Synthesis of the C1-C23 fragment of spirastrellolide A

Article abstract of DOI:10.1021/ol8008057

(Chemical Equation Presented) Synthesis of the C1-C23 fragment in spirastrellolide A is described, featuring a cyclic acetal-tethered RCM for stereoselective constructions of spiroketal, and a 1,3-anti aldol involving methyl ketone enolate and Mukaiyama c

Full text of DOI:10.1021/ol8008057

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2525-2528
Synthesis of the C1-C23 Fragment of
Spirastrellolide A
Jin-Haek Yang, Jia Liu, and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, 777 Highland
AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received April 8, 2008
ABSTRACT
Synthesis of the C1-C23 fragment in spirastrellolide A is described, featuring a cyclic acetal-tethered RCM for stereoselective constructions
of spiroketal, and a 1,3-anti aldol involving methyl ketone enolate and Mukaiyama conditions.
The isolation of (+)-spirastrellolide A, a novel spiroketal-
rich macrolide from marine sponge Spirastrellolide coccinea,
was reported by Roberge and Andersen et al.1 In addition
to its ability to initiate premature entry into mitosis and
untimely mitotic arrest in cells, spirastrellolide A exhibits a
potent inhibitory activity against protein phosphatase 2A
[IC50 ) 1 nM] with an excellent selectivity for PP2A over
PP1 [ratio of IC50 values ) 1:50],1,2 and it does not inhibit
PP2C. Its biological activities, therefore, resemble other
known Ser/Thr phosphatase inhibitors fostriecin and okadaic
acid. Development of protein phosphatase inhibitors has
lagged behind interest in kinase inhibitors because of the
perceived notion that kinases are more highly regulated and
specific.3 However, there has been a renewed interest in
recent years because reversible protein phosphorylation is
critical “as the other half” of checkpoints in cell cycles, and
protein phosphatases assume an equally important role in
regulating cellular signal transductions and should not be
ignored. Designing phosphatase inhibitors can lead to new
paradigms in developing cancer therapeutics.3
As a result, this natural product has attracted an elegant
array of synthetic efforts,4 and most recently, the first total
synthesis by Paterson.5 We became interested in spiras-
trellolide A when we developed a cyclic acetal tethered RCM
as an unconventional approach to the synthesis of spiroket-
als.6,7 Consequently, we pursued the synthesis of an epimer
[at C22] of the C11-23 fragment to showcase our method.8
(3) (a) For a leading review, see: Oliver, C. J.; Shenolikar, S. Front.
Biosci. 1998, 3, 961. Also see: (b) Paterson, I.; Anderson, E. A. Science
2005, 310, 451. (c) Koehn, F. E.; Carter, G. T. Nat. ReV. Drug DiscoVery
2005, 4, 206. (d) Paterson, I.; Yeung, K.-S. Chem. ReV. 2005, 105, 4237.
(e) Newmann, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461.
(4) For elegant synthetic efforts toward spirastrellolide A, see: (a)
Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett. 2005,
7, 4121. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org.
Lett. 2005, 7, 4125. (c) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim,
J. H.; Maltas, P.; Moessner, C. Chem. Commun. 2006, 4186. (d) Paterson,
I.; Anderson, E. A.; Dalby, S. M. Synthesis 2005, 3225. (e) Fu¨rstner, A.;
Fenster, M. D. B.; Fasching, B.; Godbout, C.; Radkowski, K. Angew. Chem.,
Int. Ed. 2006, 45, 5506. (f) Fu¨rstner, A.; Fenster, M. D. B.; Fasching, B.;
Godbout, C.; Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5510. (g)
Pan, Y.; De Brabander, J. K. Synlett 2006, 853. (h) Wang, C.; Forsyth,
C. J. Org. Lett. 2006, 8, 2997. (i) Paterson, I.; Anderson, E. A.; Dalby,
S. M.; Lim, J. H.; Loiseleur, O.; Maltas, P.; Moessner, C. Pure Appl. Chem.
2007, 79, 667. (j) Smith, A. B., III; Kim, D.-S. Org. Lett. 2007, 9, 3311.
(k) Keaton, K. A.; Phillip, A. J. Org. Lett. 2008, 10, 1083.
(1) For isolations of spirastrellolide A, see: (a) Williams, D. E.; Roberge,
M.; Van Soest, R.; Andersen, R. J. J. Am. Chem. Soc. 2003, 125, 5296. (b)
Williams, D. E.; Lapawa, M.; Feng, X.; Tarling, T.; Roberge, M.; Andersen,
R. J. Org. Lett. 2004, 6, 2607. For isolations of spirastrellolide B, see: (c)
Warabi, K.; Williams, D. E.; Patrick, B. O.; Roberge, M.; Andersen, R. J.
J. Am. Chem. Soc. 2007, 129, 508. For C-G, see: (d) Williams, D. E.;
Keyzers, R. A.; Warabi, K.; Desjardine, K.; Riffell, J. L.; Roberge, M.;
Andersen, R. J. J. Org. Chem. 2007, 72, 9842.
(2) Roberge, M.; Cinel, B.; Anderson, H. J.; Lim, L.; Jiang, X.; Xu, L.;
Bigg, C. M.; Kelly, M. T.; Andersen, R. J. Cancer Res. 2000, 60, 5052
.
10.1021/ol8008057 CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society

We report here our concise synthesis of the southern half of
(+)-spirastrellolide A consisting of the C1-C23 fragment.
Retrosynthetically, while the reconnection at C40-41 will
be accomplished by using Julia-Kocienski olefination [also
documented by Smith4j], the central macrolactone core can
be divided into three major fragments: A, B, and C [Scheme
1]. A macrolactonization could link C1 and C37 between
Scheme 2
Scheme 1. Spirastrellolide A
hydroboration, and SO3-Pyr/DMSO oxidation that led to
methoxy aldehyde 3. Stereochemistry at C20 was confirmed
by using Mosher ester analysis12 after the asymmetric
allylation.
With aldehyde 3 in hand, we explored the possibilities of
further shortening of our synthesis. Enone 4 was first
prepared from 3 via addition of vinyl magnesium bromide
followed by MnO2 oxidation [Scheme 3]. The idea was to
fragments A and C. A methyl ketone enolate 1,3-anti-aldol
reaction will be used to connect fragments A and B at C10
and C11. While Fu¨rstner4e adopts the same disconnection,
we independently reported this specific retro-synthetic ap-
proach.9 Another anti-aldol would link together fragments
B and C at C23 and C24 but will require the addition of the
C25-oxo group. Synthesis of fragment B would feature a
cyclic acetal tethered RCM.7
Scheme 3
To prepare the C11-C23 fragment [B] with the desired
C22-stereocenter, we designed a shorter and more practical
route in comparison with our previous effort.8 We com-
menced the synthesis of fragment B with (+)-2,3-(O)-
isopropylidene-L-threitol10 as shown in Scheme 2. Mono-
protection of the hydroxyl group with TBDPSCl followed
by SO3-Pyr/DMSO oxidation11 gave aldehyde 112 in 68%
yield. A three-carbon chain extension of aldehyde 1 was
accomplished in a four-step sequence featuring Brown’s
asymmetric allylation,13 O-methylation [to give 2], 9-BBN
(5) For the first total synthesis by Paterson, see: (a) Paterson, I.;
Anderson, E. A.; Dalby, S. M.; Lim, J. H.; Genovino, J.; Maltas, P.;
Moessner, C. Angew. Chem., Int. Ed. 2008, 47, 3016. (b) Paterson, I.;
Anderson, E. A.; Dalby, S. M.; Lim, J. H.; Genovino, J.; Maltas, P.;
Moessner, C. Angew. Chem., Int. Ed. 2008, 47, 3021. Also for a highlight,
see: (c) Perkins, M. V. Angew. Chem., Int. Ed. 2008, 47, 2921.
(6) For a review on chemistry of spiroketals, see: (a) Aho, J. E.; Pihko,
P. M.; Rissa, T. K. Chem. ReV. 2005, 105, 4406. (b) Mead, K. T.; Brewer,
B. N. Curr. Org. Chem. 2003, 7, 227. (c) Brimble, M. A.; Fares, F. A.
Tetrahedron 1999, 55, 7661. (d) Fletcher, M. T.; Kitching, W. Chem. ReV.
1995, 95, 789. (e) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617.
(7) (a) Ghosh, S. K.; Hsung, R. P.; Wang, J. Tetrahedron Lett. 2004,
45, 5505. (b) Ghosh, S. K.; Ko, C.; Liu, J.; Wang, J.; Hsung, R. P.
Tetrahedron 2006, 62, 10485.
condense enone 4 with a homoallyl alcohol such as 7 under
Lewis or Brønsted acidic conditions concomitantly with
removal of the acetonide group to generate vinyl oxocarbe-
nium ion 5, which can be trapped internally by the free C21-
OH to give vinyl cyclic acetal 6. However, after screening
a range of Lewis and Brønsted acids, we were unable to
(8) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273.
(9) Liu, J.; Yang, J.-H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006,
47, 6121.
(10) Liu, J. Ph.D. Dissertation Thesis, University of Minnesota, 2006.
(11) Paikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(12) See the Supporting Information.
(13) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432.
2526
Org. Lett., Vol. 10, No. 12, 2008

succeed in this transformation.14 Instead, in most cases, we
were able to still recover the starting enone 4, thereby
suggesting that the acetonide protecting group was suf-
ficiently robust under theses conditions to prevent C21-OH
from being unveiled for the cyclic acetal formation.
Scheme 4
Recognizing that we might have asked too much in an
attempt to shorten the synthesis, we removed the acetonide
group in allyl alcohol 8 after the addition of vinyl Grignard
to aldehyde 3, and a subsequent MnO2 oxidation gave enone
9 containing the free diol in 46% overall yields. However,
again, attempts to access cyclic acetal 6 from 9 via
condensing with homoallyl alcohol 7 failed. From these
attempts, we were able to isolate bicyclic acetal 10 with the
yield being as high as 81% when using Tf2NH.15–17 The
formation of 10 is clearly a result of trapping of vinyl
oxocarbenium ion 11 by the free C22-OH. Given that 6 and
10 are both derived through 11 and should be reversible,
we tried longer reaction time and higher temperature to force
10 toward 6 but were met with decompositions.
We were able to ultimately succeed in synthesizing the
key vinyl cyclic acetal [see 17] via the route shown in
Scheme 4. Lindgren oxidation18 of aldehyde 3 afforded acid
12. Removal of the acetonide group led to a selective lactone
formation involving only C21-OH, and subsequent capping
of C22-OH with PivCl gave lactone 13 in 64% overall yield.
The ensuing addition of vinyl magnesium bromide followed
by treatment of the resulting lactol mixture 14a/b with
Tf2NH8,17 in the presence of alcohol 1619 afforded the desired
vinyl cyclic acetal 17 in 56% yield.
The key ring-closing metathesis [RCM] of vinyl cyclic
acetal 17 furnished the spiroketal in the C11-C23 fragment
18 [or fragment B] in 95% yield, using Grubbs’ Generation-
II Ru-catalyst.20 Selected NOE experiments of 18 revealed
that it possesses the desired relative stereochemistry, and that
they closely resemble those reported for the same region in
spirastrellolide A.1 It is noteworthy that the current synthesis
of the C11-C23 fragment 18 that commenced with (+)-
2,3-(O)-isopropylidene-L-threitol is only 12 steps in com-
parison with the previous route of 18 steps from D-glucose
that also led to the wrong stereochemistry at C22 [see 18′]
[Scheme 5].8
(14) Lewis acids screened: BF3-OEt2, TiCl4, TMSOTf, In(OTf)3, and
MgBr2. Brønsted acids screened: Tf2NH, p-TsOH, TFA, and K-10.
Temperature: -20 °C to rt.
Scheme 5
(15) For studies on the acidity of HNTf2, see: (a) Thomazeau, C.; Olivier-
Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003,
125, 5264. (b) Foropoulus, J.; DesMarteau, D. D. Inorg. Chem. 1984, 23,
3720
.
(16) For some examples, see: (a) Sakakura, A.; Suzuki, K.; Nakano,
K.; Ishihara, K. Org. Lett. 2006, 8, 2229. (b) Sun, J.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 13512. (c) Inanaga, K.; Takasu, K.; Ihara, M. J. Am.
Chem. Soc. 2005, 127, 3668. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 10204. (e) Cossy, J.; Lutz, F.; Alauze, V.; Meyer, C. Synlett
2002, 45. (f) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 1851.
(g) Kuhnert, N.; Peverley, J.; Roberston, J. Tetrahedron Lett. 1998, 39,
3215
.
To complete the synthesis of the C1-C23 fragment or
the Southern half, the C11-C23 fragment 18 was trans-
formed to aldehyde 19 via removal of the PMB protecting
group followed by SO3-Pyr/DMSO oxidation [Scheme 6].
To connect the C10-11 bond, aldehyde 19 was subjected
to Mukaiyama aldol conditions21 employing TMS-enol ether
20 that was derived in situ by using LDA and TMSCl from
methyl ketone 21,9 which contains the C1-C10 fragment.9
(17) Ko, C.; Hsung, R. P. Org. Biomol. Chem. 2007, 5, 431
.
(18) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. A. Tetrahedron 1981, 37,
2091.
(19) For the synthesis of 16, see: (a) Zampella, A.; Sepe, V.; D’Orsi,
R.; Bifulco, G.; Bassarello, C.; D’Auria, M. V. Tetrahedron: Asymmetry
2003, 14, 1787. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986,
108, 5919.
(20) For reviews on metathesis, see: (a) Grubbs, R. H.; Miller, S. J.;
Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schrock, R. R. Tetrahedron
1999, 55, 8141. (c) Mori, M. In Topics in Organometallic Chemistry;
Fu¨rstner, A., Ed.; Springer-Verlag : Berlin, Germany, 1998; Vol. 1, p 133.
(d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (e) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(21) Mukaiyama, T.; Banno, K.; Naraska, K. J. Am. Chem. Soc. 1974,
96, 7503.
Org. Lett., Vol. 10, No. 12, 2008
2527

of BF3-Et2O at -78 °C. The aldol product 22 was obtained
as a single isomer in 62% yield with C11-13 relative
stereochemistry assigned as anti based on Fu¨rstner’s related
aldol4e and our own model studies9 with both being
consistent with Evans’s nonchelation 1,3-asymmetric induc-
tion model.22 Directed reduction led to diol 23 with a 3:1
ratio in favor of the C9-11-anti isomer. Acetonide formation
of both anti and syn isomers gave the desired southern half
24-anti and 24-syn isomers, respectively. By employing
Rychnovsky-Evans’s method,23 we could unambiguously
assign the C9-11 relative stereochemistry in both 24-anti
and 24-syn.
Scheme 6
We have described here our synthesis of the C1-C23
fragment in spirastrellolide A featuring a cyclic acetal-
tethered RCM approach to the spiroketal synthesis and a
Mukaiyama-methyl ketone 1,3-anti aldol. Efforts toward
synthesis of the northern half and completing a total synthesis
of spirastrellolide A are underway.
Acknowledgement. We thank ACS-PRF-AC for funding
and UW-Madison for funding.
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectra and characterizations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8008057
(22) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston,
A. B. J. Am. Chem. Soc. 1995, 117, 6619. (b) Evans, D. A.; Dart, M. J.;
Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322. (c) Evans,
D. A.; Duffy, J. D.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537.
(23) (a) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511. (b) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945. (c) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett.
1990, 31, 7099.
It was important that TMS-enol ether 20 was first added to
aldehyde 19 prior to the addition of a stoichiometric amount
2528
Org. Lett., Vol. 10, No. 12, 2008