Total synthesis of paecilospirone

Article abstract of DOI:10.1002/anie.201103117

Neutrality is the best policy: Key features of the first total synthesis of paecilospirone include an anti-selective, lactate-derived aldol reaction, and a double deallylation/spirocyclization conducted at neutral pH to construct the sensitive hydroxy-substituted benzannulated spiroacetal (see scheme; Bn=benzyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl).

Full text of DOI:10.1002/anie.201103117

Communications
DOI: 10.1002/anie.201103117
Natural Product Synthesis
Total Synthesis of Paecilospirone**
Tsz-Ying Yuen, Sung-Hyun Yang, and Margaret A. Brimble*
In 2000, Namikoshi et al. reported the isolation and structural
elucidation of a novel [5,6]-bisbenzannulated spiroacetal[1]
from the marine fungus Paecilomyces sp.[2] This unique
spiro[chroman-2,1’(3’H)-isobenzofuran] derivative was iden-
tified as a potential antimitotic agent (20% inhibition at
50 mm) using an assay screening for microtubule assembly
inhibitors and was subsequently named paecilospirone (1).[3]
Scheme 1. Standard acid-catalyzed deprotection/cyclization of ketone
2, acid=Bi(OTf)3, TMSBr, NaHSO4·SiO2, CBr4 or PPTS. MOM=me-
thoxymethyl, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesul-
fonyl, TMS=trimethylsiyl, PPTS=pyridinium p-toluenesulfonate.
derived from bromide 6 to aldehyde 7 (Scheme 2). An anti-
selective aldol reaction between ketone 8 bearing a chiral
auxiliary and aldehyde 9 should then establish the contiguous
stereogenic centers in aldehyde 7. Overall, the proposed
retrosynthetic strategy was designed with maximum flexibility
to allow production of a focused library of analogues for
future biological evaluation.
Despite the isolation of paecilospirone more than a decade
ago, no total synthesis of this novel compound has yet been
reported.[5] Herein, we present the first enantioselective
synthesis of paecilospirone 1.
Initial synthetic studies focused on the acid-catalyzed
cyclization of ketone 2 to the spiroacetal core of paecilospir-
one (Scheme 1). However, under standard acidic conditions,
ketone 2 readily underwent elimination to afford unsaturated
spiroacetals 3 and 4. This problem was exacerbated by the
axial orientation of the hydroxy group positioned b to the
spirocentre and anti to a vicinal hydrogen atom. Based on this
observation, reaction conditions were carefully developed to
assemble the spiroacetal core using a pH-neutral double
deprotection/cyclization strategy.
Construction of aldehyde fragment 9 began with known
aldehyde 10 (Scheme 3).[6] The phenolic moiety was protected
as an allyl ether (11). Reduction of the aldehyde group and
silyl protection of the resulting alcohol furnished 12, which
was subjected to a lithium–halogen exchange/formylation
procedure to afford the requisite aldol precursor 9 in good
overall yield (72%).
It was proposed that bis(allyl) ether ketone 5 would
undergo palladium(0)-catalyzed removal of protecting groups
and in situ spiroacetalization. In turn, ketone 5 would be
constructed through addition of the aryllithium intermediate
[*] T.-Y. Yuen, S.-H. Yang, Prof. Dr. M. A. Brimble
Department of Chemistry
The University of Auckland
23 Symonds Street, Auckland (New Zealand)
E-mail: m.brimble@auckland.ac.nz
Homepage: http://web.chemistry.auckland.ac.nz/staffsites/brim-
bleM/
[**] We thank the New Zealand Foundation for Research, Science and
Technology for the award of a Top Achiever Doctoral Scholarship to
Tsz-Ying Yuen. We also thank Assoc. Prof. Peter Boyd and Tania
Groutso for X-ray crystallographic analysis of compound 16.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103117.
Scheme 2. Retrosynthetic analysis. Bn=benzyl.
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Scheme 3. Construction of aldehyde 9. Reagents and conditions:
a) K2CO3, allyl bromide, EtOH, reflux, 16 h, 93%; b) NaBH4, EtOH, RT,
15 min; c) TBSCl, imidazole, DMF, RT, 16 h, 92% over two steps;
d) tBuLi, Et2O, ꢀ788C, 1 min; then DMF, ꢀ788C!RT, 14 h, 84%.
DMF=N,N’-dimethylformamide.
Initial attempts to access aldehyde 7 using Evans’ MgCl2-
catalyzed anti-selective aldol methodology[7] only afforded
the desired anti-aldol adduct in low yield (19%), albeit with
high diastereoselectivity. Further modifications did not
improve the yield to an acceptable level. The lack of success
associated with the reaction was attributed to the highly
sterically hindered nature of aldehyde 9. Thus, an alternative
aldol protocol based on the use of a lactate-derived CH-
(OBz)Me group as the chiral auxiliary was investigated.[8]
Ketone 13 was synthesized using conditions similar to that
described by Paterson et al. (Scheme 4).[8] Pleasingly, the
Scheme 5. Absolute configuration of bis(benzoate) 16. a) Et3N·3HF,
THF, 9 h; b) p-BrC6H4COCl, pyridine, 48 h, 60% over two steps.
Known benzaldehyde 17 (Scheme 6),[12] required for the
preparation of bromide 6, was readily synthesized from
salicylaldehyde. Benzyl protection of the phenol group and
subsequent reduction with NaBH4 provided alcohol 18, which
underwent allylation to afford the required bromide coupling
partner 6 (80% over 3 steps).
Scheme 4. Synthesis of aldehyde 7. Reagents and conditions:
a) cHex2BCl, Me2NEt, Et2O, 08C, 2 h; then 9, ꢀ788C!ꢀ268C, 14 h;
b) H2O2, pH 7 buffer, MeOH, 08C, 1 h, 79% over two steps (d.r. 3:1);
c) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ508C, 3 h, 65%; d) LiBH4, THF,
ꢀ788C!RT, 24 h; e) Pb(OAc)4, Na2CO3, CH2Cl2, 08C, 1 h, 50% over
two steps. Bz=benzoyl, cHex2BCl=chlorodicyclohexylborane, TES=
triethylsilyl, THF=tetrahydrofuran.
Scheme 6. Construction of bromide 6. a) BnBr, K2CO3, TBAI, DMF, RT,
14 h, 99%; b) NaBH4, EtOH, RT, 15 min, 90%; c) NaH, THF, 08C;
then allyl bromide, TBAI, RT, 16 h, 90%. TBAI=tetrabutylammonium
iodide.
union of fragments 13 and 9 proceeded smoothly to afford an
inseparable mixture of aldol diastereoisomers 14 in good yield
(d.r. 3:1). Silyl protection of the b-hydroxy ketones 14 as TES
ethers allowed separation of the individual anti-isomers.[9]
Subsequent reductive cleavage (LiBH4) of the benzoate
ester and oxidative glycol cleavage with lead(IV) acetate[10]
successfully delivered aldehyde 7 as the single 4R,5S isomer.
To establish the absolute configuration of the newly
formed chiral centers, silyl ether 15 was treated with
Et3N·3HF and converted into bis(benzoate) derivative 16
(Scheme 5). The absolute configuration of 16 was unambig-
uously confirmed by single-crystal X-ray analysis.[11]
Scheme 7 summarizes the final elaboration to paecilospir-
one 1. Treatment of bromide 6 with nBuLi (1.3 equiv) and
subsequent addition of aldehyde 7 at ꢀ788C afforded the
corresponding alcohol as
a diastereoisomeric mixture.
Attempts to improve the yield of the addition using tBuLi
were unsuccessful, rather, partial cleavage of the phenolic
allyl ether took place.[13] Subsequent oxidation of the secon-
dary alcohol yielded ketone 5. Pleasingly, the critical double
deallylation/spirocyclization was effected using catalytic Pd0
in the presence of a PMHS–ZnCl2 complex,[14] and provided
advanced [5,6]-benzannulated spiroacetals 19 in 75% yield as
an inseparable mixture of anomers (d.r. 3.5:1).
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Communications
The major isomer 21a obtained from the spirocyclization
step was confirmed to be anomerically stabilized by nOe
experiments. Oxidation of benzyl alcohol 21a and subsequent
stepwise removal of the TES and benzyl groups furnished
paecilospirone 1. The spectroscopic data (1H NMR,
13C NMR, and HRMS analyses) for the synthetic material
were in full agreement with those reported for the natural
product and the ee value was determined to be 95% by HPLC
on a chiral stationary phase.[2,17]
In summary, the first total synthesis of paecilospirone 1
has been successfully executed in 19 steps in the longest linear
sequence. Key features include the use of an anti-selective
lactate-derived aldol reaction[8] between chiral ketone 13 and
sterically congested aldehyde 9 and the novel application of a
palladium(0)-catalyzed double deallylation/spirocyclization
for the construction of the sensitive spiroacetal core. The
overall approach is enantioselective, scalable, and highly
amenable to the production of analogues. Synthesis and
biological evaluation of such molecules may provide more
potent antimitotic agents.
Received: May 6, 2011
Revised: June 22, 2011
Published online: July 20, 2011
Keywords: aldol reactions · antitumor agents ·
.
natural products · spiroacetals · total synthesis
[1] For a recent review on the isolation, biological activity, and
synthesis of benzannulated spiroacetal natural products, see: J.
Sperry, Z. E. Wilson, D. C. K. Rathwell, M. A. Brimble, Nat.
Prod. Rep. 2010, 27, 1117 – 1137.
[2] M. Namikoshi, H. Kobayashi, T. Yoshimoto, S. Meguro, Chem.
Lett. 2000, 308 – 309.
[3] Interestingly, another structurally unrelated 2-oxaspiro[4.5]dec-
8-ene-1,7-dione derivative, also named paecilospirone, was
isolated nine years earlier from a soil sample of Paecilomyces
sp. collected in Takatsuki City, Japan, see Ref. [4].
[4] A. Hirota, M. Nakagawa, H. Hirota, Agric. Biol. Chem. 1991, 55,
1187 – 1188.
[5] For reports on the synthesis of the spiro[chroman-2,1’(3’H)-
isobenzofuran] core, see: a) J. W. Clark-Lewis, E. J. McGarry,
Aust. J. Chem. 1975, 28, 1145 – 1147; b) M. A. Marsini, Y. D.
Huang, C. C. Lindsey, K. L. Wu, T. R. R. Pettus, Org. Lett. 2008,
10, 1477 – 1480; c) M. Jay-Smith, D. P. Furkert, J. Sperry, M. A.
Brimble, Synlett 2011, 1395 – 1398.
Scheme 7. Completion of paecilospirone 1. Reagents and conditions:
a) nBuLi, THF, ꢀ788C, 1 min; then 7, ꢀ788C!RT, 14 h, 49%;
b) DMP, pyridine, CH2Cl2, RT, 90 min, 93%; c) [Pd(PPh3)4], PMHS,
ZnCl2, THF, RT, 24 h, 75% (ca. 3.5:1 mixture of anomers);
d) Et3N·3HF, THF, 08C, 9 h, 77% after two cycles; e) TPAP, NMO,
M.S. (4 ꢀ), MeCN, 10 min, f) C8H17MgBr, THF, 08C!RT, 2 h, 21a
60%, 21b 13% over two steps after two cycles; g) TPAP, NMO, M.S.
(4 ꢀ), MeCN, 30 min, 85%; h) Et3N·3HF, THF, RT, 30 min, 88%;
i) 10% Pd/C, H2, MeOH, 6 h, 73%. DMP=Dess–Martin periodinane,
M.S.=molecular sieves, NMO=4-methylmorpholine N-oxide, nOe=
nuclear Overhauser enhancement, PMHS=polymethylhydrosiloxane,
TPAP=tetrapropylammonium perruthenate.
[6] G. Stavrakov, M. Keller, B. Breit, Eur. J. Org. Chem. 2007, 5726 –
5733.
[7] D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W. Downey, J. Am.
Chem. Soc. 2002, 124, 392 – 393.
[8] I. Paterson, D. J. Wallace, C. J. Cowden, Synthesis 1998, 639 –
652.
The primary TBS group was selectively removed in the
presence of a secondary TES group using Et3N·3HF under
controlled conditions (08C, 9 h, unchanged starting material
was recovered and recycled). TPAP oxidation[15] followed by
immediate addition of octylmagnesium bromide to the crude
aldehyde afforded readily separable alcohols 21a and 21b (as
single isomers at the benzylic position) along with Grignard
reduction product 20 (30%). The latter was recycled and all
attempts to limit its formation using inorganic additives such
as LiCl or CeCl3[16] were unsuccessful.
[9] The relative configuration at C4 and C5 was deduced to be anti
1
based on the coupling constants in the H NMR spectrum (JH4–
H5 = 10.1 Hz (major), JH4–H5 = 9.0 Hz (minor)).
[10] R. Criegee, L. Kraft, B. Bank, Justus Liebigs Ann. Chem. 1933,
507, 159.
[11] CCDC 823856 (16) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
[12] A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau, J. Org.
Chem. 1998, 63, 3128 – 3132.
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[13] W. F. Bailey, M. D. England, M. J. Mealy, C. Thongsornkleeb, L.
Teng, Org. Lett. 2000, 2, 489 – 491.
[14] S. Chandrasekhar, C. R. Reddy, R. J. Rao, Tetrahedron 2001, 57,
3435 – 3438.
[15] W. P. Griffith, S. V. Ley, Aldrichimica Acta 1990, 23, 13 – 19.
[16] a) T. Imamoto, Y. Sugiura, N. Takiyama, Tetrahedron Lett. 1984,
25, 4233 – 4236; b) T. Imamoto, N. Takiyama, K. Nakamura,
Tetrahedron Lett. 1985, 26, 4763 – 4766.
[17] Although the structure of synthetic 1 is not in doubt, we note
there is a significant tenfold difference observed for the aD value
of
the
synthetic
material
(½aꢁ2D0 = +
26.9 deg cm3 gꢀ1 dmꢀ1(c=0.39 gcmꢀ3 in MeOH)) and that
reported
for
the
natural
product
(½aꢁ2D0 = +
202.5 degcm3 gꢀ1 dmꢀ1 (c = 0.37 gcmꢀ3 in MeOH)). Unfortu-
nately, an authentic sample of paecilospirone 1 could not be
obtained for direct comparison.
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