Toward the synthesis of spirastrellolide A: Construction of two C 1-C25 diastereomers containing the BC-spiroacetal

Article abstract of DOI:10.1021/ol051405x

(Chemical Equation Presented) Stereocontrolled syntheses of two possible C₁-C₂₅ diastereomers of spirastrellolide A containing the cis-disubstituted tetrahydropyran and [6,6]-spiroacetal are reported, exploiting boron-mediated asymme

Full text of DOI:10.1021/ol051405x

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4125-4128
Toward the Synthesis of Spirastrellolide
A: Construction of Two C1 C25
Diastereomers Containing the
BC Spiroacetal
−
−
Ian Paterson,* Edward A. Anderson, Stephen M. Dalby, and Olivier Loiseleur
UniVersity Chemical Laboratory, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, UK
ip100@cam.ac.uk
Received June 16, 2005
ABSTRACT
Stereocontrolled syntheses of two possible C1−C25 diastereomers of spirastrellolide A containing the cis-disubstituted tetrahydropyran and
[6,6]-spiroacetal are reported, exploiting boron-mediated asymmetric aldol and allylation methodology.
Spirastrellolide A (1, Scheme 1) is a novel antimitotic
macrolide isolated by Andersen and co-workers from the
Caribbean sponge Spirastrella coccinea,1 which represents
a potent and selective inhibitor of protein phosphatase 2A.
In the preceding communication,2 we describe a stereocon-
trolled synthesis of the C26-C40 subunit 3, corresponding to
the fully functionalized [5,6,6]-bis-spiroacetal (DEF rings)
of spirastrellolide A. We report herein the construction of
two possible diastereomers of the C1-C25 southern hemi-
sphere of spirastrellolide, containing the C3-C7 cis-disub-
stituted tetrahydropyan (A ring), the [6,6]-spiroacetal (BC
rings), and the challenging C20-C24 stereopentad.3
Our proposed retrosynthesis of spirastrellolide is outlined
in Scheme 1. As indicated previously,2 we envisaged initial
disconnections of spirastrellolide that would isolate subunits
3 and 4 from the C1-C25 southern hemisphere. Mindful of
the need to maintain a flexible synthetic strategy with respect
to the unknown relative stereochemistry between C3-C7 and
C9-C24, we targeted the two diastereomeric spiroacetals 5
and 6 (which differ in configuration at C3 and C7) as suitable
fragments for eventual coupling with the northern hemisphere
subunit 3. Spiroacetals 5 and 6 might arise through thermo-
dynamically controlled spiroacetalization of the respective
open-chain precursors 7 and 8 following deprotection. These
cis-enones could themselves be derived from the coupling
of the lithiated alkynes 9 and 10 with aldehyde 11, followed
by reoxidation at C17 and Lindlar reduction. Alkynes 9 and
10 might be prepared, in turn, from a common tetrahydro-
pyran 12, while aldehyde 11 could arise from the tartrate-
derived aldehyde 13. Our selected routes to both these
fragments exploit a combination of boron-mediated asym-
metric allylation and aldol methodology.
(3) For other synthetic studies, see: (a) Liu, J.; Hsung, R. P. Org. Lett.
2005, 7, 2273. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur,
O. Abstracts of Papers, 229th National Meeting of the American Chemical
Society, San Diego, Mar 13-17, 2005; American Chemical Society:
Washington, DC, 2005; ORGN-331. (c) Wang, C.; Forsyth, C. J. Abstracts
of Papers, 229th National Meeting of the American Chemical Society, San
Diego, Mar 13-17, 2005; American Chemical Society: Washington, DC,
2005; ORGN-414.
(1) (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.
(2) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett.
2005, 7, 4121.
10.1021/ol051405x CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/17/2005

Scheme 1. Retrosynthetic Analysis of Spirastrellolide A
The synthesis of the C3,C7-epimeric alkynes 9 and 10
utilizes the pseudo-S2 symmetry of the tetrahydropyran 12
(Scheme 2). This pyran could be conveniently derived from
sure of the resulting allylic alcohol 156 to potassium tert-
butoxide effected a smooth hetero-Michael cyclization under
thermodynamic conditions to provide exclusively the 2,6-
cis-tetrahydropyran 12 (83%). Subsequent ozonolysis of 12
and Brown asymmetric allylboration7 provided alcohol 16
with high stereoselectivity (dr > 95:5, 71%, two steps).
Reduction of the ester with LiAlH4, followed by bis-TBS
protection, and a second ozonolysis, delivered aldehyde 17
in 88% yield (three steps).
Scheme 2
The C3,C7-epimeric aldehyde 19 could be accessed ef-
ficiently via a similar route. A four-step sequence, which
converted the common pyran 12 into aldehyde 18 (68%),
was followed by an allylboration,7 which again proceeded
with excellent stereocontrol (dr > 95:5), to install the C9
hydroxyl-bearing stereocenter. Finally, conversion of this
allylation product into aldehyde 19 was achieved by TBS
protection and ozonolysis (63%, three steps).
Transformation of the aldehydes 17 and 19 to alkynes 9
and 10 is shown in Scheme 3. The required 11,14-syn
relationship was established through application of our boron-
mediated aldol methodology employing methyl ketone 20.8
Enolization of 20 with (-)-Ipc2BCl followed by addition of
aldehyde 17 afforded aldol adduct 21 in excellent yield and
selectivity (87%, dr > 20:1). A highly selective 1,3-anti
reduction,9 followed by acetonide formation, delivered 23
(4) De Brabander has described a similar sequence to deliver the
corresponding enantiomeric methyl ester of 12, see: (a) Bhattacharjee, A.;
Soltani, O.; De Brabander, J. K. Org. Lett. 2002, 4, 481. (b) Evans, D. A.;
Carreira, E. M. Tetrahedron Lett. 1990, 31, 4703.
(5) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 112, 2389.
(6) See Supporting Information for proof of stereochemistry of novel
compounds.
(7) Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org. Chem.
1986, 51, 432.
(8) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241.
lactol 14.4 Thus, a Wittig reaction of lactol 14 was followed
by Swern oxidation and a Brown allylation using B-methoxy-
bis(2-isocaranyl)borane (three steps, 58%, 90% ee).5 Expo-
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Org. Lett., Vol. 7, No. 19, 2005

as a single isomer (90%, two steps). This acetonide was then
converted into alkyne 9 by hydrogenolysis of the benzyl
group, Dess-Martin oxidation and Corey-Fuchs alkynyla-
tion (58%, four steps).10
the C20 hydroxyl-bearing stereocenter (dr > 95:5), which was
subsequently O-methylated. Desilylation with TBAF, fol-
lowed by Dess-Martin oxidation, delivered aldehyde 25
(36%, four steps).
Installation of the C23 and C24 stereocenters was achieved
through application of a second boron-mediated aldol reac-
tion, in this case making use of (S)-ethyl lactate-derived
ketone 26. Here, reaction of aldehyde 25 with the (E)-boron
enolate of 26 (c-Hex2BCl, Et3N) gave â-hydroxyketone 27
as a single isomer in 79% yield.12 TBS protection was
followed by efficient cleavage of the auxiliary and PMB
protection of the resultant primary alcohol. Finally, the
required C17 oxygenation was established through hydrobo-
ration/Dess-Martin oxidation to deliver aldehyde 11 (51%
yield, five steps).
Scheme 3
At this point, we were set to couple the appropriate
fragments to generate the open-chain precursors for spiroac-
etal formation (Scheme 5). Coupling of aldehyde 11 with 9
and 10 was achieved via alkyne lithiation using n-BuLi,
followed by addition of 11, to furnish the desired coupled
products, each being isolated as an inconsequential ca. 1:1
epimeric mixture at C17. Dess-Martin oxidation followed
by Lindlar hydrogenation smoothly delivered the corre-
sponding (Z)-enones 7 (77%, three steps) and 8 (66%).
With the targeted enones in hand, the crucial spiroacetal-
ization reaction was investigated. In the event, treatment of
enone 7 with HF in aqueous MeCN led to complete
desilylation, and acetonide remoVal followed by the forma-
tion of a single spiroacetal product 5 (55%). The diastere-
omeric enone 8 underwent spirocyclization (70%) under
analogous conditions. The choice of HF/MeCN to mediate
the cyclization reaction proved to be critical, as alternative
reagents (CSA/MeOH, Dowex 50Wx8 resin, HCl/THF) led
to extensive decomposition.
Application of this reaction sequence to the diastereomeric
aldehyde 19 proved to be equally efficient. Aldol coupling
proceeded selectively for the desired adduct 22 (68%, dr >
20:1), and an analogous six-step sequence enabled the
completion of alkyne 10 (57%).5
The successful formation of the desired spiroacetal ster-
eochemistry could be readily confirmed by comparison of
the 1H and 13C NMR data of 5 and 6 with that of the methyl
ester derivative 2 of spirastrellolide.1b,13 There was a close
correlation between the NMR data for the synthetic subunit
and natural product in the C11-C24 spiroacetal-containing
region. The 13C NMR spectra exhibited characteristic C17
acetal resonances at 95.1 (5) and 94.8 ppm (6), also in close
agreement with that of the natural product (93.8 ppm). In
addition to these similarities, diagnostic strong NOE en-
hancements between H13 and H21, which had also been
observed for the natural product, served to confirm that the
C17 stereocenter of 5 and 6 possessed the desired configu-
ration.
The synthesis of aldehyde 11 (the coupling partner for
alkynes 9 and 10) commenced with the known aldehyde 13,
which is available in four steps from (R,R)-diethyl tartrate
(Scheme 4).11 Brown allylboration7 of 13 proceeded to install
Scheme 4
In contrast to these markedly similar regions of the
synthetic and natural compounds, comparison of the C7-C9
portion of the two diastereomers revealed substantial differ-
(9) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(10) Corey E. J., Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(11) Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc. 1996,
118, 10412.
(12) (a) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett.
1994, 35, 9083. (b) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis
1998, 639.
(13) See Supporting Information for full NMR comparisons.
Org. Lett., Vol. 7, No. 19, 2005
4127

Scheme 5
ences by NMR analysis. In terms of prediction of the
carried out to enable additional NMR comparisons with the
equivalent natural product derivatives (Scheme 6).1b Again,
both sets of compounds showed a similar degree of correla-
tion with the corresponding spirastrellolide derivatives,
emphasizing the need for further synthetic studies.
In summary, we have completed convergent syntheses of
two diastereomers of the ABC-ring containing C1-C25 region
of spirastrellolide. Ongoing work into the coupling of these
subunits with the C26-C40 northern hemisphere2 should
enable elucidation of the remaining unknown relative ster-
eochemistry and ultimately a total synthesis of spirastrellolide
A.
relationship between the C3-C7 and C9-C24 stereoclusters,
it was anticipated that one of the isomers would correlate
significantly more closely with spirastrellolide than the other,
thus allowing a possible resolution of this stereochemical
ambiguity. As can be seen from the chart in Scheme 5,
spiroacetal 5 seems to exhibit a closer match to spiras-
trellolide at H7 and H9 than its isomer 6, although comparison
of the resonances at H8 remains somewhat inconclusive.
Scheme 6
Acknowledgment. We thank the EPSRC (EP/C541677/
1), Homerton College, Cambridge (Research Fellowship to
E.A.A.), Syngenta Crop Protection (secondment of O.L.),
and Merck for support and Professor Raymond Andersen
(University of British Columbia) for helpful discussions.
Supporting Information Available: Spectroscopic data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, derivatization of the spiroacetals 5 and 6 as the
pentaacetates (28 and 29) and peracetonides (30 and 31) was
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