Total syntheses of amphidinolides T1, T3, and T4

Article abstract of DOI:10.1002/anie.201305467

Concise and high-yielding total syntheses of amphidinolides T1, T3, and T4 have been completed using an alkynyl macrolactone as a common late-stage intermediate. The required α-hydroxy ketone motif was installed by sequential alkyne hydrosilylation, epoxidation, and Fleming-Tamao oxidation. An oxonium ylide rearrangement formed the trisubstituted tetrahydrofuran core found in the natural products.

Full text of DOI:10.1002/anie.201305467

Angewandte
Chemie
DOI: 10.1002/anie.201305467
Natural Products
Total Syntheses of Amphidinolides T1, T3, and T4**
J. Stephen Clark* and Filippo Romiti
The amphidinolides are macrolides isolated from marine
dinoflagellates of the genus Amphidinium sp., which are
symbionts found on acoel flatworms of the Amphiscolops
species.[1] More than 30 amphidinolides have been isolated
and most of them display cytotoxic activities.[1,2] Some of the
amphidinolides possess other biological activities, but insuffi-
cient quantities of material are available to fully establish
their therapeutic potential in most cases.
The amphidinolide T subgroup comprises five compounds
(T1–T5), which exhibit cytotoxic activities against L1210
murine lymphoma cells and KB human epidermoid carci-
noma cells.[1c] These compounds, first isolated and character-
ized by the Kobayashi group,[3] are 19-membered lactones
possessing seven or eight stereogenic centers, an exocyclic
alkene, an a-hydroxy ketone motif, and a trisubstituted
tetrahydrofuran (Figure 1). Amphidinolides of the T series
by a hydroxy group at C13. Amphidinolides T3–T5 are
isomers of T1, displaying a reversal of the hydroxy ketone
pattern and have diastereomeric relationships at C12 and
C14.
The challenging structures and bioactivities of amphidi-
nolides T1–T5 make them attractive synthetic targets.[2,4]
Fꢀrstner and co-workers completed the synthesis of amphi-
dinolide T4 in 2002 and then used their elegant strategy to
synthesize amphidinolides T1, T3, and T5.[5] The groups of
Ghosh (T1),[6] Jamison (T1, T4),[7] Zhao (T3),[8] Yadav (T1),[9]
and Dai (T1–T4)[10] have also completed syntheses of
members of the family. In many of these syntheses, substitu-
ents and stereocenters in the C12–C14 region have been
introduced before or during formation of the macrocycle,
which has meant that the route to each member is differ-
entiated at an early stage or that several steps are required to
change oxidation states or invert stereocenters in order to
access more than one natural product. The exception is the
route of Dai and co-workers in which ring-closing metathesis
ꢀ
(RCM) was used to close the macrocycle with C12 C13 bond
formation and the resulting alkene was dihydroxylated.[10] In
this case, however, the RCM and dihydroxylation reactions
were not stereoselective and several steps were required to
convert mixtures of isomeric products into each natural
product.
As part of our programme concerning the synthesis of
marine natural products, we became interested in synthesiz-
ing amphidinolides T1 and T3–T5 from a single macrocycle.
Because of the similarities between targets 1 and 3–5, we
proposed that they could be accessed from the common
intermediate A. The desired a-hydroxy ketone motif could be
installed thereafter by sequential hydrosilylation of the
alkyne, epoxidation of the resulting vinyl silane, and Flem-
ing–Tamao oxidation[11] (Scheme 1).
Disconnection of the intermediate A through the lactone
ꢀ
ꢀ
C O bond and the C11 C12 bond gave the western and
eastern fragments B and C, respectively (Scheme 1). Frag-
ment B could be prepared from the alkene E[5] and the trans
Figure 1. Amphidinolides T1–T5.
differ only in their oxygenation pattern and stereochemistry
in the C12–C14 region with the exception of amphidino-
lide T2 (2), which possesses a longer, C21-hydroxylated side
chain. Amphidinolide T1 (1) features a ketone at C12 flanked
[*] Prof. Dr. J. S. Clark, F. Romiti
WestCHEM, School of Chemistry, University of Glasgow
Joseph Black Building, University Avenue, Glasgow G12 8QQ (UK)
E-mail: stephen.clark@glasgow.ac.uk
Homepage: http://www.chem.gla.ac.uk/staff/stephenc/
[**] We gratefully acknowledge WestCHEM and the University of
Glasgow for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305467.
Scheme 1. Retrosynthetic analysis of amphidinolides T1, T3, and T4.
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2,5-disubstituted dihydrofuranone D, which should be readily
accessible by rearrangement of an oxonium ylide or a metal-
bound ylide equivalent generated from a metal carbenoid.[12]
Fragment C could be synthesized from protected b-hydroxy
ester F (Scheme 1).
The tetrahydrofuran-containing fragment 11 was pre-
pared from the commercially available alcohol 6, which can
be obtained from dimethyl d-malate in two steps
(Scheme 2).[13] The alcohol 6 was converted into the corre-
Scheme 4. a) 11, EDC, DMAP, CH2Cl2, RT, 85%; b) RCM; c) EDC,
DMAP, salicylaldehyde, CH2Cl2, RT; d) NaClO2, NaH2PO4·2H2O,
2-methyl-2-butene, tBuOH/H2O, RT, 76% over two steps. EDC=
N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride.
order to circumvent this problem, the use of a salicylate
spacer group to facilitate RCM was explored.
Esterification of carboxylic acid 12 with salicylaldehyde
and subsequent oxidation of the aldehyde gave carboxylic
acid 17 (Scheme 4). Coupling of the alcohol 11 to acid 17
proceeded under Mitsunobu conditions[17] and delivered
triene 18 (Scheme 5). The RCM reaction of 18, promoted
Scheme 2. a) CH2CHCH2OC(NH)CCl3, CF3SO3H, petroleum ether, RT,
87%; b) KOH, MeOH, RT, 83%; c) iBuO2CCl, Et3N, Et2O, RT, then
CH2N2, 88%; d) [Cu(acac)2] (10 mol%), THF, reflux, 91%;
e) [Ph3PCH3]+Brꢀ, tBuOK, THF, RT; f) nBu4NF, THF, RT, 99% over two
steps. acac=acetylacetonate.
sponding allyl ether 7 under acidic conditions. Sequential
ester saponification, activation of the acid as a mixed
anhydride, and treatment with diazomethane afforded the
a-diazo ketone 8. Treatment of 8 with [Cu(acac)2] in THF at
reflux delivered the required trans dihydrofuranone 9 in 91%
yield with excellent diastereocontrol (d.r. ꢁ 98:2).[12d,f,i–k]
Ketone methylenation gave the diene 10 and subsequent
cleavage of the silyl ether provided the alcohol 11.
Scheme 5. a) Ph3P, DIAD, THF, 08C!RT, 99%; b) 19 (12 mol%),
CH2Cl2, reflux, 96% (E/Z=1.2:1); c) KOH, MeOH, RT; d) [Ir(cod)-
(PCy3)(py)]PF6, H2, CH2Cl2, RT, 85% over two steps. DIAD=diiso-
propyl azodicarboxylate.
Assembly of the C1–C11 fragment by cross-metathesis
(CM) of the dienes 10 or 11 with the alkene 13 was attempted
(Scheme 3). The carboxylic acid 12, which can be accessed by
by catalyst 19, afforded an inconsequential isomeric mixture
(E/Z = 1.2:1) of the lactone 20.[18] Base-mediated excision of
the spacer group and directed hydrogenation of the resulting
diene provided the complete western (C1–C11) fragment 21
as a single diastereomer with the required configuration at
C8.[19]
Scheme 3. a) Me3SiCHN2, Et2O, MeOH, 08C, 61%; b) CM with 10 or
11.
Synthesis of the eastern fragment commenced with
asymmetric reduction[20] of ethyl 3-oxohexanoate (22) and
protection of the resulting alcohol to give 23 (Scheme 6).
Treatment of the ester 23 with an excess of the organocerium
reagent prepared from trimethylsilylmethylmagnesium chlo-
ride resulted in double Grignard addition.[21,22] Base-mediated
Peterson elimination of the intermediate tertiary alcohol
delivered an allylic silane, which was then converted into the
bromide 24 by treatment with pyrrolidone hydrotribromide
(PHT).[23] Deprotonation of N-propionyloxazolidinone (25)
with NaHMDS and enolate alkylation with bromide 24
followed by reductive cleavage of the oxazolidinone auxiliary
provided alcohol 26.[24] Oxidation of the alcohol 26 and
conversion of the resulting aldehyde into the corresponding
using Evansꢁ methodology[14,15] and has been prepared by us
and others,[5,12i] was methylated to give ester 13. Unfortu-
nately, it was not possible to effect cross-metathesis of dienes
10 or 11 with the alkene 13 to give 14, a finding that contrasts
with the outcome of the cross-metathesis reaction of closely
related substrates.[6]
To avoid using cross-metathesis, we decided to couple the
acid 12 to the alcohol 11 to give the ester 15 and then perform
RCM (Scheme 4). However, attempted formation of the 11-
membered lactone 16 by RCM of the diene 15 failed.[16] In
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using [Cp*Ru(CH3CN)3]PF6 delivered a separable mixture
(1:1) of the isomeric Z-vinylsilanes 32 and 33 in a combined
yield of 89% (Scheme 7).[28,29] Pleasingly, treatment of 32 with
m-CPBA resulted in selective epoxidation of the vinylic
silane, rather than the exocyclic alkene (Scheme 8). Fleming–
Tamao oxidation[11] of the resulting silyl-substituted epoxide
Scheme 6. a) [{(R)-Tol-BINAP}RuCl2], H2 (5 bar), EtOH, 958C, 97%
(98% ee); b) TBSCl, imidazole, DMF, 08C !RT, 98%; c) CeCl3,
Me3SiCH2MgCl, THF, ꢀ788C!RT; d) NaHMDS, THF, 08C, 93% over
two steps; e) PHT, pyridine, THF, ꢀ108C!RT, 96%; f) 25, NaHMDS,
ꢀ788C, THF, then 24, nBu4NI, ꢀ308C, 60% (76% brsm), d.r.=15:1;
g) LiBH4, H2O, Et2O, 08C, 99%; h) DMP, CH2Cl2, RT; i) dimethyl 1-
diazo-2-oxopropylphosphonate, K2CO3, THF/MeOH, 08C!RT, 82%
over two steps. TBS=tert-butyldimethylsilyl; NaHMDS=sodium hex-
amethyldisilazide; PHT=pyrrolidone hydrotribromide; DMP=Dess–
Martin periodinane.
Scheme 8. a) m-CPBA, CH2Cl2, 08C; b) KHF2, KHCO3, 30% H2O2,
THF, MeOH, RT. m-CPBA=3-ClC6H4CO3H.
alkyne using the Ohira–Bestmann reagent[25] afforded the
eastern (C12–C21) fragment 27.
afforded amphidinolide T1 in 73% yield over two steps, along
with a minor product, the data for which are consistent with
13-epi-amphidinolide T1 (34). Spectroscopic and other data
for synthetic 1 are identical to those reported for amphidi-
nolide T1.[3a]
Treatment of 33 under the same conditions as 32 delivered
amphidinolides T4 (4) and T3 (3) as a separable mixture
(d.r. = 1.6:1) of diastereomers in 79% yield (Scheme 9).
Spectroscopic and other data for synthetic 3 and 4 are
identical to those reported in the literature.[3b,5]
The efficiency of the route to 3 and 4 could be improved
by increasing the diastereoselectivity of the epoxidation
reaction. Epoxidation of the vinylic silane 33 under Shi
conditions,[30,31] employing the d-fructose-derived ketone 35,
followed by Fleming–Tamao oxidation afforded amphidino-
lide T3 in 61% yield over two steps (Scheme 9). Furthermore,
when the vinylic silane 33 was subjected to the same
conditions, but using the l-fructose-derived ketone ent-35 to
perform epoxidation, amphidinolide T4 was formed in 57%
yield over two steps. In each case, a high degree of reagent
control was observed and the other diastereomer was not
obtained. Amphidinolide T4 can be epimerized at C14 to give
Coupling of the eastern and western fragments was
accomplished by conversion of the alcohol 21 into the triflate
28 and subsequent displacement of triflate by the alkynyl
lithium species generated by deprotonation of fragment 27
(Scheme 7). The coupled product 29 was obtained in 68%
yield and competitive addition of the alkynyl lithium inter-
mediate to the ester was not observed. The seco acid 30, which
was required for lactonization, was produced in a one-pot
fashion by ester cleavage using potassium trimethylsilano-
late[26] and quenching the reaction with concentrated HCl.
Macrolactonization of 30 under Yamaguchi conditions[27] gave
the common late-stage intermediate 31, corresponding to A in
our retrosynthetic analysis (Scheme 1).
Following the preparation of lactone 31, installation of the
various oxygenation patterns found in amphidinolides T1, T3,
and T4 was explored. Catalytic hydrosilylation of the alkyne
Scheme 7. a) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ788C; b) 27, nBuLi, HMPA,
Et2O, ꢀ788C, 68% over two steps; c) Me3SiOK, THF, RT, then conc.
HCl, 86%; d) 2,4,6-Cl3PhCOCl, iPr2NEt, toluene, RT, then DMAP, 458C,
80%; e) [Cp*Ru(MeCN)3]PF6, (EtO)2MeSiH, CH2Cl2, 08C!RT, 44% of
32 and 45% of 33. Cp*=1,2,3,4,5-pentamethylcyclopentadienyl;
Tf =SO2CF3. HMPA=hexamethylphosphoramide.
Scheme 9. a) Epoxidation conditions A: oxidant, CH2Cl2, 08C; condi-
tions B: oxidant, Na2B4O7·10H2O, nBu4NHSO4, KHCO3, Na2EDTA,
H2O, MeCN, DMM, 08C; b) KHF2, KHCO3, 30% H2O2, THF, MeOH,
RT.
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In conclusion, efficient and high-yielding synthetic routes
to members of the amphidinolide T family of natural products
via a single late-stage intermediate (31) have been estab-
lished. The syntheses of amphidinolides T1, T3, and T4 were
completed in 17 steps from the alcohol 6. The macrolactone
31 was prepared from 6 in 14 steps and 21.6% yield; the
overall yields of amphidinolides T1, T3, and T4 were 6.9%,
5.9%, and 5.5%, respectively. The key tetrahydrofuran unit
was assembled by rearrangement of an oxonium ylide, or its
metal-bound equivalent, generated from a copper carbenoid,
further demonstrating the utility of this methodology for the
synthesis of complex natural products.[12f,i–k,32]
Received: June 25, 2013
Published online: && &&, &&&&
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Keywords: diazo ketone · natural products · oxidation ·
rearrangement · total synthesis
.
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