Efficient synthesis of the spiroacetal core of paecilospirone via oxidative radical cyclisation

Article abstract of DOI:10.1055/s-0030-1260564

The spiroacetal core of the microtubule assembly inhibitor paecilospirone has been prepared using two separate oxidative cyclisation methods. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260564

LETTER
1395
Efficient Synthesis of the Spiroacetal Core of Paecilospirone via Oxidative
Radical Cyclisation
Synthesis of the
S
piroa
o
cetal
C
ore
o
r
f
Paecilo
g
spirone an Jay-Smith, Daniel P. Furkert, Jonathan Sperry, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 25 February 2011
ic stabilisation and minimum steric interactions.4 Despite
the prevalence of this method, it is not always practical for
the synthesis of acid-sensitive substrates and some
spiroacetals exist in the nonanomeric form.5 This research
group has focused on the total synthesis of paecilospirone
via acid-induced deprotection–cyclisation of a diprotected
dihydroxyketone of type 3; however, undesired elimina-
tion of the sensitive b-hydroxy group (protected or unpro-
tected) during the spirocyclisation event has significantly
hampered this route to date. Indeed, no advanced spiro-
acetal intermediates (e.g., 4) have been successfully pre-
pared using this classical approach (Scheme 1).6
Abstract: The spiroacetal core of the microtubule assembly inhibi-
tor paecilospirone has been prepared using two separate oxidative
cyclisation methods.
Key words: paecilospirone, microtubule, spiroacetal, oxidative
radical cyclisation, DDQ
Paecilospirone (1) is a novel bisbenzannulated spiroacetal
isolated from Paecilomyces sp. collected at Yap island,
Micronesia that has been shown to inhibit microtubule as-
sembly (Figure 1).1,2 To date, no other natural products
have been described that contain the spiro[chroman-
2,1¢(3¢H)-isobenzofuran] core and no total syntheses of 1
have been reported. The novel chemical scaffold embed-
ded in 1 provides the opportunity for development of a
flexible synthetic route to the natural product and ana-
logues thereof in order to probe their promising biological
activity. Paecilospirone is structurally related to the rubro-
mycin family of natural products that exhibit antimicrobi-
al and anticancer properties.3
RO
PO
RO
H+
OR
O
PO
OR
OR
O
O
OR
3
4
Scheme 1 Problematic acid-catalysed formation of the spiroacetal
HO
core of paecilospirone6
OH
O
O
Synthetic studies towards the paecilospirone spiroacetal
ring system are scarce and the only report to date by Pettus
and co-workers involves an elegant inverse electron-
demand [4+2] cycloaddition of a 1,3-dihydroisobenzofu-
ran enol ether with an ortho-quinone methide.7 Herein we
report our own efforts towards the synthesis of the bis-
benzannulated spiroacetal core of 1 that provides a viable
alternative to the troublesome acid-catalysed cyclisation
encountered in our laboratory.
O
1
O
HO
O
O
O
OH
OH
CO2Me
MeO
O
O
Our research group has a long-standing interest in the syn-
thesis of spiroacetals using the oxidative radical cyclisa-
tion of cyclic ethers containing a hydroxyalkyl side
chain.8 Thus, we were interested in extending this meth-
odology toward the synthesis of the spiroacetal frame-
work of 1, mindful of the fact that participation of
benzylic alcohols in this type of reaction had not been ex-
plored previously.
2
Figure 1 Paecilospirone (1) and g-rubromycin (2)
Spiroacetals are commonly synthesised by acid-catalysed
cyclisation of a dihydroxyketone precursor, forming the
thermodynamic products favoured by maximum anomer-
Our key retrosynthetic disconnection of the paecilo-
spirone core 5 makes use of an oxidative radical cyclisa-
tion of benzylic alcohol 6 to form the C8–O bond of the
isobenzofuran moiety. Benzylic alcohol 6 should be ac-
SYNLETT 2011, No. 10, pp 1395–1398
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260564; Art ID: D06611ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

1396
M. Jay-Smith et al.
LETTER
Table 1 Claisen–Schmidt Condensation
cessible from the corresponding chalcone 7a or 7b, pre-
pared by Claisen–Schmidt condensation of an
appropriately protected aldehyde 8a or 8b with commer-
cially available 2¢-hydroxyacetophenone 9, respectively
(Scheme 2).
O
O
O
HO
+
OR
OR
HO
oxidative
8a R = TBS
8b R = PMB
9
7a R = TBS
7b R = PMB
radical
cyclisation
8
O
Entry Substrate Solvent Base
(equiv)
Conditions
Yield
(%)
8
OH
O
O
6
a
5
1
2
3
4
5
6
7
8
9
8a
8a
8a
8a
8a
8b
8b
8b
8b
PhMe
PhMe
EtOH
EtOH
EtOH
PhMe
EtOH
THF
piperidine (0.2) 110 °C, 24 h
–
oxa-
Michael
addition
a
piperidine (2)
piperidine (2)
KOH (5)
110 °C, 40 h
80 °C, 40 h
r.t., 5 h
–
a
–
O
a
–
O
O
Claisen–
Schmidt
a
KOH (5)
80 °C, 40 h
110 °C, 40 h
80 °C, 30 h
r.t. to 50 °C, 2 h
r.t., 2 h
–
HO
+
OR
a
piperidine (2)
piperidine (2)
NaH (3)
–
HO
9
7a R = TBS
7b R = PMB
OR
8a R = TBS
8b R = PMB
a
–
a
–
Scheme 2 Retrosynthetic analysis of paecilospirone spiroacetal
core 5
THF
NaH (3)
69
80
10 8b
THF
NaH (3)
r.t., 16 h
Thus, the synthesis of the benzaldehyde coupling partners
8a and 8b was initiated. Simple reduction of phthalide 10
with lithium aluminium hydride gave diol 11 which un-
derwent smooth monoprotection with TBSCl or PMBCl,
affording the desired alcohols 12a and 12b, respectively.
PCC oxidation of 12a and 12b gave 8a and 8b, respective-
ly, with Swern oxidation of 12b affording aldehyde 8b in
higher yield than the PCC protocol (Scheme 3).
a Inseparable complex mixture containing 3–10% 7a or 7b.
These initial results suggested that the desired chalcones
7a,b decomposed at elevated temperatures and conduct-
ing the condensation under ambient conditions would pro-
vide more positive results. Thus, exposure of 2¢-
hydroxyacetophenone 9 and aldehyde 8b to sodium hy-
dride in THF at room temperature for two hours afforded
7b in good yield (entry 9). The yield of 7b was increased
to a pleasing 80% by employing an extended reaction time
(entry 10).
O
a
OH
O
OH
Next, the intramolecular conjugate addition of chalcone
7b was investigated (Scheme 4). Somewhat disappoint-
ingly, the cyclisation of chalcone 7b to the desired
chromene 14 via ketone reduction and intramolecular
oxa-Michael addition using sodium borohydride initially
halted at the intermediate allylic alcohol. Thus, the cycli-
sation was driven to completion by adjustment of the re-
action mixture pH by addition of dilute acetic acid at this
intermediate stage, gratifyingly affording chromene 14 in
excellent yield.
11
b or c
10
O
d or e
OH
OR
OR
8a R = TBS
8b R = PMB
12a R = TBS
12b R = PMB
Scheme 3 Preparation of aldehydes 8a and 8b. Reagents and condi-
tions: (a) LiAlH4, Et2O–THF, r.t., 97%; (b) NaH, TBSCl, THF, 84%
(12a); (c) NaH, PMBCl, DMF, cat. NaI, 80% (12b); (d) PCC, CH2Cl2,
70% (8a) or 70% (8b); (e) (COCl)2, DMSO, CH2Cl2, –78 °C, then
Et3N, 97% (8b).
Initial attempts to reduce the double bond in 14 by hydro-
genation over 10% palladium on carbon in ethyl acetate
somewhat surprisingly afforded o-tolylchroman 15 as the
sole product, presumably via reductive cleavage of the
PMB group at the proximal benzylic methylene. In con-
trast, palladium on carbon deactivated with ethylenedi-
amine, Pd/C(en),14 cleanly effected the desired reduction
to chroman 16, that then underwent uneventful deprotec-
tion with DDQ to give the key oxidative radical cyclisa-
tion substrate 6. Gratifyingly, irradiating a cyclohexane
With aldehydes 8a and 8b in hand, the Claisen–Schmidt
condensation9,10 to form chalcone 7a or 7b was investigat-
ed. Although numerous examples detailing the condensa-
tion between benzaldehydes and acetophenones exist in
the literature,11–13 this transformation proved troublesome
to achieve in practice. Initial attempts resulted in complex
product mixtures only containing approximately 3–10%
of the desired chalcone 7a or 7b (Table 1, entries 1–8).
Synlett 2011, No. 10, 1395–1398 © Thieme Stuttgart · New York

LETTER
Synthesis of the Spiroacetal Core of Paecilospirone
1397
solution of 6 with iodobenzene diacetate and iodine at
room temperature furnished spiroacetal 5 in 61% yield
(Scheme 4).15 To the best of our knowledge, this is the
first reported example of spiroacetal ring-system forma-
tion achieved by the oxidative radical cyclisation of a ben-
zylic alcohol.
b
a
5
O
O
O
17
OPMB
14
a
b
O
7b
O
O
OPMB
14
15
OH
18
c
Scheme 5 Concomitant PMB deprotection–spiroacetal formation
using DDQ. Reagents and conditions: (a) DDQ, CH2Cl2–H2O, 1.5 h,
95%; (b) 10% Pd/C(en), H2, EtOAc, 88%.
d
O
O
OPMB
16
OH
methods for spiroacetal formation. As the reaction condi-
tions for DDQ deprotection are suitably mild for late-
stage transformations, this method has potential to be ap-
plied to late-stage spiroacetal formation in complex syn-
thetic targets. The application of this new
spiroacetalisation methodology toward the total synthesis
of 1 is ongoing and will be reported in due course.
6
e
O
O
5
Acknowledgment
Scheme 4 Synthesis of spiroacetal 5 via oxidative radical cyclisati-
on. Reagents and conditions: (a) NaBH4, THF–EtOH, 60 °C, 10 min,
then 50% AcOH, 16 h, 88%; (b) 10% Pd/C, H2, EtOAc, 22%; (c) 10%
Pd/C(en), H2, EtOAc, 78%; (d) DDQ, CH2Cl2–H2O, 95%; (e) hn,
PhI(OAc)2, I2, cyclohexane, r.t., 2 h, 61%.
We thank the Maurice Wilkins Centre for Molecular Biodiscovery
for financial support. We are grateful to Dr. Daniel Heinrich for
conducting preliminary experiments.
References and Notes
A complementary route to spiroacetal 5 from chromene
14 was also investigated (Scheme 5). Interestingly, in the
presence of an excess of DDQ (3 equiv) the expected al-
cohol 18 was not observed. Instead, spiroacetal 17 was di-
rectly formed as the only product.16 It appears that
additional resonance stabilisation of the benzylic position
due to the double bond is sufficient to favour further oxi-
dation and spiroacetal formation, possibly through the in-
termediacy of alcohol 18. This appears to be the first
incidence of oxidative cyclisation to form a spiroacetal
ring system mediated by DDQ and is a useful addition to
existing methods for spiroacetal synthesis. Furthermore,
the double bond in 17 serves as a useful synthetic handle
when considering a total synthesis of 1. Finally, spiroace-
tal 17 was smoothly hydrogenated over the deactivated
catalyst Pd/C(en) in two hours at room temperature, af-
fording spiroacetal 5 in 88% yield.
(1) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S.
Chem. Lett. 2000, 29, 308.
(2) Kobayashi, H.; Sunaga, R.; Furihata, K.; Morisaki, N.;
Iwasaki, S. J. Antibiot. 1995, 48, 42.
(3) (a) Brasholz, M.; Sorgel, S.; Azap, C.; Reißig, H. U. Eur. J.
Org. Chem. 2007, 3801. (b) Sperry, J.; Wilson, Z. E.;
Rathwell, D. C. K.; Brimble, M. A. Nat. Prod. Rep. 2010, 27,
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(4) Raju, B. R.; Saikia, A. K. Molecules 2008, 13, 1942.
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(6) Yuen, T. Y. PhD Thesis; University of Auckland: New
Zealand, unpublished work.
(7) Marsini, M.; Huang, Y.; Lindsey, C.; Wu, K.-L.; Pettus,
T. R. R. Org. Lett. 2008, 10, 1477.
(8) (a) Brimble, M. A.; Williams, G. M. J. Org. Chem. 1992, 57,
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Synlett 1999, 295. (c) Allen, P. A.; Brimble, M. A.; Fares, F.
A. J. Chem. Soc., Perkin Trans. 1 2001, 379. (d) Brimble,
M. A.; Horner, G. M.; Stevenson, R. J. Aust. J. Chem. 1996,
49, 189. (e) Brimble, M. A. Molecules 2004, 9, 394.
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(g) Furkert, D. P.; Brimble, M. A. Org. Biomol. Chem. 2004,
2, 3573. (h) Meilert, K.; Brimble, M. A. Org. Lett. 2005, 7,
3497. (i) Meilert, K.; Brimble, M. A. Org. Biomol. Chem.
2006, 4, 2184. (j) Liu, Y.-C.; Sperry, J.; Rathwell, D. C. K.;
Brimble, M. A. Synlett 2009, 793. (k) Sperry, J.; Liu, Y. C.;
Brimble, M. Org. Biomol. Chem. 2010, 8, 29.
In summary, the oxidative radical cyclisation approach to
spiroacetal synthesis has been extended to the use of ben-
zylic alcohol substrates, further increasing the scope of
this methodology. It is therefore envisaged that oxidative
radical cyclisation will be applicable to future synthetic
studies towards the total synthesis of paecilospirone and
analogues thereof. The concomitant DDQ-mediated PMB
deprotection and cyclisation of 14 to spiroacetal 17 is also
notable, presenting an interesting alternative to existing
(9) Schmidt, J. Ber. Dtsch. Chem. Ges. 1881, 14, 1459.
Synlett 2011, No. 10, 1395–1398 © Thieme Stuttgart · New York

1398
M. Jay-Smith et al.
LETTER
H, m, Ar, PhH). 13C NMR (100 MHz, CDCl3): d = 21.8
(CH2, PhCH2CH2), 30.2 (CH2, PhCH2CH2), 71.7 (CH2,
PhCH2O), 108.2 (q, spiroacetal), 117.1 (CH, Ar), 120.8 (CH,
Ar), 121.3 (CH, Ar), 121.7 (q, Ar), 122.0 (CH, Ar), 127.4
(CH, Ar), 127.9 (CH, Ar), 129.1 (CH, Ar), 129.4 (CH, Ar),
140.0 (2 × q, 2 × Ar), 153.2 (q, Ar). MS (ESI+): m/z (%) =
239(100) [MH+]. HRMS: m/z calcd for C16H15O2 [M + H]+:
239.1072; found: 239.1075.
(10) Claisen, A.; Claparede, A. Ber. Dtsch. Chem. Ges. 1881, 14,
2460.
(11) Deffieux, D.; Gaudrel-Grosay, S.; Grelard, A.; Chalumeau,
C.; Quideau, S. Tetrahedron Lett. 2009, 50, 6567.
(12) Jung, S.; Park, S.; Kim-Pak, Y.; Lee, H.; Park, K.; Shin, K.;
Ohuchi, K.; Shin, H.; Keum, S.; Lim, S. Chem. Pharm. Bull.
2006, 3, 368.
(13) Won, S.-J.; Liu, C.-T.; Tsao, L.-T.; Weng, J.-R.; Ko, H.-H.;
Wang, J.-P.; Lin, C.-N. Eur. J. Med. Chem. 2005, 103.
(14) Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63,
7990.
(16) Spiroacetal 17
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (67 mg, 0.30
mmol) was added to a solution of compound 14 (70 mg, 0.20
mmol) in CH2Cl2–H2O (9:1, 3.3 mL total). The dark green
reaction was stirred for 90 min at r.t. and then filtered
through cotton wool. The reaction mixture was washed with
brine, extracted with EtOAc, and the aqueous layer was
further extracted with EtOAc. The combined organic phases
were then dried over anhyd MgSO4 and the solvent removed
in vacuo. Purification by flash column chromatography
using hexane–EtOAc (9:1) afforded the title compound 17
(45 mg, 0.19 mmol, 95%) as a yellow oil. Rf = 0.59 (2:1,
hexane–EtOAc). IR: 2854, 1611, 1512, 1486, 1456, 1246,
1033, 820, 757 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.05
(1 H, d, J = 12.4 Hz, CH2, PhCH2O), 5.33 (1 H, d, J = 12.4
Hz, CH2, PhCH2O), 5.87 (1 H, d, J = 9.6 Hz, PhCH=CH),
6.90 (2 H, t, J = 10.0 Hz, PhCH=CH, PhH), 6.98 (1 H, t,
J = 7.6 Hz, Ar, PhH), 7.20–7.22 (2 H, m, Ar, PhH), 7.34 (1
H, dt, J = 7.6, 0.8 Hz, Ar, PhH), 7.39–7.40 (2 H, m, Ar,
PhH), 7.42–7.46 (1 H, m, Ar, PhH). 13C NMR (100 MHz,
CDCl3): d = 71.8 (CH2, PhCH2O), 107.7 (q, spiroacetal),
116.6 (CH, PhCH=CH), 119.7 (q, Ar), 121.1 (CH,
(15) Spiroacetal 5
Iodine (67 mg, 0.26 mmol) and iodobenzene diacetate (84
mg, 0.26 mmol) were added to a solution of benzyl alcohol
6 (30 mg, 0.13 mmol) in cyclohexane (5 mL), and the
reaction mixture was irradiated with a 60 W desk lamp. After
stirring for 1 h at r.t., the reaction mixture was diluted with
hexane–EtOAc (1:1, 20 mL total) and shaken with sat. aq
Na2S2O3 (4 mL) until colourless. The mixture was washed
with brine, extracted with EtOAc, and the aqueous layer was
further extracted with EtOAc. The combined organic phases
were then dried over anhyd MgSO4 and the solvent removed
in vacuo. Purification via flash column chromatography
using hexane–EtOAc (9:1) as eluent afforded the title
compound 5 (18 mg, 0.076 mmol, 61%) as a pale yellow oil.
Rf = 0.40 (2:1, hexane–EtOAc). IR: 2923, 2868, 1656, 1582,
1487, 1456, 1373, 1232, 1110, 1004, 904, 746 cm–1. 1H
NMR (400 MHz, CDCl3): d = 2.21 (1 H, ddd, J = 13.2, 5.6,
2.0 Hz, CH2, PhCH2CH2), 2.45 (1 H, td, J = 13.2, 5.6 Hz,
CH2, PhCH2CH2), 2.88 (1 H, ddd, J = 16.0, 5.6, 2.0 Hz, CH2,
PhCH2CH2), 3.29 (1 H, ddd, J = 16.0, 13.6, 6.0 Hz, CH2,
PhCH2CH2), 5.05 (1 H, d, J = 12.4 Hz, CH2, PhCH2O), 5.30
(1 H, d, J = 12.4, CH2, PhCH2O), 6.79 (1 H, dd, J = 8.0, 1.2
Hz, Ar, PhH), 6.90 (1 H, td, J = 3.6, 0.8 Hz, Ar, PhH), 7.10
(1 H, t, J = 7.6 Hz, Ar, PhH), 7.15 (1 H, d, J = 7.6 Hz, Ar,
PhH), 7.33 (1 H, dt, J = 7.2, 0.8 Hz, Ar, PhH), 7.38–7.44 (3
PhCH=CH), 121.2 (CH, Ar), 121.5 (CH, Ar), 123.2 (CH,
Ar), 126.9 (CH, Ar), 127.0 (CH, Ar), 128.1 (CH, Ar), 129.6
(CH, Ar), 129.6 (CH, Ar), 139.7 (q, Ar), 140.2 (q, Ar), 151.5
(q, Ar). MS (ESI+): m/z (%) = 237(100) [MH+]. HRMS: m/z
calcd for C16H13O2 [M + H]+: 237.0910; found: 237.0915.
Synlett 2011, No. 10, 1395–1398 © Thieme Stuttgart · New York