Stereoselective synthesis of the CDE ring system of antitumor saponin scillascilloside E-1

Article abstract of DOI:10.1021/ol500657f

A stereoselective synthesis of the CDE ring portion of the antitumor saponin scillascilloside E-1 has been achieved, utilizing an Ireland-Claisen rearrangement to construct the contiguous tetrasubstituted stereocenters at C13 and C17 simultaneously and intramolecular nitrile oxide cycloaddition to form the five-membered ring as key steps.

Full text of DOI:10.1021/ol500657f

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of the CDE Ring System of Antitumor
Saponin Scillascilloside E‑1
Yoshihiro Akahori,† Hiroyuki Yamakoshi,† Shunichi Hashimoto,‡ and Seiichi Nakamura*,†
†Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
‡Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: A stereoselective synthesis of the CDE ring
portion of the antitumor saponin scillascilloside E-1 has been
achieved, utilizing an Ireland−Claisen rearrangement to
construct the contiguous tetrasubstituted stereocenters at
C13 and C17 simultaneously and intramolecular nitrile oxide
cycloaddition to form the five-membered ring as key steps.
Scheme 1. Retrosynthetic Analysis of Aglycon 2
cillascillosides are a family of eucosterol oligoglycosides
isolated by Kawasaki and co-workers in 1985 from the fresh
S
bulbs of Scilla scilloide, a traditional Chinese medicine.1 These
compounds were later found to exhibit remarkable cytotoxicity
(ED50: 1.53−3.06 nM) against several human tumor cell lines
and to prolong the life span of Sarcoma 180-bearing mice.2
Scillascilloside E-1 (1), the most potent antitumor agent of this
family, carries a branched pentasaccharide appended to the C3
hydroxyl group of the triterpenoid aglycon, which features an
oxapentacyclic system including five tetrasubstituted stereo-
centers. Despite the remarkable biological activities of this
family, total synthesis of eucosterols has not been reported, and
only the groups of Corey3 and Kobayashi4 accomplished total
syntheses of related lanostane-type triterpenoids (lanostenol
and fomitellic acid B, respectively). As part of our studies
directed toward the total synthesis of the antitumor saponin 1,
we report herein a stereoselective synthesis of a CDE ring
fragment of the saponin, employing an Ireland−Claisen
rearrangement and intramolecular nitrile oxide cycloaddition.
In our retrosynthetic strategy, we envisioned CDE ring
fragment 3 as a suitable precursor to aglycon 2 by way of a
coupling with an A ring fragment and late-stage intramolecular
Heck reaction to construct the B ring (Scheme 1). Tricyclic
compound 3 would be elaborated from nitro compound 6a via
enone 4 by a sequence involving an intramolecular 1,3-dipolar
cycloaddition of nitrile oxide 5a. While the contiguous
tetrasubstituted stereocenters at C13 and C17 in 7a appeared
to be established in a single operation by an Ireland−Claisen
rearrangement, our initial study revealed that severe steric
repulsion resulting from the methyl group at C20 led to the
predominant formation of an undesired stereoisomer 7c by the
Received: March 3, 2014
Published: March 20, 2014
© 2014 American Chemical Society
2054
dx.doi.org/10.1021/ol500657f | Org. Lett. 2014, 16, 2054−2057

Organic Letters
Letter
Scheme 2. Construction of the Contiguous Tetrasubstituted
Stereocenters by an Ireland−Claisen Rearrangement
reaction of 8a (eq 1).5 We therefore considered that a change
in hybridization of the C20 stereocenter from sp3 to sp2 would
minimize the repulsion and favor formation of desired isomer
7b. Ester 8b would be available via union of aldehyde 9 and α-
diazoester 10.
Synthesis of the rearrangement precursor 8b was initiated
with the preparation of α-diazoester 10 (Scheme 2). Acylation
of alcohol 115,6 with diketene in Et2O was followed by diazo
transfer with methanesulfonyl azide in MeCN to give α-diazo-
β-ketoester 12 (88% yield), which upon exposure to LiOH in
aqueous THF gave α-diazoester 10 in 86% yield. After the
coupling of α-diazoester 10 with aldehyde 97 according to the
Wenkert procedure (88% yield),8 the resultant β-hydroxyester
13 underwent oxidation with IBX9 to afford α-diazo-β-ketoester
14 in 94% yield. Removal of the C23 TES group with TFA in
MeOH/CH2Cl2 provided δ-hydroxy-α-diazoester 15 in 88%
yield and set the stage for construction of the tetrahydrofuran
(E) ring.
As expected from the precedent,10 the Rh2(OAc)4-catalyzed
intramolecular O−H insertion of 15 in refluxing benzene
proceeded to completion within 5 min; however, the product
16 partially decomposed upon exposure to silica gel. We
therefore investigated the following carbonyl olefination
reaction without purification. After considerable experimenta-
tion with regard to the conversion of 16, it was found that
desired olefination could only be attained under the Lebel
conditions11 and that olefin conjugation occurred under these
conditions to provide α,β-unsaturated ester 17 in 60% yield in
two steps.
With substrate 17 in hand, efforts were next focused on the
key Ireland−Claisen rearrangement.12,13 The rearrangement of
silyl ketene acetal 18, generated by the reaction of 17 with LDA
and TMSCl in THF at −78 °C, reached completion within 30
min even at 0 °C to furnish the rearranged product, which upon
exposure to TMSCHN2 gave methyl ester 7b in 62% yield in
two steps, along with a trace amount of its C17-isomer (dr =
>100:1). The stereochemical assignment of major isomer 19
was established by a NOESY experiment performed on
iodolactone 20 obtained by the reaction of 19 with I2 and
NaHCO3 in aqueous MeCN at 0 °C. Since carboxylic acid 19
would be a product resulting from chairlike transition state A, it
was confirmed that the selectivity of the transition state
conformation is regulated by the substituent at C20.
As a prelude to the one-carbon homologation, methyl ester
7b was transformed to aldehyde 22 by a two-step sequence
involving DIBALH reduction in CH2Cl2 at −78 °C and Dess−
Martin oxidation14 (Scheme 3). The addition of nitromethane
to aldehyde 22 was best accomplished by the catalytic use of
N,N,N′,N′-tetramethylguanidine as a base,15 providing nitro
compound 23 in 89% yield, along with recovered aldehyde 22.
Due to the propensity of 23 to undergo retro nitroaldol
reaction under basic conditions, the C16 hydroxyl group in 23
was acetylated with Ac2O in the presence of sulfuric acid at 0
°C and was removed by a two-step sequence involving
elimination with Et3N in CH2Cl2 and 1,4-reduction with
NaBH4 in dioxane/EtOH, providing cycloaddition precursor 6b
in 85% yield in three steps. As anticipated, intramolecular 1,3-
dipolar cycloaddition16,17 of nitrile oxide 5b, generated from 6b
under Mukaiyama conditions,18 proceeded in a stereoselective
manner to give tetracyclic compound 25 in 97% yield.
2055
dx.doi.org/10.1021/ol500657f | Org. Lett. 2014, 16, 2054−2057

Organic Letters
Letter
Scheme 3. Construction of the CDE Ring System via an
Intramolecular Nitrile Oxide Cycloaddition
Scheme 4. Completion of the Synthesis of the CDE Ring
Fragment
With the olefins differentiated by the cycloaddition, our
attention was next focused on a hydrogenation of the remaining
olefin at C20. Prior to hydrogenation, the isoxazoline 25 was
reduced with DIBALH in toluene at −20 °C to yield
isoxazolidine 26 in 97% yield.19 Although the olefin at C20
was unreactive due to steric hindrance, the hydrogenation of
C20 olefin could be effected by the use of PtO2 as a catalyst,
whereby N−O bond cleavage also occurred to give amino
alcohol 27. The diastereomeric ratio of 27 was determined to
1
be 4.3:1 by H NMR analysis after protection of the amino
predominant formation of the cis-fused isomer after treatment
with NaOH.21 Given these results, a decision was made to
reduce the carbonyl group at C8 in preparation for the
hydroxyl-directed cyclopropanation reaction.22 As anticipated,
Luche reduction23 took place selectively from the less hindered
β face to give allyl alcohol 30 (91% yield), which underwent
cyclopropanation24 to afford cyclopropyl alcohol 31 exclusively
in 92% yield. While hydrogenolytic cleavage of the three-
membered ring in 31 did not occur even at elevated
temperature under high-pressure conditions, this problem was
effectively circumvented by removal of the TBDPS group at
C24 with Bu4NF in THF (96% yield), leading to the exclusive
formation of trans-fused hydrindane 33 in 74% yield.25
Reprotection of the primary alcohol with TBDPSCl was
followed by oxidation of the secondary alcohol with Dess−
Martin periodinane to give ketone 3 in 84% yield in two steps,
thereby completing the synthesis of the CDE ring system of
scillascilloside E-1 (Scheme 4).
group with ClCO2Me in the presence of Na2CO3 followed by
Dess−Martin oxidation (67% yield, three steps from 26).20
While unprecedented in the literature, we found that exposure
of ketone 29 to 5% TFA in toluene at 60 °C resulted in the
elimination of the superfluous (methoxycarbonyl)amino group
at the β position of the carbonyl group, leading to the
formation of enone 4 in 86% yield.
The remaining operation necessary for synthesis of the CDE
ring portion of scillascilloside E-1 involved a stereoselective
introduction of an angular methyl group at C14. In this regard,
Corey and co-workers reported in their synthesis of lanostenol
that a cyclopropanation of the TMS enol ether, prepared from
Grundemann ketone, followed by base-catalyzed cleavage of the
resultant cyclopropyl carbinol resulted in the preferential
formation of a trans-fused hydrindane derivative.3 However,
in our case, cyclopropanation of the TMS enol ether derived
from enone 4 proceeded from the convex β face, leading to
2056
dx.doi.org/10.1021/ol500657f | Org. Lett. 2014, 16, 2054−2057

Organic Letters
Letter
Claisen Rearrangement: Methods and Applications; Hiersemann, M.,
Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007; pp 117−210.
(c) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38,
3133−3148.
(13) For a precedent for simultaneous construction of contiguous
tetrasubstituted stereocenters by an Ireland−Claisen rearrangement of
cyclohex-2-enyl esters, see: Gu, Z.; Herrmann, A. T.; Stivala, C. E.;
Zakarian, A. Synlett 2010, 1717−1722.
(14) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−
4156. (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−
7287.
(15) For a review on Henry reaction, see: Luzzio, F. A. Tetrahedron
2001, 57, 915−945.
(16) For recent reviews on 1,3-dipolar cycloadditions, see: (a) Nair,
V.; Suja, T. D. Tetrahedron 2007, 63, 12247−12275. (b) Rane, D.; Sibi,
M. Curr. Org. Synth. 2011, 8, 616−627. (c) Browder, C. C. Curr. Org.
Synth. 2011, 8, 628−644.
In summary, we have achieved a stereoselective synthesis of
the [6,5,5]-tricyclic ring portion of scillascilloside E-1. This
synthesis features simultaneous and stereoselective construction
of the contiguous tetrasubstituted stereocenters (C13 and C17)
by an Ireland−Claisen rearrangement and D ring formation by
an intramolecular nitrile oxide cycloaddition. Further efforts
toward a total synthesis of scillascilloside E-1 are currently
underway in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterization data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) For combinational use of Ireland−Claisen rearrangement and
intramolecular nitrile oxide cycloaddition for the synthesis of bicyclic
compounds, see: (a) Mulzer, J.; Castagnolo, D.; Felzmann, W.;
Marchart, S.; Pilger, C.; Enev, V. S. Chem.Eur. J. 2006, 12, 5992−
6001. (b) Enev, V. S.; Drescher, M.; Mulzer, J. Tetrahedron 2007, 63,
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: nakamura@phar.nagoya-cu.ac.jp.
Notes
5930−5939. (c) Parthasarathy, G.; Besnard, C.; Kundig, E. P. Chem.
̈
The authors declare no competing financial interest.
Commun. 2012, 48, 11241−11243.
(18) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339−
ACKNOWLEDGMENTS
5342.
■
(19) For a review on cleavage of isoxazolines, see: Nagireddy, J. R.;
Raheem, M.-A.; Haner, J.; Tam, W. Curr. Org. Synth. 2011, 8, 659−
700.
(20) The stereochemistry at C20 of major isomer 29 was confirmed
by a crosspeak between C20-CH3 and C23-H in the NOESY spectrum
of enone 4.
(21) A similar observation was made by Kobayashi and co-workers
during their synthesis of fomitellic acid B. See ref 4.
(22) For a review on heteroatom-directed organic reactions, see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307−
1370.
This research was supported in part by the Japan Society for the
Promotion of Science (Grant-in-Aid for Scientific Research),
the Ministry of Education, Culture, Sports, Science and
Technology, Japan (Platform for Drug Discovery, Informatics,
and Structural Life Science), the Uehara Memorial Foundation,
and the Naito Foundation. We are grateful to the Fukuyama
group of Nagoya University for the use of their mass
spectrometer.
REFERENCES
■
(23) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454−
5459.
(1) Sholichin, M.; Miyahara, K.; Kawasaki, T. Chem. Pharm. Bull.
1985, 33, 1756−1759.
(24) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 3353−3354. (b) Furukawa, J.; Kawabata, N.; Nishimura, J.
Tetrahedron 1968, 24, 53−58.
(25) The stereochemistry at C14 was unambiguously confirmed by a
crosspeak between C14-CH3 and C9-Hax in the NOESY spectrum of
ketone 3.
(2) Lee, S.-M.; Chun, H.-K.; Lee, C.-H.; Min, B.-S.; Lee, E.-S.; Kho,
Y.-H. Chem. Pharm. Bull. 2002, 50, 1245−1249.
(3) Corey, E. J.; Lee, J.; Liu, D. R. Tetrahedron Lett. 1994, 35, 9149−
9152.
(4) Yamaoka, M.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2009,
50, 6764−6768.
(5) Akahori, Y.; Yamakoshi, H.; Sawayama, Y.; Hashimoto, S.;
Nakamura, S. J. Org. Chem. 2014, 79, 720−735.
(6) ter Halle, R.; Bernet, Y.; Billard, S.; Bufferne, C.; Carlier, P.;
Delaitre, C.; Flouzat, C.; Humblot, G.; Laigle, J. C.; Lombard, F.;
Wilmouth, S. Org. Process Res. Dev. 2004, 8, 283−286.
(7) Wang, C.; Forsyth, C. J. Org. Lett. 2006, 8, 2997−3000.
(8) (a) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94,
́
8084−8090. (b) Schollkopf, U.; Banhidai, B.; Frasnelli, H.; Meyer, R.;
̈
Beckhaus, H. Liebigs Ann. Chem. 1974, 1767−1783.
(9) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019−
8022.
(10) (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem.
1985, 50, 5223−5230. (b) Heslin, J. C.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 1 1988, 1417−1423. (c) Moody, C. J.; Taylor, R. J. J.
Chem. Soc., Perkin Trans. 1 1989, 721−731. (d) Cox, G. G.; Moody, C.
J.; Austin, D. J.; Padwa, A. Tetrahedron 1993, 49, 5109−5126.
(11) (a) Lebel, H.; Paquet, V.; Proulx, C. Angew. Chem., Int. Ed. 2001,
40, 2887−2890. (b) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126,
320−328. (c) Lebel, H.; Guay, D.; Paquet, V.; Huard, K. Org. Lett.
2004, 6, 3047−3050.
(12) For reviews on Ireland−Claisen rearrangements, see: (a) Chai,
Y.; Hong, S.-P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C.
Tetrahedron 2002, 58, 2905−2928. (b) McFarland, C. M.; McIntosh,
M. C. The Ireland−Claisen Rearrangement (1972−2004). In The
2057
dx.doi.org/10.1021/ol500657f | Org. Lett. 2014, 16, 2054−2057