Synthesis of the C11-C23 fragment of spirastrellolide A. A ketal-tethered RCM approach to the construction of spiroketals

Article abstract of DOI:10.1021/ol050653q

(Chemical Equation Presented) The synthesis of the C11-C23 fragment in spirastrellolide A is described here featuring a ketal-tethered RCM as an alternative approach to the construction of spiroketals.

Full text of DOI:10.1021/ol050653q

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2273-2276
Synthesis of the C11−C23 Fragment of
Spirastrellolide A. A Ketal-Tethered RCM
Approach to the Construction of
Spiroketals
Jia Liu and Richard P. Hsung*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received March 27, 2005
ABSTRACT
The synthesis of the C11−C23 fragment in spirastrellolide A is described here featuring a ketal-tethered RCM as an alternative approach to
the construction of spiroketals.
Roberge and Andersen et al. reported in 2003 the isolation
of spirastrellolide A, a novel macrolide from marine sponge
Spirastrellolide coccinea,1a and recently, the structure of
spirastrellolide A was revised as shown in Figure 1.1b In
addition to its ability to cause untimely mitotic arrest in cells,
spirastrellolide A was shown to exhibit potent inhibitory
activity against protein phosphatase 2A (IC50 ) 1 nM) along
with a good selectivity for PP2A over PP1 (ratio of IC50
values 1:50).1,2 We became interested in spirastrellolide A
as a result of our recent interest and efforts in developing
an unconventional approach to the synthesis of spiroketals.3
Specifically, we have been developing ketal-tethered reac-
tions such as IMDA4 and RCM5 using cyclic ketals 1 to
construct spiroketals 2 (Scheme 1), which are among the
most prevalent structural motifs in natural products.
This seldom-employed approach is in distinct contrast with
the classical internal ketalization using keto diols 3. By
(1) (a) William, D. E.; Roberge, M.; Van Soest, R.; Andersen, R. J. Am.
Chem. Soc. 2003, 125, 5296. (b) William, D. E.; Lapawa, M.; Feng, X.;
Tarling, T.; Roberge, M.; Andersen, R. Org. Lett. 2004, 6, 2607.
(2) Roberge, M.; Cinel, B.; Anderson, H. J.; Lim, L.; Jiang, X.; Xu, L.;
Kelly, M. T.; Andersen, R. J. Cancer Res. 2000, 60, 5052.
(3) For reviews, see: (a) Mead, K. T.; Brewer, B. N. Curr. Org. Chem.
2003, 7, 227. (b) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617.
(4) Wang, J.; Hsung, R. P.; Ghosh, S. K. Org. Lett. 2004, 6, 1939.
(5) Ghosh, S. K.; Hsung, R. P.; Wang, J. Tetrahedron Lett. 2004, 45,
5505.
Figure 1.
10.1021/ol050653q CCC: $30.25
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utilizing a cyclic ketal as a template for synthesis, an
anomeric effect of 1.5 kcal mol-1, such as shown with the
axially oriented C2-oxygen substituent in 1,3a,6 could be
advantageous in either promoting reactivities4 or controlling
remote stereochemistry7 away from the pending spiro center
at C2. This lack of development is likely because ketals are
mostly regarded as protecting groups (see 4 and 5). Although
there are limited reports featuring reactions of 18 and 6,9 this
approach to spiroketal construction has been largely under-
appreciated.10,11 Given the synthetic prowess of RCM,12 we
have been pursuing applications in natural product synthesis
to feature the ketal-tethered RCM (Scheme 1). We com-
(Scheme 2). We note here that the relative stereochemistry
at C22 (see the arrow) was not unambiguously assigned when
we began our study.1a We elected to go with C22 being R
because of its availability. After C22 was assigned as S,1b
we continued our efforts with the C22-R stereochemistry to
focus on establishing the feasibility of the ketal-tethered
RCM approach.
Scheme 2
Scheme 1
municate here our efforts in the synthesis of the C11-C23
fragment of spirastrellolide A.13
Retrosynthetically, the synthesis of the C11-C23 fragment
(7) would feature the ketal-tethered RCM of cyclic ketal 8
Cyclic ketal 8 can be envisioned from an acid-promoted
ketal formation through substitution at the C17 anomeric
position of lactol 9 with the known alcohol 10 (11 + 12).14
Lactol 9 can be attained from a vinyl Grignard addition to
lactone 13, which can be prepared from aldehyde 15 through
diol 14. The stereochemistry at C20 will be set using a known
allylation protocol,15 and stereocenters at C21 and C22-R
could be borrowed from D-glucose.16
(6) For reviews on the anomeric effect related to carbohydrate chemistry,
see; (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Ann Arbor,
MI, 1995. Also see: (b) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J.
Am. Chem. Soc. 1992, 114, 859. (c) Miljkovic, M.; Yeagley, D.; Deslong-
champs, P.; Dory, Y. L. J. Org. Chem. 1997, 62, 7597.
(7) Ghosh, S. K.; Hsung, R. P.; Liu, J. Submitted for publication in J.
Am. Chem. Soc.
Our synthetic efforts commenced with transforming D-
glucose (16) to the vinyl alcohol 17 in three steps using
reported procedures (Scheme 3).16 Protection of C22-OH
in 17 as a benzyl ether followed by hydrolysis of benzylidene
acetal gave 1817 in 82% yield over two steps. A double
silylation using TBSCl capped both C21 and C23 hydroxyl
groups, and an oxidative cleavage sequence led to aldehyde
15 in 74% overall yield from 18. With aldehyde 15 in hand,
a BF3‚Et2O-promoted allylation15 was accomplished to afford
(8) (a) van Hooft, P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. A.;
van der Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron
Lett. 1998, 39, 6061. (b) Leeuwenburgh, M. A.; Appeldoorn, C. C. M.;
van Hooft, P. A. V.; Overkleeft, H. A.; van der Marel, G. A.; van Boom,
J. H. Eur. J. Org. Chem. 2000, 837. (c) Bassindale, M. J.; Hamley, P.;
Leitner, A.; Harrity, J. P. A. Tetrahedron Lett. 1999, 40, 3247.
(9) (a) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2004, 126, 15074. (b)
Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2003, 125, 9582. (c) Keller, V.
A.; Martinellie, J. R.; Strieter, E. R.; Burke, S. D. Org. Lett. 2002, 4, 467.
(d) Voight, E. A.; Rein, C.; Burke, S. D. J. Org. Chem. 2002, 67, 8489 and
references cited therein. (e) Scholl, M.; Grubbs, R. H. Tetrahedron Lett.
1999, 40, 1425.
(10) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.; Russcher, J.
C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; van Maarseveen,
J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal.
2002, 344, 736.
(11) For some examples of ketal-tethered reactions, see: (a) Roush, W.
R.; Barba, D. A. Tetrahedron Lett. 1997, 38, 8781. (b) Wong, T.; Wilson,
P. D.; Woo, S.; Fallis, A. G. Tetrahedron Lett. 1997, 38, 7045. (c)
Ainsworth, P. J.; Craig, D.; White, A. J. P.; Williams, D. J. Tetrahedron
1996, 52, 8937. (d) Boeckman, R. K., Jr.; Estep, K. G.; Nelson, S. G.;
Walters, M. A. Tetrahedron Lett. 1991, 32, 4095. (e) Jung, M. E.; Street,
L. J. J. Am. Chem. Soc. 1984, 106, 8327.
(13) For recent synthetic efforts toward spirastrellolide A, see: (a) Dalby,
S. M.; Loiseleur, O.; Paterson, I. Abstracts of Papers, 229th National
Meeting of the American Chemical Society, San Diego, CA, Spring 2005;
American Chemical Society: Washington, DC, 2005; ORGN-331. (b)
Wang, C.; Forsyth, C. J. Abstracts of Papers, 229th National Meeting of
the American Chemical Society, San Diego, CA, Spring 2005; American
Chemical Society: Washington, DC, 2005; ORGN-414.
(14) For the synthesis of 10, 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.
(12) 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, Heidelberg, 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.
(15) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265.
(16) For the synthesis of 17, see: (a) Paquette, L. A.; Zeng, Q.; Tsui,
H.-C.; Johnston, J. N. J. Org. Chem. 1998, 63, 8491. (b) Baker, S. R.;
Clissold, D. W.; McKillop, A. Tetrahedron Lett. 1988, 29, 991.
(17) See the Supporting Information for procedures and characterization
data for all new compounds.
2274
Org. Lett., Vol. 7, No. 11, 2005

lactone intermediate. Removal of the C23 TBS group in this
lactone intermediate using TBAF followed by reprotection
of C23-OH with TBDPSCl gave lactone 13 in 82% overall
yield (Scheme 4). This latter exchange of the protecting
group was pursued because the C23 TBS ether did not
survive the cyclic ketal formation later under the acidic
conditions. Thus, we had to return to this stage and buttress
the choice of protecting groups for C23-OH. Addition of
vinylmagnesium bromide to 13 gave the desired lactol 9 in
73% yield as a single diastereomer.
Scheme 3
Despite having protocols that we have developed in the
ketal formation using simple pyranyl systems4,5,7 and those
reported for more robust carbohydrate based systems,8a,b the
cyclic ketal formation using lactol 9, which contains the
anomeric vinyl group at C17, proved to be a major challenge.
A partial summary of acids examined to achieve an efficient
cyclic ketal formation is shown in Table 1.
Table 1.
the Felkin-Anh product 19 as a single diastereomer in 95%
yield. The relative stereochemistry at C20 was further
confirmed via NOE of acetonide 20 prepared from 19.17
Capping the C20-OH in 19 with Meerwein’s salt gave
methyl ether 21 in 85% yield (Scheme 4). Removal of both
Scheme 4
product
amt,
(yield,
%)
entry
acid
equiv solvent
temp, °C
time
1
2
3
BF3‚Et2O 1.0
TMSOTf 1.0
CH2Cl2 -78
CH2Cl2
100 min 24 (82)
0
15 min
24 (88)
24 (89)
K-10
1.2-2.5 benzene room temp- 5-15 h
reflux
4
5
CSA or
PPTS
Tf2NH
0.5-1.0 CH2Cl2 room temp- 1-15 h no reacn
reflux
1.0
CH2Cl2 -78
5 min
23 (89)
The problem involved competing pathways. In addition
to the 1,2-addition of 3-buten-1-ol to oxocarbenium ion 25
(Table 1), which should lead to the desired cyclic ketal 23,
we found over additions that proceeded through 1,4- and
then 1,2-additions to oxocarbenium ion 25 to give 24. In
some cases, we also observed an elimination of a proton from
25 to give 26, which appeared to be a nonproductive
pathway, although the elimination is likely reversible via
reprotonation of enol ether 26.
C21- and C23-TBS groups using TBAF and subsequent
monoprotection of C23-OH using TBSCl gave 22.18
A
standard BH3‚SMe2 hydroboration-oxidation yielded diol
14 in 78% overall yield from 21. The utility of 9-BBN was
also feasible but required a large excess.
The preparation of lactone 13 experienced some problems,
but ultimately TEMPO oxidation of diol 14 led to the desired
(18) This excessive manipulation occurred because we had to abandon
earlier plans on the synthesis of lactone 13 in which the bis-TBS ether 21
would have been feasible.
Org. Lett., Vol. 7, No. 11, 2005
2275

A range of acids as well as solvents and temperatures were
screened, and surprisingly, while most frequently used Lewis
acids and Brønsted acids in anomeric substitutions6 led to
the overaddition product 24, Tf2NH19 (entry 5) proved to be
an excellent Brønsted acid at -78 °C, leading to 23 as the
sole product in 89% yield as a single diastereomer with the
oxo-butenyl group (OR) being axial (see below).
Scheme 6
The ensuing RCM of 23 gave spiroketal 27 in 95% yield
using Grubbs’ generation I Ru catalyst12 (Scheme 5). Selected
Scheme 5
ments in CDCl3 and C6D6 could be obtained to confirm the
key relative stereochemistry in spiroketal 7 (see the box in
Scheme 6; the dashed arrow implies a relatively weak NOE).
Despite being epi at the C22 stereocenter relative to the
natural product, most proton chemical shifts in C6D6 (i.e.,
protons from C13-C21) along with their respective coupling
constants in 7 are quite similar to those reported for the
methyl ester of spirastrellolide A.1 More importantly, the key
NOE enhancements observed for 7 closely matched those
reported for the same region in spirastrellolide A.1
We have described here a ketal-tethered RCM approach
to the construction of spiroketals by featuring the synthesis
of the C11-C23 fragment in spirastrellolide A. Applications
of this alternative spiroketal synthesis toward completing a
total synthesis of spirastrellolide A are currently ongoing.
NOE experiments of 27 revealed that the C17 spiro center
possesses the desired relative stereochemistry, thereby
confirming that the addition of 3-buten-1-ol (ROH in Table
1) to oxocarbenium ion 25 had occurred from an anomeri-
cally favored axial trajectory. In addition, due to the
conformational rigidity of this spiroketal, coupling constants
of C20-H are 4, 10, and 10 Hz, thereby suggesting two
vicinal di-axial couplings similar to those reported for the
methyl ester of spirastrellolide A.1
Success in this model system allowed us to complete the
synthesis of the fragment C in spirastrellolide A. As shown
in Scheme 6, the known chiral alcohol 10 was prepared
according to literature procedures,14 and cyclic ketal 8 was
obtained20 from lactol 9 as a single isomer under the same
Tf2NH conditions. A successful RCM was achieved to give
spiroketal 7 in 50% overall yield.
Acknowledgment. We thank the ACS-PRF-AC for
funding.
It is noteworthy that most of the protons in spiroketal 7
are well resolved,17 and thus, comprehensive NOE experi-
Supporting Information Available: Text and figures
giving experimental procedures as well as 1H NMR spectral
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) For a study on the acidity of HNTf2, see: Thomazeau, C.; Olivier-
Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003,
125, 5264.
(20) On occasion, we also found diene 26, presumably because alcohol
10 is more sterically demanding than the model system.
OL050653Q
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Org. Lett., Vol. 7, No. 11, 2005