Enantioselective total synthesis of (+)-amphidinolide T1

Article abstract of DOI:10.1021/ja021385j

An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C₁-C₁₀ segment 2 and C₁₁-C₂₁ segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C₄-C₅ carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C_16-exo-methylene and the C_13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C₂ and C₃ stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1. Copyright

Full text of DOI:10.1021/ja021385j

Published on Web 02/06/2003
Enantioselective Total Synthesis of (+)-Amphidinolide T1
Arun K. Ghosh* and Chunfeng Liu
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607
Received November 27, 2002 ; E-mail: arunghos@uic.edu.
Amphidinolides are a series of unique cytotoxic macrolides
isolated from the marine dinoflagellates Amphidinium sp., and they
have shown significant antitumor properties against a variety of
NCI tumor cell lines.1 Amphidinolides are extremely scarce, and
as a result, biological studies have been very limited. Amphidinolide
T1 (1), a 19-membered macrolide, has shown potent activity against
murine lymphoma L1210 as well as human epidermoid carcinoma
KB cell lines.2 The structure of 1 was initially established by NMR
studies. Later, its absolute configuration was elucidated through
X-ray analysis by Kobayashi and co-workers.3 The significant
clinical potential and unique structural features of the amphidinolide
family of natural products have stimulated considerable interest in
their syntheses and structure-function studies.4 Herein, we report
the first total synthesis of (+)-amphidinolide T1.
As outlined in Figure 1, our synthetic strategy for amphidinolide
T1 is convergent and involves the assembly of C1-C10 segment 2
and C11-C21 segment 3 by an oxocarbenium ion-mediated alkyl-
ation and macrolactonization sequence. This alkylation is expected
to proceed stereoselectively through a five-membered ring oxocar-
benium ion intermediate derived from sulfone 2. Our approach to
the synthesis of fragment 2 involves an efficient cross metathesis
Figure 1. Retrosynthetic analysis.
Scheme 1 a
and hydrogenation sequence between the terminal olefins of 5 and
6 to form the C4-C5-carbon-carbon bond. Enol ether 4 is designed
to be the surrogate of fragment 3 where the sensitive C16-exo-
methylene and the C13-hydroxyl group are being protected as a
bromohydrin derivative during the Lewis acid-catalyzed alkylation
and macrolactonization reactions. We planned to unravel this
functionality at the final stage of the synthesis. Two of the three
stereocenters in fragment 5 as well as the C2 and C3 stereocenters
in fragment 4 are accessed by a highly diastereoselective ester-
derived titanium enolate-mediated syn-aldol reaction.5
The synthesis of C1-C10 segment 2 is outlined in Scheme 1.
Aldol condensation of (1R,2S)-1-(N-tosylamino)-2-indanyl propi-
onate (7) with benzyloxypropionaldehyde at -78 °C furnished aldol
adduct 8 as a single diastereomer in 90% yield.5 Reduction of 8 by
lithium aluminum hydride in THF at 23 °C afforded diol 9. This
was transformed into γ-lactone 10 by selective sulfonylation of the
primary alcohol, displacement of the resulting sulfonate with
cyanide, followed by acid-promoted lactonization to afford 10 in
aReaction conditions: (a) TiCl4, i-Pr2NEt; BnO(CH2)2CHO (90%); (b)
81% overall yield. DIBAL reduction of 10 at -78 °C in CH2Cl2
LAH, THF, 23 °C (91%); (c) PhLi, TrisCl, THF, -78 to 23 °C (86%); (d)
NaCN, DMSO, 80 °C (95%); (e) aq. HCl, MeOH, 23 °C (98%); (f) Dibal-
followed by reaction with trimethylsilylethanol and p-TsOH af-
forded acetal 11 and its isomer as a 3.5:1 mixture, which can be
separated by column chromatography after removal of the benzyl
group by hydrogenolysis. Swern oxidation of the resulting alcohol
followed by Wittig olefination furnished alkene 5, one of the
substrates for cross metathesis.
Cross metathesis6 of 5 with oxazolidinone derivative 67 in the
presence of 5 mol % second generation Grubbs’s catalyst9 afforded
a 1:1 mixture (E:Z) of cross metathesis product 12 in 60% yield
along with alkene dimers of 5 and 6 which can be separated by
silica gel chromatography. Exposure of these alkene dimers to 5
mol % second generation Grubbs’s catalyst further afforded cross
H, -78 °C, then TMS(CH2)2OH, p-TsOH, MgSO4, 23 °C (91%); (g) H2,
Pd/C, EtOAc (98%); (h) Swern Ox; (i) Ph3P)CH2, THF (84%): (j) 6,
CH2Cl2, 40 °C Cl2(PCy3)(IMes)RudCHPh (96%); (k) BnOH, BuLi, THF,
0 °C (85%); (l) HSO2Ph, CaCl2, CH2Cl2, 23 °C (95%).
metathesis product 12 in 36% yield (1:1 mixture of E:Z olefins).
Thus, the overall yield of cross metathesis product 12 was 96%
after two cycles. Catalytic hydrogenation of the alkene mixture
followed by treatment of the saturated derivative with lithium
phenylmethoxide furnished benzyl ester 13 in 85% yield. Exposure
of 13 to phenylsulfinic acid and CaCl2 afforded sulfone derivative
2 and its isomer as a 7:1 mixture in 95% yield.8
9
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J. AM. CHEM. SOC. 2003, 125, 2374-2375
10.1021/ja021385j CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
Scheme 3 a
a Reaction conditions: (a) 4, DTBMP, AlCl3, -35 °C (73%); (b) HF‚Py,
Py (87%); (c) H2, 10% Pd-C; (d) 2,4,6-(Cl3)PhCOCl, i-Pr2NEt, then
DMAP, toluene (71%); (e) Zn, NH4Cl, EtOH, 80 °C (61%).
Yamaguchi conditions17 afforded macrolactone 24 in 71% yield
(Scheme 3). Reductive unmasking of the bromoether with Zn and
NH4Cl in ethanol provided synthetic amphidinolide T1 (1). Spectral
data (1H and 13C NMR) of synthetic 1 ([R]23D +16, c 0.1, CHCl3)
23
is in agreement to that of natural amphidinolide T1 (lit.3 [R]D
a Reaction conditions: (a) TiCl4, i-Pr2NEt; BnOCH2CHO (93%); (b)
TIPSOTf, i-Pr2NEt, 0 °C (95%); (c) Dibal-H, -40 °C (91%); (d) I2, PPh3,
Imidazole, 23 °C (95%); (e) i. BuLi, 1,3-dithiane; ii. EtMgBr, CuI (64%,
two steps); iii. TBSOTf, i-Pr2NEt; iv. MeI, CaCO3, aq. MeCN (73%, two
steps); (f) t-BuLi, Et2O, -78 to 23 °C, then 18 (80%); (g) TPAP, NMO,
23 °C; (h) Cp2TiMe2, THF, 80 °C (84%); (i) Li/NH3, -33 °C, THF; (j)
LAH, THF, 23 °C (90%); (k) NBS, 0 to 23 °C (91%); (l) MeMgBr, -78
to 23 °C; (m) LiHMDS, TBSCl, HMPA, -78 to 23 °C (95%).
+18, c 0.3, CHCl3).
Thus, a stereocontrolled and convergent synthesis of (+)-
amphidinolide T1 has been achieved. The functional group tolera-
bilty of the oxocarbenium ion-mediated alkylation reaction along
with efficient cross methathesis, diastereoselective aldol reactions,
and use of a cyclic bromoether as a novel protection of the exo-
methylene group are noteworthy features.
Synthesis of the C11-C22 fragment is outlined in Scheme 2. Aldol
reaction of ent-7 with benzyloxyacetaldehyde afforded a single syn-
diastereomer (14) in 95% yield.5 Protection of the resulting alcohol
as a TIPS ether followed by Dibal-H reduction furnished alcohol
15 which was readily converted into the corresponding iodide (16).
Reaction of glycidyl tosylate 17 with lithium 1,3-dithiane followed
by ethyl cuprate provided the corresponding secondary alcohol
which, after protection as a TBS ether and removal of dithiane,
afforded aldehyde 18.9 Treatment of iodide 16 with t-BuLi generated
the corresponding alkanyllithium, which was reacted with aldehyde
18 to afford a 1:1 diastereomeric mixture of alcohols which, upon
TPAP oxidation, provided ketone 19.10 Olefination of 19 utilizing
Petasis conditions11 furnished alkene 20. Reductive removal of the
benzyl and TIPS ethers12 followed by reaction of the resulting diol
with NBS afforded bromotetrahydrofuran 21 as a 3:1 diastereo-
meric mixture. Our motive for forming this bromolactone is to
protect the C13-alcohol as well as to protect the sensitive exo-
methylene group during the oxocarbenium ion-mediated alkylation
process.13 The hydroxymethyl group of 21 was then converted to
methyl ketone 22 in 60% overall yield. Treatment of 22 with
LiHMDS followed by reaction of the resulting enolate with TBSCl
furnished the vinyl ether segment (4).
Our subsequent synthetic strategy calls for the assembly of
fragments 2 and 4 by an oxocarbenium ion-mediated alkylation
reaction; however, this proved to be a formidable task. Our
successful path using modified Ley’s protocol14 is presented here.15
Treatment of 2 and 4 in the presence of 2 equiv of AlCl3 at -35
°C resulted in only very low yield (10%) of desired product 23.
Under optimized conditions in the presence of excess AlCl3 (6
equiv) and DTBMP (1.2 equiv) coupling product 23 was obtained
in 73% yield as a single isomer (by 1H- and 13C NMR analysis).16
The depicted trans-stereochemistry is assigned on the basis of
analysis of NOESY data. The C18-silyl ether was then removed by
exposure to HF‚Py, and subsequent hydrogenolysis removed the
benzylester. Macrolactonization of the resulting hydroxy acid under
Acknowledgment. Financial support by the National Institutes
of Health (GM 53386) is gratefully acknowledged. We also thank
Mr. Xiaoming Xu for preliminary experimental assistance.
Supporting Information Available: Experimental procedures and
spectral data for compounds and 13C NMR for compounds 2, 4-24
and 1 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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