Synthetic studies towards iriomoteolide 1a: Stereocontrolled construction of C1-C9 and C11-C23 segments using lactate aldol chemistry

Article abstract of DOI:10.1055/s-0029-1219347

The stereocontrolled construction of C1-C9 and C13-C23 segments of the cytotoxic macrolide iriomoteolide 1a is reported, exploiting boron aldol additions of enantiomeric lactate-derived ketones and a Suzuki-Miyaura cross-coupling reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219347

LETTER
571
Synthetic Studies towards Iriomoteolide 1a: Stereocontrolled Construction of
C1–C9 and C11–C23 Segments Using Lactate Aldol Chemistry
S
ynthetic
a
Studies To
n
w
ardsIriomoteoli
P
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336362; E-mail: ip100@cam.ac.uk
Received 1 December 2009
Dedicated to Professor Gerry Pattenden on the occasion of his 70th birthday
lines, has led to it becoming an attractive target for syn-
Abstract: The stereocontrolled construction of C1–C9 and C13–
C23 segments of the cytotoxic macrolide iriomoteolide 1a is report-
ed, exploiting boron aldol additions of enantiomeric lactate-derived
ketones and a Suzuki–Miyaura cross-coupling reaction.
thetic efforts and SAR studies to probe the pharmaco-
phore and mechanism of action. To date, several groups
have reported fragment syntheses and proposed coupling
strategies towards iriomoteolide 1a.5 As part of our inter-
est in bioactive marine macrolides,6 we initiated a pro-
gramme towards developing a flexible and convergent
total synthesis of iriomoteolide 1a (1). By exploiting our
versatile lactate aldol methodology for stereocontrolled
polyketide synthesis, we now report the construction of 2
and 3 as protected C13–C23 and C1–C9 segments of this
important marine macrolide.
Key words: macrolide, anticancer, aldol reactions, cross-coupling,
asymmetric synthesis
Marine macrolides with potent antimitotic properties rep-
resent promising lead structures for the development of
new anticancer agents, provided a sustainable supply can
be realised.1 Dinoflagellates of the genus Amphidinium
have proven to be a prolific source of novel polyketide
metabolites with pronounced biological activities.2 Iriomo-
teolide 1a, a cytotoxic macrolide isolated from a marine
dinoflagellate Amphidinium species (strain HYA024) col-
lected off Iriomote Island, Japan, was first reported in
2007 by Tsuda et al.3 The unique structure of iriomo-
teolide 1a (1, Scheme 1),4 as determined by extensive
NMR analysis, combined with its remarkably potent anti-
proliferative activity against various human cancer cell
Iriomoteolide 1a (1) has a 23-carbon backbone and fea-
tures a 20-membered macrolide, with an embedded six-
membered hemiacetal ring, and has nine stereocentres and
four isolated alkenes. As outlined in the retrosynthesis in
Scheme 1, we envisaged the late-stage introduction of the
labile hemiacetal ring by a suitable allylation to form the
C12–C13 bond and a macrolactonisation engaging the
C19 hydroxy, leading back to the C13–C23 aldehyde 2
and C1–C12 bromide 4. The allylic bromide 4 should be
lactate aldol #1
OTBS
23
OTES
OTBS
OTES
PMBO
13
PMBO
OH
O
I
H
21
19
I
18
22
H
TESO
O
Takai olefination
6
8
7
9
crotylation
allylation
12
OH
19
O
OP
9
TBSO
OTBS
23
OTES
OH
12
19
O
O
Br
H
13
1
9
macro-
lactonisation
H
1
5
O
TESO
O
OMe
HWE
allylation
4
Suzuki coupling
2
OH
O
1
iriomoteolide 1a (1)
OH
5
O
O
4
9
PMBO
PMBO
lactate aldol #2
3
5
Scheme 1 Retrosynthetic analysis of iriomoteolide 1a (1) and key C13–C23 and C1–C9 segments 2 and 3
SYNLETT 2010, No. 4, pp 0571–0574
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Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219347; Art ID: D34609ST
© Georg Thieme Verlag Stuttgart · New York

572
I. Paterson, P. Rubenbauer
LETTER
accessible in turn from elaboration of d-lactone 3, whose dinane afforded the aldehyde 9, which was used crude for
Z-configured trisubstituted olefin would be accessed the subsequent boron aldol reaction. Based on our stan-
through an intramolecular HWE reaction. The requisite dard protocol,7 enolisation of the ethyl ketone (S)-14 [de-
C4–C5 anti relationship in its precursor 5 would then be rived from ethyl (S)-lactate] with c-Hex2BCl and Et3N at
installed by employing our boron-mediated lactate aldol 0 °C provided the corresponding E-enolate, which was
reaction.7 As the projected coupling partner for bromide 4, treated with aldehyde 9 at –78 °C to afford the desired
aldehyde 2 would be formed through a Suzuki–Miyaura anti-configured aldol adduct 15 in 85% yield over two
cross-coupling8 of a borane derived from iodide 6 with steps and with excellent stereocontrol (>97:3 dr). The
vinyl iodide 7, itself available from aldehyde 8.9 For the newly formed alcohol was silylated (TESOTf) to provide
preparation of iodide 6, a second lactate aldol reaction 16 and the auxiliary cleaved using a three-step procedure
used in combination with Brown crotylation methodology involving LiBH4 reduction of the ketone and the benzoate,
was planned to configure the required C18–C19 anti and oxidative cleavage of the ensuing diol with Pb(OAc)4, fol-
C21–C22 syn relationships, respectively.
lowed by reduction with NaBH4.12 This provided the alco-
hol 17 in 87% yield. Finally, the targeted iodide 6 was
accessed through treatment of 17 with I2, PPh3, and imida-
zole in THF (98%).
Synthesis of the C13–C16 vinyl iodide 7 (Scheme 2) com-
menced with the enantioselective preparation of diol 10
from methallyl alcohol following the Sharpless dihydrox-
ylation procedure reported by Corey.9 Selective PMB
ether formation on the primary alcohol in 10 (PMBTCA,
CSA), followed by silylation of the tertiary alcohol
(TESOTf), then provided the orthogonally protected triol
11 in 72% yield. Cleavage of the para-methoxybenzoyl
(PMBz) ester with DIBAL-H and oxidation of the result-
ing primary alcohol 12 under Swern conditions cleanly af-
forded aldehyde 8 (90%). Finally, Takai olefination10 with
CrCl2 and CHI3 provided the targeted vinyl iodide 7
(82%) as a single geometric isomer.
O
OTBS
OTBS
a–c
HO
H
13
d
H
BzO
O
O
e
(S)-14
9
OH
OTBS
ref. 9
OH
HO
OPMBz
BzO
10
O
OR
15: R = H
a, b
f
16: R = TES
g–i
OTES
OPMBz
OTES
OH
c
PMBO
PMBO
PMBO
OTBS
j
X
12
11
17: X = OH
6: X = I
TESO
d
Scheme 3 Preparation of iodide 6. Reagents and conditions: (a)
KOt-Bu, n-BuLi, (+)-Ipc2BOMe, cis-butene, THF, –78 °C; NaOH,
H2O2; (b) TBSCl, imidazole, CH2Cl2; (c) BH3·SMe2, THF, 0 °C; pH
7 buffer, H2O2, 40% over three steps; (d) DMP, NaHCO3, CH2Cl2; (e)
c-Hex2BCl, Et3N, Et2O, 0 °C; 13, –78 °C to –20 °C, Et2O, 85% over
two steps; (f) TESOTf, 2,6-lutidine, CH2Cl2, –78 °C, 99%; (g) LiBH4,
THF, 0 °C to r.t.; (h) Pb(OAc)4, Na2CO3, CH2Cl2, 0 °C; (i) NaBH4,
EtOH, 0 °C, 87% over three steps; (j) I2, Ph3P, imidazole, 0 °C, THF,
98%.
OTES
OTES
O
e
PMBO
I
H
8
7
Scheme 2 Preparation of vinyl iodide 7. Reagents and conditions:
(a) PMBTCA, CSA, CH2Cl2, 73%; (b) TESOTf, 2,6-lutidine, CH2Cl2,
–78 °C, 99%; (c) DIBAL-H, CH2Cl2, –78 °C, 93%; (d) oxalyl chlo-
ride, DMSO; Et3N, CH2Cl2, –78 °C to 0 °C, 97%; (e) CrCl2, CHI3,
THF, 82%.
With the two building blocks 6 and 7 now in hand, their
cross-coupling was explored (Scheme 4). First, iodide 6
was converted into the boronate 18 through halogen–lith-
ium exchange with t-BuLi and subsequent trapping with
9-BBNOMe. This intermediate boronate was then treated
with vinyl iodide 7, AsPh3, Cs2CO3, and Pd(dppf)Cl2 (7
mol%) in DMF–H2O, which effected a smooth sp2–sp3
Suzuki–Miyaura coupling.13 Following cleavage of the
PMB ether with DDQ, the alcohol 19 was obtained in a
pleasing 70% yield over the two steps. Finally, oxidation
under Swern conditions gave the fully elaborated C13–
The synthesis of the C17–C23 iodide partner 6 is shown
in Scheme 3. Crotylation of acetaldehyde, performed un-
der Brown’s conditions using in situ generated (Z)-crotyl-
diisopinocampheylborane, followed by TBS protection of
the resulting adduct, provided the corresponding syn ho-
moallylic ether, with excellent stereocontrol (95% ee,
95:5 dr).11 After hydroboration–oxidation of the olefin, al-
cohol 13 was isolated in 40% yield over the three steps
from acetaldehyde. Oxidation with Dess–Martin perio-
Synlett 2010, No. 4, 571–574 © Thieme Stuttgart · New York

LETTER
Synthetic Studies Towards Iriomoteolide 1a
573
6
O
O
a
a
PMBO
H
PMBO
H
20
21
OMe
B
OTBS
b
BzO
(R)-14
O
TESO
18
OR
O
7
b
OBz
PMBO
OTBS
OTES
OTES
HO
22: R = H
c
d–f
O
23: R = TBS
TESO
19
c
OR
OTBS
PMBO
13
H
24: R = TBS
5: R = H
23
g
O
TESO
h, i
2
O
Scheme 4 Suzuki–Miyaura coupling of 6 and 7. Reagents and con-
ditions: (a) t-BuLi, 9-BBNOMe, Et2O–THF, –78 °C to r.t.; 7, AsPh3,
Cs2CO3, cat. Pd(dppf)Cl2, DMF–H2O; (b) DDQ, CH2Cl2–pH 7 buf-
fer, 70% over two steps; (c) oxalyl chloride, DMSO, CH2Cl2, Et3N,
–78 °C to 0 °C, 95%.
1
O
9
PMBO
3
Scheme 5 Completion of dihydropyrone 3. Reagents and conditi-
ons: (a) Ph3P=CHCHO, MeCN, 80 °C, 58%; (b) c-Hex2BCl, Et3N,
Et2O, 0 °C; 21, –78 °C to –20 °C, Et2O, 95%; (c) TBSOTf, 2,6-luti-
dine, CH2Cl2, –78 °C, 99%; (d) MeMgI, Et2O, –78 °C to –10 °C; (e)
DIBAL-H, CH2Cl2, –78 °C; (f) NaIO4, MeOH–pH 7 buffer, 86% over
three steps; (g) HF·pyridine, pyridine, THF, 92%; (h)
HO2CCH2PO(OEt)2, 2,4,6-trichlorobenzoyl chloride, Et3N, 0 °C,
PhMe; (i) Ba(OH)2, THF–H2O, 60%.
C23 segment 2 in 95% yield, corresponding to the north-
ern hemisphere of iriomoteolide 1a.14
The synthesis of the C1–C9 segment 3 required for the
southern hemisphere started with the aldehyde 20
(Scheme 5), which was submitted to a Wittig reaction
with Ph3P=CHCHO to afford the E-enal 21. A second lac-
tate aldol reaction, in this case using the enantiomeric eth-
yl ketone (R)-14, was now required to configure the C4
and C5 stereocentres of iriomoteolide. Under standard
conditions,7 this provided the desired anti-adduct 22 in
95% yield and with >97:3 dr.
these intermediates to achieve the total synthesis of
iriomoteolide A.
The b-hydroxy ketone 22 was converted into the corre- Acknowledgment
sponding TBS ether 23, then advanced to 24 via a three-
We thank the EPSRC (EP/F025734/1) and the DAAD (Postdoctoral
Fellowship to P.R.) for support.
step protocol. Initial MeMgI addition to the ketone was
followed by scission of the benzoate with DIBAL-H and
oxidative cleavage of the ensuing 1,2-diol using NaIO4,
which proceeded in 86% overall yield. This procedure
proved higher yielding than attempted cleavage of the
benzoate concomitant with ketone addition.12 Removal of
the TBS group (HF·pyridine, pyridine) then delivered the
alcohol 5. Finally, treatment of 5 with diethylphospho-
noacetic acid generated the corresponding ester that un-
derwent Ba(OH)2-promoted HWE cyclisation15 to give
the dihydropyrone 3,16 incorporating the D2,3-alkene of
iriomoteolide.
References and Notes
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In summary, the stereocontrolled synthesis of the C13–
C23 and C1–C9 segments 2 and 3 of the potent cytotoxic
macrolide, iriomoteolide 1a, has been accomplished, fea-
turing a combination of boron-mediated aldol reactions
and a Suzuki–Miyaura cross-coupling to unite two frag-
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Synlett 2010, No. 4, 571–574 © Thieme Stuttgart · New York

574
I. Paterson, P. Rubenbauer
LETTER
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5.32 (1 H, d, J = 15.4 Hz), 3.65–3.70 (2 H, m), 2.13–2.18 (1
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(500 MHz, CDCl3): d = 7.24 (2 H, d, J = 8.6 Hz), 6.87 (2 H,
d, J = 8.6 Hz), 5.79 (1 H, dt, J = 15.5, 6.8 Hz), 5.77 (1 H, s),
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Synlett 2010, No. 4, 571–574 © Thieme Stuttgart · New York