Convergent route to the spirohexenolide macrocycle

Article abstract of DOI:10.1021/ol1018163

Using key functional dissections, the synthesis of spirohexenolides is examined through a three-component strategy that features a 1,2-addition to couple tetronate and aldehyde components forming the C2 - C3 bond and a Stille coupling to install the third sulfone-containing component. The macrocycle is completed by an intramolecular Julia - Kocienski reaction to form the C10 - C11 trans-disubstituted olefin. Application of this strategy is described in progress toward the synthesis of (±)-spirohexenolide B.

Full text of DOI:10.1021/ol1018163

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4516-4519
Convergent Route to the
Spirohexenolide Macrocycle
Brian D. Jones, James J. La Clair, Curtis E. Moore, Arnold L. Rheingold, and
Michael D. Burkart*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
mburkart@ucsd.edu
Received August 3, 2010
ABSTRACT
Using key functional dissections, the synthesis of spirohexenolides is examined through a three-component strategy that features a 1,2-
addition to couple tetronate and aldehyde components forming the C2-C3 bond and a Stille coupling to install the third sulfone-containing
component. The macrocycle is completed by an intramolecular Julia-Kocienski reaction to form the C10-C11 trans-disubstituted olefin.
Application of this strategy is described in progress toward the synthesis of (()-spirohexenolide B.
The spirohexenolides A (1a) and B (1b)1 comprise a family
of structurally unique spirotetronate natural products2 isolated
from strains of Streptomyces platensis (Scheme 1).3 Pre-
liminary cytotoxic screening studies indicated that the
spirohexenolides displayed a unique activity in the NCI-60
cell line analysis while maintaining a low toxicity in mice.1
These data combined with a unique uptake and localization
within tumor cells suggested a novel mode of action, which
was recently shown to target the human macrophage migra-
tion inhibitory factor (hMIF).4 Exploratory studies on the
natural material identified only one position, the C8 carbinol,
which could be readily modified and retain activity.4 Efforts
were focused on developing synthetic entry to the class to
perform more complete structure-activity relationship (SAR)
studies for preclinical evaluation.
(1) Kang, M.; Jones, B. D.; Mandel, A. L.; Hammons, J. C.; DiPasquale,
A. G.; Rheingold, A. L.; La Clair, J. J.; Burkart, M. D. J. Org. Chem. 2009,
74, 9054–9061.
Given the comparable activity1,4 of spirohexenolide A (1a),
B (1b), and the corresponding acetate 1c (Scheme 1), our
studies focused on preparation of the putative biosynthetic
deoxy-precursor 1b.
(2) For reviews on the spirotetronate natural products, see: (a) Zografos,
A. L.; Georgiadis, D. Synthesis 2006, 3157–3188. (b) Schobert, R.; Schlenk,
A. Bioorg. Med. Chem. 2008, 16, 4203–4221. (c) Athanasellis, G.; Igglessi-
Markopoulou, O.; Markopoulos, J. Bioinorg. Chem. Appl. 2010, doi:10.1155/
2010/315056.
A modular strategy was implemented based on dissection
of the molecule into three components: spirotetronate 5,
aldehyde 6, and sulfone 7 (Scheme 1). A four-staged process
was envisoned for their assembly that began by the addition
of the lithium salt of 5 to aldehyde 6.5 The resulting adduct
(3) For other natural products isolated from S. platensis, see: (a)
Hochlowski, J. E.; Whittern, D. N.; Hill, P.; McAlpine, J. B. J. Antibiot.
1994, 47, 870–874. (b) Woo, E. J.; Starks, C. M.; Carney, J. R.; Arslanian,
R.; Cadapan, L.; Zavala, S.; Licari, P. J. Antibiot. 2002, 55, 141–146. (c)
Asai, N.; Kotake, Y.; Niijima, J.; Fukuda, Y.; Uehara, T.; Sakai, T. J.
Antibiot. 2007, 60, 364–369. (d) Kohama, T.; Maeda, H.; Sakai, J. I.;
Shiraishi, A.; Yamashita, K. J. Antibiot. 1996, 49, 91–94. (e) Furumai, T.;
Eto, K.; Sasaki, T.; Higuchi, H.; Onaka, H.; Saito, N.; Fujita, T.; Naoki,
H.; Igarashi, Y. J. Antibiot. 2002, 55, 873–880. (f) Herath, K. B.; Attygalle,
A. B.; Singh, S. B. J. Am. Chem. Soc. 2007, 129, 15422–15423.
(4) Yu, W.-L.; Jones, B. D.; Kang, M. J.; Hammons, J. C.; La Clair,
J. J.; Burkart, M. D. J. Am. Chem. Soc. 2010, submitted.
(5) Franci, X.; Martina, S. L. X.; McGrady, J. E.; Webb, M. R.; Donald,
C.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 7735–7740.
10.1021/ol1018163  2010 American Chemical Society
Published on Web 09/17/2010

Scheme 1
.
Retrosynthetic Analysis of Spirohexenolide B (1b)
Scheme 2. Synthesis of the Tetronate Component 5
4 had the required vinyl stannane handle for a Stille coupling
with iodide component 7. With all three components in place,
a Julia-Kocienski olefination would then complete the
carbocyclic framework enabling completion of the synthesis
through dehydrative pyran formation, as illustrated in the
conversion of 2 to 1b (Scheme 1).
Our studies began by preparation of the northern compo-
nent, spirotetronate 5 (Scheme 2). Diastereoselective con-
struction of the cyclohexene system was accomplished by
the Lewis acid catalyzed Diels-Alder reaction of triene 9,
prepared from readily available ester 8,6 with R-acetoxyac-
rolein7 as the dienophile. The reaction favored the desired
regioisomer, as precedented by a previously reported reaction
using a similar triene substrate with R-bromoacrolein as the
dienophile under Lewis acid catalysis.8a The adduct formed
with high endo selectivity, as expected from previous studies
on similar substrates.8 Adduct (()-10 could be separated
chromatographically from the other nonaldehydic byproducts,
which constituted the majority of the remainder of the
reaction mixture, when a benzoate protecting group was used
on the primary alcohol. Using this procedure, pure (()-10
could be obtained in a 74% overall yield from 8.
Oxidation of aldehyde 10 proved difficult; buffered
KMnO49 and NaClO210 both failed to provide good conversion
to the carboxylic acid. However, it was found that I2 in basic
methanol11 offered acceptable conversion to the methyl ester.
While effective, the highly alkaline nature of this reaction
resulted in the removal of the acetate and partial cleavage
of the benzoate group, which necessitated further processing
to converge at diol 11. The structure of 11 was further
confirmed by collection of an X-ray crystal structure of a
derivatized p-bromobenzoate 12 (inset, Scheme 2).
With the structure of ester 11 confirmed, we turned to
reinstall an acetate at the tertiary hydroxyl group to construct
the tetronate ring by a Dieckmann cyclization. Lewis acid
catalysis with Sc(OTf)3 provided excellent conversion to the
corresponding bis-acetylated product,12 which was then
converted to the primary TBS ether 13. Switching to TBS
(6) (a) Moses, J. E.; Baldwin, J. E.; Brueckner, S.; Eade, S. J.; Adlington,
R. M. Org. Biomol. Chem. 2003, 1, 3670–3684. (b) Patel, P.; Pattenden,
G. Tetrahedron Lett. 1985, 26, 4789–4792.
(9) Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron
Lett. 1986, 27, 4537–4540.
(7) Funk, R. L.; Yost, K. J. J. Org. Chem. 1996, 61, 2598–2599.
(8) (a) Marshall, J. A.; Xie, S. P. J. Org. Chem. 1992, 57, 2987–2989.
(b) Zografos, A. L.; Yiotakis, A.; Georgiadis, D. Org. Lett. 2005, 7, 4515–
4518. (c) Roush, W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org.
Lett. 2002, 4, 1543–1546. (d) Roush, W. R.; Barda, D. A. J. Am. Chem.
Soc. 1997, 119, 7402–7403.
(10) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–
890.
(11) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett. 1992,
33, 4329–4332.
(12) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560–4567.
Org. Lett., Vol. 12, No. 20, 2010
4517

protection at C11 was key to achieving a satisfactory yield
of the spirotetronate product 5. The desired Dieckmann
cyclization was effected by the treatment of 13 with LiHMDS
in a mixture of HMPA and THF,13,14 followed by methyl-
ation of the incipient tetronic acid salt with dimethyl sulfate
(Scheme 2). While not fully optimized, this route offered a
22% overall yield of 5 in nine steps from 8.
The assembly process began with the coupling of com-
ponents 5 and 6. Using established protocols,19 lithium salt
of tetronate 5 was prepared and added to aldehyde 6 to afford
stannane 4 as an inseparable 1:1 mixture of diastereomers
(Scheme 4). The resulting product was then coupled under
Scheme 4. Component Assembly
Our studies then turned to construction of the component
7. By applying methods of Bates,15 gram quantities of alkyne
14 were prepared from oxetane and then converted to the
corresponding 1-phenyl-1H-tetrazol-5-yl (PT)16 sulfone 15
in two steps under conventional conditions (Scheme 3). At
Scheme 3. Synthesis of the Vinyl Iodide Component 7
scales greater than 0.1 mol, the oxidation conditions and
workup directly effected deprotection of the THP group,
affording carbinol 15.
We then turned to complete fragment 7 by installation of
the vinyl iodide. While it was expected that the primary
carbinol would direct the hydrostannation,17 the regioselec-
tivity of this process was low, which after iodination afforded
16 in only 18% yield after purification. Given the rapid access
to precursor 15 (an overall yield of 84% in two steps from
14), we did not focus on optimization. Rather, we turned
our efforts to evaluate the component assembly. This
necessitated protection of 16 as the 3,4-dimethoxybenzyl
ether 7 using lepidine 17 in a comparable manner to that
developed by Dudley for the formation of PMB ethers.18
modified Stille conditions20 to vinyl iodide 7 to afford adduct
3. Protecting group manipulations, followed by oxidation
with TPAP,21 delivered aldehyde 18, as a 1:1 mixture of
inseparable diastereomers. Macrocyclization was achieved
by the intramolecular Julia-Kocienski olefination22 of one
of the diastereomers of 18 to afford E-olefin 2 (Scheme 1),
which was desilylated to provide alcohol 19. Evidence for
the trans-configuration at the C10-C11 bond was indicated
(13) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J. Org.
Chem. 1997, 62, 8708–8721
.
by a JH10-H11 ) 15.5 Hz in 2 and 16.0 Hz in 19.23
3
(14) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, 44, 3041–
3052
.
(15) (a) Bates, R. W.; Sridhar., S. J. Org. Chem. 2008, 73, 8104–8105.
(b) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron 1984, 40, 4261–
4266.
(19) Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetrahedron
Lett. 1991, 32, 4925–4928.
(20) Marshall, J. A.; Adams, N. D. J. Org. Chem. 2002, 67, 733–740.
(21) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
(16) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28.
(17) Marshall, J. A.; Bourbeau, M. P. Tetrahedron Lett. 2003, 44, 1087–
1089.
(22) This is one of a few examples of an intramolecular Julia-Kocienski
olefination. See: (a) Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am.
Chem. Soc. 2009, 131, 16632–16633. (b) Aissa, C. J. Org. Chem. 2006,
71, 360–363. (c) Giesbrecht, H. E.; Knight, B. J.; Tanguileg, N. R.; Emerson,
C. R.; Blakemore, P. R. Synlett 2010, 374–378.
(18) (a) Albiniak, P. A.; Dudley, G. B. Synlett 2010, 841–841. (b)
Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. (c) Stewart,
C. A.; Peng, X. W.; Paquette, L. A. Synthesis 2008, 433–437.
4518
Org. Lett., Vol. 12, No. 20, 2010

Initial attempts to purify the macrocycle 18 were hindered
by coelution of oligomeric byproducts, presumably from the
diastereomer of 18 that did not cyclize. We eventually
isolated pure 1922 by improved chromatographic conditions.
With the full carbocyclic framework intact, conversion to
spirohexenolide B (1b) seemed to be just at hand through a
three-step sequence (left, Scheme 5). As outlined, the plan
called for oxidation at C3 followed by removing the DMB
protecting group at C21 and a dehydrative deprotection of
tetronate 2.
providing a single ketone product (see Supporting Informa-
tion). However, inspection of the resulting 1H NMR spectrum
showed that the disubstituted olefin in the enone chemical
shift region was trans, with a JH-H ) 16.0 Hz, indicating
that the product was not ketone 20.
3
In the process of further evaluating the structure of 22,
we removed the DMB protecting group with DDQ. Samples
of the resulting carbinol 23 were crystallized (mp )170-172
°C). The X-ray crystallographic structure was determined
(Scheme 5), indicating that transposition of the allylic alcohol
from C3 to C5 had occurred during the oxidation of 19,
which then oxidized to afford dienone 22 and not the desired
isomer 20. To confirm that the rearrangement had occurred
at the oxidation step and not during some previous operation,
we conducted gCOSY, gHSQC, and gHMBC analyses of
compound 19, all of which support the proposed structure.
This NMR evidence, combined with the crystal structure of
dienone 23, indicates that the macrolide core of 1b was
complete.
Scheme 5. Attempted Conversion to Spirohexenolide B (1b)
To date, we have demonstrated methods to prepare the
intact, racemic skeleton of the spirohexenolides. Efforts are
now underway to establish methods to install the pyran motif
at an earlier stage within the synthesis as well as to develop
routes that could deliver intermediates 20 or 21 en route to
a total synthesis of 1b.
Acknowledgment. Financial support from the American
Cancer Society (RSG-06-011-01-CDD) is gratefully ac-
knowledged. B.D.J. was supported by the Ruth L. Kirschstein
National Research Service Award T32 CA009523 (NCI/
NIH). We thank Dr. Yongxuan Su (UC San Diego) for mass
spectral analyses and Drs. Anthony Mrse (UC San Diego)
and Prof. James Golen (UMass Dartmouth) for assistance
with collection of the NMR data and the X-ray data on 12,
respectively.
Supporting Information Available: Experimental pro-
cedures and copies of NMR spectra from compounds 2-5,
7, 8-13, and 15-19, cif files for the X-ray structures of 12
and 23, as well as a further description of the oxidation of
19 and related model studies. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL1018163
(23) Assignment of the relative stereochemistry at C3 in 2 or 19 was
not attempted but may be possible through NOESY studies or modification
of the C3 -OH of 19 to form a crystalline derivative.
Unfortunately, the oxidation of allylic alcohol 19 was
problematic, with only Dess-Martin periodinane or IBX
Org. Lett., Vol. 12, No. 20, 2010
4519