Toward the total synthesis of spirastrellolide A. Part 3: Intelligence gathering and preparation of a ring-expanded analogue

Article abstract of DOI:10.1039/b707835h

Different methods for the formation of the C.25-C.26 bond of spirastrellolide A (1) are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame. The Royal Society of C

Full text of DOI:10.1039/b707835h

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Toward the total synthesis of spirastrellolide A. Part 3: Intelligence
gathering and preparation of a ring-expanded analogue{
Alois Fu¨rstner,* Bernhard Fasching, Gregory W. O’Neil, Michae¨l D. B. Fenster, Ce´drickx Godbout and
Julien Ceccon
Received (in Cambridge, UK) 23rd May 2007, Accepted 8th June 2007
First published as an Advance Article on the web 26th June 2007
DOI: 10.1039/b707835h
Wittig and Horner–Emmons reactions (Scheme 1); a related Julia
olefination4 could also be achieved, although product 7 was
obtained as an inseparable mixture of isomers. Moreover,
hydroboration of the terminal olefin in 3 (R4 = TES) with
9-BBN followed by a Suzuki reaction5 of the resulting alkylborane
with 2-bromopropene as a model electrophile was successful (3 A
8). This result holds considerable promise for an endgame based
on cross coupling methodology.
Different methods for the formation of the C.25–C.26 bond of
spirastrellolide A (1) are evaluated that might qualify for the
end game of the projected total synthesis, with emphasis on
metathetic ways to forge the macrocyclic frame.
Spirastrellolide A (1), a potent and selective inhibitor of protein
phosphatase 2A isolated from the Caribbean sponge Spirastrella
coccinea, elicits considerable interest due to its captivating
molecular architecture and promising antimitotic activity.1,2 In
this context, we have recently described concise entries into the
‘southern’ (2) as well as the ‘northern’ domains (3) of this 38-
membered macrolide,3 and now wish to present preliminary
investigations concerning the fusion of these segments. Since these
studies had been initiated before the stereostructure of 1 was fully
unravelled,1a they address, in part, the enantiomer or diastereo-
mers of the natural product.
It is obvious, however, that olefin metathesis constitutes a more
direct means to form the C.25–C.26 bond.6 Despite considerable
experimentation, however, all attempts to engage dienes of type 9
in RCM-based macrocyclizations were unsuccessful, either leading
to no reaction or resulting in partial olefin isomerization and/or
incorporation of the LCHPh unit of the catalyst, when more
forcing conditions were employed. As evident from the represen-
tative examples depicted in Scheme 2, this outcome was largely
independent of the chosen protecting group pattern and the
absence or presence of the dithiane moiety at C.16.7
This failure is likely caused by the massive chlorinated bis-
spiroketal unit flanking the ‘northern’ olefin, which not only
renders its conversion into a ruthenium carbene difficult but even
prevents metal carbenes from approaching to this particular site in
a productive manner.8 In line with this notion, the detached
The incomplete structural information available at the outset of
the project1b,c enforced an overall synthesis plan dissecting 1 into
regions of known relative stereochemistry. One such site is the non-
stereogenic C.25–C.26 bond to be forged by methodology that
makes proficient use of the olefinic termini of 2 and 3.3 In an
attempt to explore different options, compound 3 (R4 = TES) was
converted into aldehyde 4 by dihydroxylation and subsequent
oxidative cleavage of the resulting diol with Pb(OAc)4; although 4
turned out to be exceptionally sensitive, it underwent productive
Scheme 1 Reagents and conditions: (a) (i) OsO4 (2 mol%), NMO,
tBuOH; (ii) Pb(OAc)4, CH2Cl2; (b) Ph3PLCHCOOMe, THF, 44% (R =
OMe, over three steps); (c) (MeO)2P(O)CH2C(O)Me, Ba(OH)2?8H2O,
THF, 85% (R = Me); (d) LiHMDS, THF, 278 uC A RT%; (e) (i) 9-BBN,
THF; (ii) 2-bromopropene, (dppf)PdCl2, (10 mol%), AsPh3 (20 mol%),
Cs2CO3, DMF, 65 uC, 41%.
Max-Planck-Institut fu¨r Kohlenforschung, D-45470, Mu¨lheim/Ruhr,
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
{ Electronic supplementary information (ESI) available: Experimental
section including spectroscopic data and spectra of all new compounds.
See DOI: 10.1039/b707835h
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Chem. Commun., 2007, 3045–3047 | 3045

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Scheme 2 Attempted cyclizations by RCM.
‘southern’ spiroacetal segment 11 per se underwent effective cross-
metathesis, whereas the ‘northern’ domain 3 essentially failed to
react under otherwise identical conditions (Scheme 3). Partial
unfolding of the bis-spiroacetal, as manifested in isoxazoline 14,3b
however, restores some of the reactivity and hence corroborates
the view that mainly steric factors account for the unsuccessful
attempts to cyclize dienes of type 9.
As a consequence, it was envisaged to effect macrocyclization by
RCM prior to the elaboration of the bis-spiroketal. To this end,
treatment of compound 163 with [(Me2N)3S][Me3SiF2] (TASF)9 in
aqueous DMF afforded hemiketal 14 upon release of the carbonyl
from the cyanohydrin and concomitant cleavage of the silyl ethers
(Scheme 4). Reprotection of the remaining hydroxyl group (14 A
17) followed by reductive cleavage of the N–O-bond with
Scheme 4 Reagents and conditions: (a) TASF, aq. DMF, 97%; (b)
TESOTf, 2,6-lutidine, CH2Cl2, 278 uC, 76%; (c) Mo(CO)6, MeCN–H2O,
90 uC, 92%; (d) compound 2 (R1 = H, R2 = R3 = TES, X = –S(CH2)3S–),
2,4,6-trichlorobenzoyl chloride, Et3N, DMAP cat., toluene, 50%; (e)
complex 10 (250 mol%), toluene, 60 uC; (f) NCS, AgNO3, 2,6-lutidine,
MeCN–H2O, 49% (over two steps).
10
Mo(CO)6 gave aldol 18, which was acylated with carboxylic
considerable line broadening in the NMR spectra. Preliminary
attempts to engender formation of the conspicuous bis-spiroacetal
subunit by acid catalyzed cyclization of the linear C.31–C.38 chain
in 21 onto the pre-existing hemiacetal met with failure. It remains
to be seen however, if application of this strategy to the correct
diastereomeric series and/or spirocyclization after saturation of the
C.25–C.26 double bond might eventually open a viable route to
spirastrellolide A.
acid 2 under Yamaguchi conditions.11 Gratifyingly, the resulting
diene 19 converted into cycloalkene 20 on treatment with the
‘second-generation’ Grubbs carbene 1012 in toluene at 60 uC; yet,
this transformation denotes a present limit of metathesis, as it
required 2.5 equivalents of the ‘‘catalyst’’, added in several
portions, to reach complete conversion. After oxidative hydrolysis
of the dithioacetal with NCS/AgNO3,13 product 21 could be
separated from traces of isomeric compounds by routine flash
chromatography. This macrocyclic compound exists as a mixture
of slowly interconverting conformers in solution which cause
A possible alternative means to overcome the deleterious steric
effects of the bis-spiroketal makes use of a suitable ‘relay’ trigger.14
The preparation of an adequate substrate was readily achieved
by adaptation of the route leading to fragment 33 and is depicted
in Scheme 5. Specifically, ozonolysis of 223 followed by
Wittig olefination of the resulting fragile aldehyde 23 with
Ph3PLCHCOOMe gave 24 in excellent yield, which was converted
into the bis-allyl ether 25 prior to elaboration of the TES-protected
cyanohydrin at the other terminus. Deprotonation of 26 using
LDA followed by alkylation of the resulting anion with the
known iodide 273 gave product 28, which was subjected to N–O-
bond cleavage and spirocyclization according to the established
protocol.3
The chain-extended building block 29 was then linked to the
southern domain 2 by means of a Yamaguchi esterification,11
which, after cleavage of the silyl groups, delivered compound 31
qualifying for metathetic ‘relay ring closure’.14 Exposure of this
substrate to catalytic amounts of carbene 10 in refluxing CH2Cl2
resulted in a clean conversion but gave the ring expanded
macrocycle 32 as the only detectable product in 64% yield. This
outcome highlights once again the exceptional reluctance of the
olefin adjacent to the chlorinated bis-spiroketal unit to undergo
Scheme 3 Reagents and conditions: 12 (10 eq.), complex 10 (10 mol%):
(a) CH2Cl2, reflux, 65% (13); (b) toluene, 80 uC, 48% (15).
3046 | Chem. Commun., 2007, 3045–3047
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Lett., 2004, 6, 2607; (c) D. E. Williams, M. Roberge, R. Van Soest and
R. J. Andersen, J. Am. Chem. Soc., 2003, 125, 5296.
2 For synthetic studies toward 1, see ref. 3 and the following: (a)
I. Paterson, E. A. Anderson, S. M. Dalby and O. Loiseleur, Org. Lett.,
2005, 7, 4121; (b) I. Paterson, E. A. Anderson, S. M. Dalby and
O. Loiseleur, Org. Lett., 2005, 7, 4125; (c) I. Paterson, E. A. Anderson,
S. M. Dalby, J. H. Lim, P. Maltas and C. Moessner, Chem. Commun.,
2006, 4186; (d) J. Liu and R. P. Hsung, Org. Lett., 2005, 7, 2273; (e)
Y. Pan and J. K. De Brabander, Synlett, 2006, 853; (f) J. Liu, J. H. Yang,
C. Ko and R. Hsung, Tetrahedron Lett., 2006, 47, 6121; (g) C. Wang
and C. J. Forsyth, Org. Lett., 2006, 8, 2997; (h) C. Wang and
C. J. Forsyth, Heterocycles, 2007, 72, 621; (i) I. Paterson, E. A.
Anderson, S. M. Dalby, J. Genovino, J. H. Lim and C. Moessner,
Chem. Commun., 2007, 1852.
3 (a) A. Fu¨rstner, M. D. B. Fenster, B. Fasching, C. Godbout and
K. Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5506; (b) A. Fu¨rstner,
M. D. B. Fenster, B. Fasching, C. Godbout and K. Radkowski, Angew.
Chem., Int. Ed., 2006, 45, 5510.
4 Review: P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 2563.
5 (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147; (b) for a review on
alkyl-Suzuki reactions, see: S. R. Chemler, D. Trauner and S. J.
Danishefsky, Angew. Chem., Int. Ed., 2001, 40, 4544.
6 Selected reviews: (a) T. M. Trnka and R. H. Grubbs, Acc. Chem. Res.,
2001, 34, 18; (b) A. Fu¨rstner, Angew. Chem., Int. Ed., 2000, 39, 3013; (c)
K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed.,
2005, 44, 4490.
7 Dithianes can potentially interfere with productive RCM, likely by
coordination to the soft ruthenium centre of the catalyst, cf. A. Fu¨rstner,
G. Seidel and N. Kindler, Tetrahedron, 1999, 55, 8215.
8 Attempts to engage vinyl groups displayed on related tetrahydropyran
templates in RCM-based macrocyclizations have previously met with
considerable difficulties or even led to failures, cf. M. Ball, B. J.
Bradshaw, R. Dumeunier, T. J. Gregson, S. MacCormick, H. Omori
and E. J. Thomas, Tetrahedron Lett., 2006, 47, 2223.
9 (a) K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S. Coffey
and W. R. Roush, J. Org. Chem., 1998, 63, 6436; (b) recent applications:
C. A¨ıssa, R. Riveiros, J. Ragot and A. Fu¨rstner, J. Am. Chem. Soc.,
2003, 125, 15512; (c) A. Fu¨rstner and T. Nagano, J. Am. Chem. Soc.,
2007, 129, 1906.
10 (a) A. Guarna, A. Guidi, A. Goti, A. Brandi and F. De Sarlo, Synthesis,
1989, 175; (b) P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini and
D. Simoni, Synthesis, 1987, 276.
11 (a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi,
Bull. Chem. Soc. Jpn., 1979, 52, 1989; (b) M. Hikota, Y. Sakurai,
K. Horita and O. Yonemitsu, Tetrahedron Lett., 1990, 31, 6367; (c)
recent applications: A. Fu¨rstner, E. Kattnig and O. Lepage, J. Am.
Chem. Soc., 2006, 128, 9194; (d) J. Mlynarski, J. Ruiz-Caro and
A. Fu¨rstner, Chem.–Eur. J., 2004, 10, 2214.
Scheme 5 Reagents and conditions: (a) O3, CH2Cl2, 278 uC, then Me2S,
95%; (b) Ph3PLCHCOOMe, THF, 0 uC A RT, 91%; (c) (i) Dibal-H,
CH2Cl2; (ii) allyl bromide, NaH, DMF, 97% (over both steps); (d) (i)
PPTS (1.2 eq.), MeOH, 82%; (ii) DMSO, oxalyl chloride, Et3N, 278 uC A
RT; (iii) KCN, Dowex1 resin, MeCN–H2O; (iv) TESOTf, 2,6-lutidine,
CH2Cl2, 73% (over three steps); (e) LDA, THF, 278 uC, 48%; (f) (i)
Mo(CO)6, MeCN–H2O, 90 uC; (ii) TASF, aq. DMF; (iii) PPTS cat.,
CH2Cl2, 45% (over three steps); (g) compound 2 (R1 = H, R2 = R3 = TES,
X = O), 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP cat., toluene, 82%;
(h) PPTS cat., MeOH, Et2O–H2O, 64%; (i) complex 10 (10 mol%),
CH2Cl2, reflux, 64%.
12 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
13 E. J. Corey and B. W. Erickson, J. Org. Chem., 1971, 36, 3553.
14 T. R. Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang and H. Zhao,
J. Am. Chem. Soc., 2004, 126, 10210.
productive metathesis yet outlines a convenient entry into
spirastrellolide analogues with enlarged backbones.15 The evalua-
tion of their phosphatase inhibitory activity16 as well as further
studies toward 1 are underway and will be disclosed in due course.
Generous financial support from the MPG, the Fonds der
Chemischen Industrie, the Alexander von Humboldt Foundation
(fellowships to G. W. O9N. and M. D. B. F.) and the Fonds de
Recherche sur la Nature et les Technologies (Que´bec, fellowship to
C. G.) is gratefully acknowledged. We thank Mrs C. Wirtz, Mrs B.
Gabor and Dr R. Mynott for expert NMR support.
15 A similar observation was recently made during an attempted synthesis
of bryostatin, in which application of the ‘relay’ trigger methodology
also led to a ring expanded analogue only, cf. B. M. Trost, H. Yang,
O. R. Thiel, A. J. Frontier and C. S. Brindle, J. Am. Chem. Soc., 2007,
129, 2206.
16 For previous syntheses and biological evaluations of phosphatase
inhibitors from this laboratory, see: (a) A. Fu¨rstner, F. Feyen, H. Prinz
and H. Waldmann, Angew. Chem., Int. Ed., 2003, 42, 5361; (b)
A. Fu¨rstner, F. Feyen, H. Prinz and H. Waldmann, Tetrahedron, 2004,
60, 9543; (c) A. Fu¨rstner, J. Ruiz-Caro, H. Prinz and H. Waldmann,
J. Org. Chem., 2004, 69, 459; (d) A. Fu¨rstner, K. Reinecke, H. Prinz and
H. Waldmann, ChemBioChem, 2004, 5, 1575; (e) M. Manger,
M. Scheck, H. Prinz, J. P. von Kries, T. Langer, K. Saxena,
H. Schwalbe, A. Fu¨rstner, J. Rademann and H. Waldmann,
ChemBioChem, 2005, 6, 1749.
Notes and references
1 (a) K. Warabi, D. E. Williams, B. O. Patrick, M. Roberge and
R. J. Andersen, J. Am. Chem. Soc., 2007, 129, 508; (b) D. E. Williams,
M. Lapawa, X. Feng, T. Tarling, M. Roberge and R. J. Andersen, Org.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3045–3047 | 3047