Alkene-alkyne coupling as a linchpin: An efficient and convergent synthesis of amphidinolide P

Article abstract of DOI:10.1021/ja045449x

A short and efficient synthesis of the cytotoxic macrolide amphidinolide P is described. A remarkably chemo- and regioselective ruthenium-catalyzed alkene-alkyne coupling allows for a convergent synthesis and demonstrates that both enynes and β-lactones are suitable coupling partners. This work also features a novel strategy for the preparation of macrolactones via intramolecular transesterification of β-lactones. The target structure was prepared in 15 steps for the longest linear sequence and 10% overall yield, 24 steps total. Copyright

Full text of DOI:10.1021/ja045449x

Published on Web 09/30/2004
Alkene-Alkyne Coupling as a Linchpin: An Efficient and Convergent
Synthesis of Amphidinolide P
Barry M. Trost* and Julien P. N. Papillon
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 28, 2004; E-mail: bmtrost@stanford.edu
Scheme 1. Retrosynthetic Analysis
The symbiotic dinoflagellates of the genus Amphidinium, which
are extracted from the cells of the okinawan flatworm Amphiscolops
sp., have proven to be a rich source of cytotoxic natural products.
Among others, over 30 macrolides, named amphidinolides, have
been isolated from various strains of cultured Amphidinium sp.1
Although they are structurally diverse, the overwhelming majority
of these macrolactones display one or more exo-methylene units.
As such, they constitute ideal targets for studying the ruthenium-
catalyzed alkene-alkyne coupling reaction developed by our
group,2 and they demonstrate the remarkable chemoselectivity of
this reaction, as well. Having already synthesized and established
the structure of amphidinolide A,3 we now report our efforts on
the synthesis of amphidinolide P (1). The isolation and the structure
elucidation of 1 were reported in 1995,4 and its structure was
confirmed by total synthesis.5
Scheme 2. Synthesis of Alkyne 4a
As shown in Scheme 1, we envisioned intermediate 2 as a
precursor to amphidinolide P (1), anticipating that the â-lactone
would allow ring expansion by a translactonization process, thereby
avoiding unproductive alcohol protection/deprotection and acyl
activation steps involved in classic macrolactonization methodolo-
gies. An alkene-alkyne coupling reaction2 would install the exo-
methylene unit at C-11 and would allow for a convergent synthesis
by the assembly of alkene 3 and enyne 4, a type of alkyne partner
not previously explored. Both 3 and 4 could be derived from
commercially available chiral building blocks 5 and 6, respectively.
The synthesis of alkyne 4, starting from (S)-glycidyl butyrate
(6) is described in Scheme 2. Epoxide 6 was most efficiently
converted to 7 using Khuong-Huu’s method,6 while we found that
dioxane was an excellent solvent for the benzyl protection of alcohol
7 using the benzyl-2,2,2-trichloroacetimidate/triflic acid methodol-
ogy. The primary alcohol was unmasked using DIBAL-H, and
Moffatt-Swern oxidation gave aldehyde 10 in 71% yield over the
four steps. Treatment of 10 with stoichiometric SnCl4 and silane
117 afforded exclusively the chelation-controlled product 12 as a
9:1 mixture of 5,6-anti/syn diastereomers in 77% yield.8 After silyl
protection, the minor diastereomer could be removed by silica gel
chromatography. Debenzylation of 13 proved rather troublesome,
giving partial migration of the TIPS group or complex mixtures.
Lewis acids (e.g., BCl3, 9-Br-9-BBN, FeCl3, or SnCl4) rapidly
converted 13 to the corresponding tetrahydrofuran derivative.9
However, DDQ in refluxing dichloroethane gave rapid and clean
conversion to afford alcohol 14 in 82% yield. Dehydration was
best carried out using DIAD/PPh3 in hot toluene to give enyne 15
in 75% yield and a pleasing 8:1 E/Z ratio. Base-induced elimination
of various sulfonyl derivatives of 14 gave poor E/Z ratios. Selective
C-Si bond cleavage afforded the first key intermediate (4) in 96%
yield.
a Reagents and conditions: (a) 1.3 equiv of trimethylsilylacetylene, 1.3
equiv of nBuLi, THF, -78 °C, 25 min, and then 1.3 equiv of AlMe3, -40
°C, 35 min, and then 1.0 equiv of (S)-glycidyl butyrate (6), -78 °C, 10
min, and then 1.3 equiv of BF3‚Et2O, -78 °C, 25 min; (b) 2.0 equiv of
benzyl-2,2,2-trichloroacetimidate, 0.2 equiv of TfOH, dioxane, 24 °C, 0.5
h; (c) 1.3 equiv of DIBAL-H, CH2Cl2, -78 °C, 15 min; (d) 2.0 equiv of
(COCl)2, 4.0 equiv of DMSO, 5.0 equiv of Et3N, CH2Cl2, -78 to 0 °C,
71% (four steps); (e) 1.0 equiv of SnCl4, 2.0 equiv of silane 11, 1:1 CH2Cl2/
pentane, -110 °C, 15 min, 9:1 dr, 77%; (f) 3.0 equiv of TIPSOTf, 4.0
equiv of 2,6-lutidine, CH2Cl2, 24 °C, 6 h, 82%; (g) 2.0 equiv of DDQ,
DCE/pH ) 7 buffer 9:1 (v/v), reflux, 45 min, 82%; (h) 3.0 equiv of PPh3,
3.0 equiv of diisopropyl azodicarboxylate, toluene, 80 °C, 20 min, 8:1 E/Z,
75%; (i) 1.0 equiv of K2CO3, MeOH, 24 °C, 2 h, 96%.
DIBAL-H and followed by treatment with the Ohira-Bestmann
reagent10 and sodium methoxide11 to give alkyne 17 in excellent
yields. Alkyne 17 could be converted into 18 uneventfully using
9-Br-9-BBN followed by acetic acid. Bromine-lithium exchange,
followed by treatment with freshly prepared (2-Th)Cu(CN)Li, gave
a mixed cuprate,12 which reacted preferentially13 with the epoxide
functionality of (R)-glycidyl tosylate. When the mixture was
warmed to 0 °C, in situ epoxide formation ensued, and after the
mixture cooled to -78 °C, the addition of freshly prepared
vinyllithium (nBuLi + tetravinylstannane) afforded alcohol 19 in
71% yield. Analysis of the O-methyl mandelate14 derivative of
alcohol 19 confirmed the absolute stereochemistry as well as the
enantiopurity of 19. Silylation of 19 followed by selective depro-
tection of the primary alcohol15 gave 21. The crude aldehyde derived
The synthesis of alkene 3 started with (R)-3-hydroxy-2-methyl-
propionate (5), as depicted in Scheme 3. DIBAL-H reduction of
the ester (16) derived from 5 gave an aldehyde that was not isolated
but, instead, was treated with methanol to quench the excess
9
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10.1021/ja045449x CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Alkene 3a
oxidation20 of 26 gave ketone 27. Desilylation of 27, followed by
the isomerization from the 8- to the 15-membered-ring lactone using
25 and by the spontaneous hemiacetal formation, afforded amphi-
dinolide P (1), whose spectral values were undistinguishable from
those reported.4,21
In conclusion, we completed the synthesis of amphidinolide P
(1) in 15 steps for the longest linear sequence and 10% overall
yield, 24 steps total. This work demonstrates the power of the
ruthenium-catalyzed alkene-alkyne coupling reaction for the rapid
assembly of complex natural products and of the â-lactone for
macrolactone formation (Scheme 4).
Acknowledgment. We thank the National Institutes of Health
for their generous support of our programs. Mass spectra were
provided by the Mass Spectrometry Regional Center of the
University of California, San Francisco, which is supported by the
NIH Division of Research Resources.
a Reagents and conditions: (a) 1.0 equiv of TBDPSCl, 1.3 equiv of
imidazole, CH2Cl2, 23 °C, 0.5 h; (b) 1.15 equiv of DIBAL-H, CH2Cl2, -78
°C, 60 min, and then 1.35 equiv of MeOH, -78 to 24 °C, and then added
to 2.5 equiv of CH3(CO)CHN2P(O)(OMe)2 and 2.5 equiv of NaOMe, THF,
-78 to 0 °C, 20 min, 83% (two steps); (c) 2.0 equiv of 9-Br-9-BBN, CH2Cl2/
hexane, 0 °C, 6 h, and then 14 equiv of AcOH, 0 °C, 1 h, 96%; (d) 2.0
equiv of tBuLi, ether, -78 °C, 45 min, and then 1.3 equiv of (2-
Th)Cu(CN)Li, THF, -78 to -45 °C, 1 h, and then 2.0 equiv of (R)-glycidyl
tosylate, THF, -45 to 0 °C, 5 h, and then 2.0 equiv of vinyllithium, 2.0
equiv of BF3‚Et2O, THF, -78 °C, 15 min, 71%; (e) 1.8 equiv of TBSOTf,
4.0 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 5 min; (f) 1.2 equiv of TBAF‚3H2O,
1.2 equiv of AcOH, DMF, 23 °C, 22 h, 77% (two steps); (g) 2.0 equiv of
(COCl)2, 4.0 equiv of DMSO, 6.0 equiv of Et3N, CH2Cl2, -78 to 0 °C, 20
min; (h) 1.0 equiv of Me2AlCl, 1.1 equiv of trimethylsilylketene, CH2Cl2,
-78 °C, 0.5 h; (i) KF‚2H2O, CH3CN, 25 °C, 1 h, and then 40% aqueous
HF, 0 °C, 0.5 h, 1.6:1 dr, 69% (three steps).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Scheme 4. Alkene-Alkyne Coupling and Completion of the
Synthesisa
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from 21 was directly engaged in a Me2AlCl-mediated cycloaddi-
tion16 with trimethylsilylketene17 to give â-lactone 23, which after
the addition of KF followed by HF, afforded alkene 3 in 69% yield
from 21 as an inconsequential mixture of diastereomers (1.6:1).
The addition reaction between â-lactone 3 and enyne 4 proceeded
smoothly in the presence of 10 mol % catalyst [CpRu(CH3CN)3]-
PF6 in acetone at room temperature to give 2 in 75% yield. It is
notable that, in contrast with typical alkene-alkyne couplings,2 no
trace of linear product could be detected. Although substrate-
controlled epoxidation gave low selectivities, the (-)-diethyl
tartrate-Ti(O-iPr)4 system18 afforded epoxide 24 in 83% yield.
Using Otera’s catalyst 25,19 isomerization from the 4- to the
8-membered-ring lactone proceeded cleanly to unmask the C-3
alcohol while protecting the C-7 alcohol. To the best of our
knowledge, this is the first example of the use of a â-lactone as an
activated acyl group to form a medium-sized ring. Dess-Martin
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(21) Data for synthetic 1 was identical to the data reported for the natural
product,4 except for the optical rotation: [R]23D -27.4° (c 0.17, MeOH),
lit.4 [R]20D +31° (c 0.098, MeOH). Williams et al. reported a synthesis of
1 with an opposite absolute configuration to the one reported herein, and
they also reported a negative optical rotation, [R]23 -30° (c 0.09,
D
MeOH).5 The source of this discrepancy is unclear.
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