Toward the synthesis of spirastrellolide B: A synthesis of the C1-C23 subunit

Article abstract of DOI:10.1021/ol702955m

A synthesis of the C1-C23 subunit of spirastrellolide B is described. The synthesis features two applications of a Kulinkovich-cyclopropanol ring-opening strategy for the coupling of esters with olefins to produce ketones.

Full text of DOI:10.1021/ol702955m

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1083-1086
Toward the Synthesis of Spirastrellolide
B: A Synthesis of the C1−C23 Subunit
Katie A. Keaton and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado at Boulder,
Boulder, Colorado 80309-0215
andrew.phillips@colorado.edu
Received December 6, 2007
ABSTRACT
A synthesis of the C1−C23 subunit of spirastrellolide B is described. The synthesis features two applications of a Kulinkovich-cyclopropanol
ring-opening strategy for the coupling of esters with olefins to produce ketones.
Spirastrellolide A and B (1 and 2, Figure 1) are two closely
related polyketides that were isolated by Anderson and co-
workers from the marine sponge Spirastrella coccinea. The
key elements of the structure of spirastrellolide A were first
disclosed in 20031 and were followed by a report describing
a structure revision and the inhibition of PP2A.2 Subsequent
cleavage of the ∆40,41 olefin and derivitization of spiras-
trellolide B produced a compound suitable for X-ray analysis3
and revealed the complete relative and absolute stereochem-
istry of the macrolide core. Recently, Anderson and co-
workers have reported that the C46 alcohol is of (R)
configuration and also described the isolation of a further 5
congeners (spirastrellolides C to G).4
The spirastrellolides have generated substantial interest
from the synthesis community, and although no total
synthesis has yet been described, a number of papers describe
the synthesis of fragments.5-10 In this communication, we
report our preliminary studies that have led to a synthesis of
the C1-C23 domain.
As shown in Figure 1, our overall plan consists of the
assembly of two large domains (3 and 4) by a combina-
tion of Nozaki-Hiyama-Kishi reaction and an esterifica-
tion or lactonization. Further dissection of the C1-C23
subunit 4 led to three fragments of similar complexity:
pyran-containing methyl ketone 5, known aldehyde 6,5b
and methyl ester 7. In the forward direction, we planned to
couple these fragments by a combination of aldol reaction
and our recently described Kulinkovich-cyclopropanol open-
ing strategy.11
(5) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273. (b) Liu, J.; Yang,
J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121. (c) Ghosh,
S. K.; Ko, C.; Liu, J.; Wang, J.; Hsung, R. P. Tetrahedron 2006, 62,
10485.
(6) (a) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org.
Lett. 2005, 7, 4125. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.;
Loiseleur, O. Org. Lett. 2005, 7, 4121. (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.; Genovino, J.; Lim,
J. H.; Moessner, C. Chem. Commun. 2007, 1852.
(7) (a) Furstner, A.; Fenster, M. D. B.; Fasching, B.; Godbout, C.;
Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5506. (b) Furstner, A.;
Fenster, M. D. B.; Fasching, B.; Godbout, C.; Radkowski, K. Angew. Chem.,
Int. Ed. 2006, 45, 5510. (c) Furstner, A.; Fasching, B.; O’Neil, G. W.;
Fenster, M. D. B.; Godbout, C.; Ceccon, J. Chem. Commun. 2007, 3045.
(8) Pan, Y.; De Brabander, J. K. Synlett 2006, 853.
(1) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R. J. J. Am.
Chem. Soc. 2003, 125, 5296.
(2) Williams, D. E.; Lapawa, M.; Feng, X.; Tarling, T.; Roberge, M.;
Andersen, R. J. Org. Lett. 2004, 6, 2607.
(3) Warabi, K.; Williams, D. E.; Patrick, B. O.; Roberge, M.; Andersen,
R. J. J. Am. Chem. Soc. 2007, 129, 508.
(4) Williams, D. E.; Keyzers, R. A.; Warabi, K.; Desjardine, K.; Riffell,
J. L.; Roberge, M.; Andersen, R. J. J. Org. Chem. 2007, 72, 9842.
(9) (a) Wang, C.; Forsyth, C. J. Org. Lett. 2006, 8, 2997. (b) Wang, C.;
Forsyth, C. J. Heterocycles 2007, 72, 621.
(10) Smith, A. B., III; Kim, D.-S. Org. Lett. 2007, 9, 3311.
(11) Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717.
10.1021/ol702955m CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

Figure 1. Structures of spirastrellolides A and B, overall synthesis plan, and key building blocks for C1-C23 of spirastrellolide B.
The synthesis of pyran 5 commences with known epoxide
7, which is readily available by application of Jacobsen’s
hydrolytic kinetic resolution to racemic starting material (see
Scheme 1).12 Opening with 3-butenylmagnesium bromide in
11 to the enone14,15 12 showed NCS in the presence of Fe-
(NO3)3 and DBU to be most effective. Application of these
conditions to the system at hand produced enone 10 in 75%
yield for the two steps. Removal of the TBS protecting group
Scheme 1. Synthesis of the C1-C10 Subunit, 5
Scheme 2. Synthesis of Ester 7
the presence of Kochi’s catalyst13 and subsequent silylation
of the secondary alcohol with TBSOTf provided 8 in 72%
yield for the two steps. Reaction of 8 with ethyl acetate in
the presence of cyclohexylmagnesium bromide and Ti-
(i-PrO)4 gave the expected intermediate cyclopropanol. A
brief survey of conditions for the opening of cyclopropanol
(12) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. J. Am. Chem. Soc. 2002,
124, 1307.
(13) Tamura M.; Kochi J. Synthesis 1971, 303.
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Org. Lett., Vol. 10, No. 6, 2008

was subsequently methylated to give 16 in 74% yield over
the two steps. Sharpless asymmetric dihydroxylation of this
compoundwithAD-mixalphasupplementedwith(DHQ)2PHAL
and OsO4 produced diol 17 in 83% yield as a single
diastereoisomer. Silylation of the alcohols (TBSOTf, Et3N,
86%) and then hydrogenolysis of the benzyl group in the
presence of Pearlman’s catalyst gave primary alcohol 18 in
91% yield. A standard sequence of Dess-Martin periodinane
oxidation, Lindgren-Pinnick oxidation, and methylation with
trimethylsilyldiazomethane gave the targeted ester 7 (90%
over 3 steps, see Scheme 2).
Scheme 3. 1,3-Anti Aldol Reaction and Reduction to Give the
C1-C16 Domain, 23
Silylation of methyl ketone 5 with TMSOTf in the
presence of Et3N gave silyl enol ether 20, which was used
immediately in the subsequent Mukaiyama aldol reaction
(Scheme 3). To this end, reaction of 20 with aldehyde 6 in
the presence of BF3‚OEt2 at -95 °C gave the expected
product 21 in 83% yield. The reaction provided a 6:1 ratio
of diastereoisomers, and the stereochemistry C11 for the
major diastereoisomer was determined to be as desired by
Mosher’s ester analysis. Diastereoselective reduction of the
ketone with Li(t-BuO)3AlH gave 22 in 89% yield [dr ) 8:1],
and subsequent silylation of the alcohols with TBSOTf
and Et3N gave the complete C1-C16 domain 23 in 82%
yield.
with HF and concomitant cyclization produced the pyran 5
in 98% yield and completed the synthesis of the C1-C10
domain.
The synthesis of methyl ester 7 commenced with the
asymmetric alkynylation of 4-(benzyloxy)butanal 13 with
TBS-protected propargyl alcohol 14 in the presence of amino
alcohol 1916 to yield 15 in 93% yield. Propargyl alcohol 15
was reduced to the (E)-allylic alcohol using Red-Al17 and
At this juncture, it was possible to examine the key subunit
coupling of alkene 23 and ester 7. Subjecting a mixture of
these two compounds to Ti(i-OPr)4 and cyclohexylmagne-
sium bromide18 at room temperature in THF resulted in clean
coupling to yield cyclopropanol 24 in 95% yield. Exposure
of this compound to Fe(NO3)3 and Bu3SnH resulted in ring
opening to give ketone 25 in 71% yield (this represents a
Scheme 4. Subunit Coupling by Kulinkovich-Cyclopropanol Opening (7+23f24f25) and Assembly of the Complete C1-C23
Domain 4
Org. Lett., Vol. 10, No. 6, 2008
1085

67% yield for the two steps). Subsequent removal of the
protecting groups with HF in MeCN also resulted in
cyclization to give the desired spiroketal 26 (83% yield),
and reprotection of the alcohols gave the targeted compound
4 in 73% yield. The structure and stereochemistry of 4 was
established by a combination of 2D-NMR experiments
(HSQC, HMBC) and NOESY (see Scheme 4).
A key feature of the synthesis is the use of a Kulinkovich-
cyclopropanol opening strategy to couple together two
complex subunits (7+23f24f25). Further studies on the
utility of this strategy for complex molecule synthesis, as
well as progress toward spirastrellolide B, will be reported
in due course.
Acknowledgment. We thank Eli Lilly and Company, the
AP Sloan Foundation, and the National Institutes of Health
(NCI CA110246) for support of this research.
In conclusion, we have described a concise 14-step
sequence to the full C1-C23 domain of spirastrellolide B.
(14) For pioneering studies on the opening of cyclopropanols with Fe-
(III) species to give â-chloroketones, see: (a) Schaafsma, S. E.; Steinberg,
H.; De Boer, Th. J. Recl. TraV. Chim. Pays-Bas 1966, 85, 73. (b) Schaafsma,
S. E.; Steinberg, H.; De Boer, Th. J. Recl. TraV. Chim. Pays-Bas 1966, 85,
70.
(15) Booker-Milburn has also observed â-chloroesters as products in the
opening of cyclopropenone acetals with Fe(III): Booker-Milburn, K. I.;
Cox, B.; Mansley, T. E. Chem. Commun. 1996, 2577.
Supporting Information Available: Procedures for the
synthesis of all new compounds, along with characterization
data, and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL702955M
(16) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524.
(17) (a) Chan, K.; Cohen, N.; DeNoble, J. P.; Specian, A. C.; Saucy, G.
J. Org. Chem. 1976, 41, 3497. (b) Denmark, S. E.; Jones, T. K. J. Org.
Chem. 1982, 47, 4595.
(18) For the initial report describing these conditions for Kulinkovich,
cyclopropanation, see: Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198.
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