactions were monitored by thin-layer chromatography (TLC) using Sili-
cycle glass-backed extra hard layer, 60 A plates (indicator F-254, 250
umn or flash chromatography was performed with the indicated solvents using
Silicycle SiliaFlashÒ P60 (230e400 mesh) silica gel as the stationary phase. All
melting points were obtained on a Gallenkamp capillary melting point appa-
ratus and are uncorrected.
4:1 hexanes/EtOAc; 1H NMR (400 MHz, CDCl3)
d
7.50 (d, J¼0.9 Hz,
1H), 7.38e7.17 (m, 10H), 6.83 (d, J¼0.9 Hz, 1H), 4.55 (s, 2H), 4.40 (s,
2H), 3.90 (s, 3H), 3.86 (dd, J¼19.0, 5.5 Hz, 1H), 3.59 (dd, J¼16.3,
5.8 Hz, 1H), 3.54e3.49 (m, 2H), 3.03 (dd, J¼14.1, 5.1 Hz, 1H), 2.23
(quint, J¼5.9 Hz, 1H), 2.04e1.96 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
186.5, 163.3, 152.2, 144.2, 138.4, 138.3, 128.5, 128.4, 127.8, 127.6,
121.7, 113.6, 72.9, 72.8, 70.8, 66.7, 52.5, 30.6, 28.3, 26.7; IR (NaCl thin
film): 3030 (w), 2924 (m), 2857 (m), 1732 (s), 1485 (m), 1306 (m),
1094 (s), 738 (m), 698 (m); HRMS (ESIeAPCI) m/z calcd for
C26H26NaO6 [MþNa]þ: 457.1622, found: 457.1625.
ꢁ
m
m). Col-
4.4. Alcohol 14
Infrared spectra were obtained using a Midac M1200 FTIR or a Nicolet Avatar
320 FTIR. 1H and 13C NMR spectra were recorded on a Bruker AM-500, Bruker
Avance DPX-500, Bruker Avance DPX-400, or Varian Inova 400 spectrometer.
A solution of 3-furoic acid (3) (0.123 g, 1.1 mmol) in THF (10 mL)
was cooled to ꢀ78 ꢁC and treated with a 0.5 M solution LDA in THF
(4.4 mL, 2.2 mmol). The reaction was stirred for 30 min at ꢀ78 ꢁC
and then bromocyclobutanone 11 (0.383 g, 1 mmol) in THF (1 mL)
Chemical shifts (
d) are reported in parts per million (ppm) relative to internal
residual solvent peaks from indicated deuterated solvents.