Toward a new palmerolide assembly strategy: Synthesis of C16-C24

Article abstract of DOI:10.1055/s-0031-1290675

Asymmetric synthesis of C16-C24 of palmerolide A is described, featuring convergent Negishi coupling, Singaram propargylation, and successful tactical maneuvering to address an unexpected allylic substitution reaction. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290675

LETTER
▌1493
letter
Toward a New Palmerolide Assembly Strategy: Synthesis of C16–C24
Synthesis of Palmerolide C16–C24
1
Marilda P. Lisboa, Jeannie H. Jeong-Im, David M. Jones, Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: gdudley@chem.fsu.edu
Received: 16.02.2012; Accepted after revision: 02.04.2012
O
Abstract: Asymmetric synthesis of C16–C24 of palmerolide A is
described, featuring convergent Negishi coupling, Singaram
EtO
propargylation, and successful tactical maneuvering to address an
unexpected allylic substitution reaction.
O
Ph2P(O)CH2Li
Key words: palmerolide, stereoselective synthesis, coupling, natu-
ral products, asymmetric catalysis
OTBS
THF, –78 to 60 °C
OTf
O
8
1–89%
O
Ph2P
VAT
O
O
Palmerolide A (1, Scheme 1) has received considerable
C1–C15 fragment
2
–4
attention from the synthetic chemistry community, ow-
ing to its trifecta of exciting biological activity, complex
Scheme 2 Previously reported synthesis of the C1–C15 subunit
5
chemical structure, and limited natural supply. The title
6
7
compound and several congeneric structures were iso-
lated from Synoicum adareanum, a tunicate species
unique to the Antarctic marine environment. Palmerolide
A is selectively cytotoxic to melanoma cells (e.g., UACC-
Our interest in the synthesis of palmerolide A grew out of
ongoing methodology for the tandem addition–fragmen-
tation of vinylogous acyl triflates (VAT). Specifically,
VAT fragmentation to produce alkyne-tethered β-keto
phosphonates and phosphine oxides enables a concise
1
0
6
2, LC 18 nM), and it is a potent inhibitor of vacuolar
50
10g
ATPase (IC 2 nM). While it may be tempting to connect
50
4f
approach to the C1–C15 subunit (Scheme 2). In the in-
these data points to suggest a mechanism of action, cyto-
toxicity data and inhibitory activity do not correlate well
terest of making further contributions to the efficient
chemical synthesis of the palmerolides, we report a con-
vergent synthesis of the C16–C24 subunit. Our strategy is
unique in that all previous syntheses involve side-chain
fragments that either extend one carbon past or end one
7
across the palmerolide family. Thus, more research is
needed to establish the therapeutic potential of the palm-
8
,9
erolides as drug development leads for melanoma.
2
–4
carbon shy of C24. We also purposefully avoid the use
O
of the potentially labile β,γ-unsaturated aldehyde 3
(Scheme 1), which figures prominently in all but one of
the previous synthetic approaches to palmerolide A.
3
d
O
1
H
N
2
3
19
7
The first key step in the synthesis of the C16–C24 subunit
O
OH
11
12
is a Negishi coupling between vinyl bromide 4 and al-
HO
13
kyl iodide 5 (Scheme 3), which we prepared by analogy
1
5
O
to reported procedures. Negishi coupling (→ 6), THP hy-
drolysis (→ 7), and oxidation of alcohol 7 provided alde-
hyde 8 in 57% overall yield.
O
NH2
palmerolide A (1)
The next synthetic challenge was to set the C19–C20 syn
stereochemistry. Based on the Felkin–Anh model, nucleo-
philic addition to chiral aldehyde 8 should favor the de-
sired syn diastereomer. However, steric differentiation
between methyl and methylene is minimal, and substrate-
controlled propargylation gave very poor diastereoselec-
tivity (Scheme 4).
OH
O
PGO
1
4
I
I
2
3
C16–C24 fragment
Scheme 1 Palmerolide A (1), with emphasis on the C16–C24 region, We thus focused our attention on reagent- or catalyst-con-
and the targeted fragment 2
trolled asymmetric propargylation of aldehydes. Singa-
1
5
ram’s propargylation emerged as our preferred choice
Scheme 4) for its operational simplicity. Treatment of a
THF solution of aldehyde 8 with propargyl bromide, indi-
(
SYNLETT 2012, 23, 1493–1496
Advanced online publication: 29.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290675; Art ID: ST-2012-S0145-L
Georg Thieme Verlag Stuttgart · New York
©

1494
M. P. Lisboa et al.
LETTER
O
O
20
MeO
OH
O
i) Br2, CH2Cl2, 99%
i) DHP, PPTS, CH2Cl2, 99%
ii) LiAlH4, THF, 0 °C, 98%
iii) Ph3P, ImH, I2, THF, 97%
ii) LiOH, DMF–H2O, 75%
iii) TBDPSCl, ImH, DMAP,
CH2Cl2, 90%
TBDPSO
Br
I
OTHP
4
5
ZnCl2, t-BuLi, Pd(PPh3)4,
THF, 72%
TBDPSO
OR
TsOH
i-PrOH
6
7
R = THP
R = H
8
5%
DMP, CH2Cl2
H2O, 93%
TBDPSO
20
O
8
Scheme 3 Convergent Negishi coupling for the preparation of aldehyde 8
OH
cohol 9 in 93% yield (95:5 dr). Chiral ligand 10 was re-
Br
TBDPSO
TBDPSO
covered in 94% yield and reused with identical results.
O
O
Negishi–Wipf16 carbometalation–iodination (9 → 11)
was supposed to conclude the synthesis of the C16–C24
subunit (Scheme 5), but unexpected complications arose.
Standard conditions converted alkyne 9 into a complex
mixture of products, one of which appeared to be the re-
sult of allylic substitution in which the TBDPS ether was
replaced with a phenyl group. We repeated this experi-
ment using alcohol 7, which lacks the alkyne moiety, and
proceeded to isolate allylbenzene 12 in 36% yield. Further
details and observations fall outside the current focus, but
the phenyl group presumably comes from the TBDPS
ether. Others have noted that silyl ethers can be problem-
Mg, HgCl2
Et2O
8
8
5
7% yield
5:45 dr
OH
Br
TBDPSO
TBDPSO
In, ligand
py, THF
8
9
HO
Ph
NH2
Ph
93% yield
5:5 dr
9
ligand =
10
Scheme 4 Chiral aldehyde 8 showed minimal bias in the addition of
propargyl Grignard (top), but catalyst control using Singaram’s meth-
od efficiently provided alcohol 9 (bottom)
1
7
atic in this reaction, but we found no prior examples of
this unusual allylic substitution.
After trying unsuccessfully to achieve the desired conver-
sion by optimizing the experimental conditions, we
changed the substrate (Scheme 6). We removed the
um metal, and pyridine in the presence of (commercially
available) amino alcohol 10 provided homopropargyl al-
OH
OH
Cp2ZrCl2
AlMe3, H2O
TBDPSO
TBDPSO
CH2Cl2; then
I2, THF
I
9
7
1
1
model study:
TBDPSO
Cp2ZrCl2
AlMe3, H2O
OH
OH
CH2Cl2; then
I2, THF
12 36%
Scheme 5 Unexpected carbometalation difficulties (top), and an unusual substitution reaction under identical conditions (bottom)
Synlett 2012, 23, 1493–1496
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Palmerolide C16–C24
1495
TBDPS ether, subjected diol 13 to carbometalation (opti- Primary Data for this article are available online at
1
6a
mally without adding water ), and thus obtained iodides http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI: mPirDyramPiartDyar
1
at 0.4125/pd0029th. mPirayrDaZteanh1l
0
1Chemyrst
i
1
→
4 and 15 in a 4:1 ratio. The minor product (15, from OH
Me substitution, cf. Scheme 5) was easily separated
from diol 14 using silica gel, and 14 was thus isolated in
6
0% yield. Selective protection of 14 gave TBS ether 2 in References and Notes
18
85% yield, completing the synthesis of our target C16–
(1) Current address: Department of Chemistry, University of
Pennsylvania, Philadelphia, PA, USA.
C24 subunit.
(
2) Total syntheses: (a) Jiang, X.; Liu, B.; Lebreton, S.; De
Brabander, J. K. J. Am. Chem. Soc. 2007, 129, 6386.
(b) Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.;
Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 5896.
(c) Penner, M.; Rauniyar, V.; Kaspar, L. T.; Hall, D. G.
J. Am. Chem. Soc. 2009, 131, 14216.
OH
Me
9
TBAF
THF, r.t., quant.
I
(3) Formal syntheses: (a) Jaegel, J.; Maier, M. E. Synthesis
15
2
009, 2881. (b) Gowrisankar, P.; Pujari, S. A.; Kaliappan, K.
(
ratio 15/14 = 1:4 ) +
P. Chem. Eur. J. 2010, 16, 5858. (c) Prasad, K. R.; Pawar, A.
B. Org. Lett. 2011, 13, 4252. (d) Pujari, S. A.; Gowrisankar,
P.; Kaliappan, K. P. Chem. Asian J. 2011, 6, 3137.
OH Cp ZrCl , AlMe ,
OH
2
2
3
CH2Cl2, r.t.;
HO
HO
(
4) Synthetic approaches: (a) Kaliappan, K. P.; Gowrisankar, P.
Synlett 2007, 1537. (b) Chandrasekhar, S.; Vijeender, K.;
Chandrashekar, G.; Reddy, C. R. Tetrahedron: Asymmetry
then I2, THF,
–30 °C to r.t.
13
I
2
007, 18, 2473. (c) Jaegel, J.; Schmauder, A.; Binanzer, M.;
14
6
0% isolated
Maier, M. E. Tetrahedron 2007, 63, 13006. (d) Cantagrel,
G.; Meyer, C.; Cossy, J. Synlett 2007, 2983. (e) Lebar, M.
D.; Baker, B. J. Tetrahedron 2010, 66, 1557. (f) Jones, D.
M.; Dudley, G. B. Synlett 2010, 223. (g) Prasad, K. R.;
Pawar, A. B. Synlett 2010, 1093.
TBSCl, ImH,
CH2Cl2, 85%
(
(
(
5) In addition to the geographical barriers to harvesting in
Antarctica, the Antarctic Treaty prohibits exploitation of
South Pole resources for commercial gain. Information
available through the Antarctic Treaty Secretariat:
http://www.ats.aq.
6) (a) Diyabalange, T.; Amsler, C. D.; McClintock, J. B.;
Baker, B. J. J. Am. Chem. Soc. 2006, 128, 5630. (b) Lebar,
M. D.; Baker, B. J. Tetrahedron Lett. 2007, 48, 8009.
(c) Riesenfeld, C. S.; Murray, A. E.; Baker, B. J. J. Nat.
Prod. 2008, 71, 1812.
OH
TBSO
C16–C24 fragment:
I
2
Scheme 6 Synthesis of target C16–C24 fragment
7) Noguez, J. H.; Diyabalanage, T. K. K.; Miyata, Y.; Xie,
X.-S.; Valeriote, F. A.; Amsler, C. D.; McClintock, J. B.;
Baker, B. J. Bioorg. Med. Chem. 2011, 19, 6608.
A C16–C24 fragment of palmerolide A has been prepared
in seven steps (27% overall yield) from known com-
pounds 4 and 5, each of which was prepared in three steps.
Highlights of this work include the convergent Negishi
coupling and application of Singaram’s indium-mediated
propargylation reaction to set the C19–C20 syn stereo-
chemistry. With efficient access to C1–C15 and C16–C24
fragments, what remains is fragment assembly and oxida-
tive installation of the enamide moiety toward completion
of the synthesis of palmerolide A. Efforts to this end are
under way and will be reported in due course.
(8) (a) Nicolaou, K. C.; Sun, Y.-P.; Guduru, R.; Banerji, B.;
Chen, D. Y.-K. J. Am. Chem. Soc. 2008, 130, 3633.
(
b) Nicolaou, K. C.; Leung, G. Y. C.; Dethe, D. H.; Guduru,
R.; Sun, Y.-P.; Lim, C. S.; Chen, D. Y.-K. J. Am. Chem. Soc.
008, 130, 10019. (c) Ravu, V. R.; Leung, G. Y. C.; Lim, C.
S.; Ng, S. Y.; Sum, R. J.; Chen, D. Y.-K. Eur. J. Org. Chem.
011, 463.
2
2
(
9) (a) Kinghorn, A. D.; Chin, Y.-W.; Swanson, S. M. Curr.
Opin. Drug Discov. Devel. 2009, 12, 189. (b) Dalby, S. M.;
Paterson, I. Curr. Opin. Drug Discov. Devel. 2010, 13, 777.
(
10) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127,
028. (b) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175.
(c) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006,
5
Acknowledgment
9
1
2
36. (d) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006,
28, 6499. (e) Kamijo, S.; Dudley, G. B. Tetrahedron Lett.
006, 47, 5629. (f) Tummatorn, J.; Dudley, G. B. J. Am.
This research was supported by a grant from the National Science
Foundation (NSF-CHE 0749918) and by the Florida State Univer-
sity Research Foundation. M.L. is a recipient of the CAPES-Ful-
bright Graduate Research Fellowship.
Chem. Soc. 2008, 130, 5050. (g) Jones, D. M.; Lisboa, M. P.;
Kamijo, S.; Dudley, G. B. J. Org. Chem. 2010, 75, 3260.
(h) Jones, D. M.; Dudley, G. B. Tetrahedron 2010, 66, 4860.
(i) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 158.
(j) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 1572.
(k) Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Org. Synth.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
n
ungIifoop
r
t
2
011, 88, 353.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1493–1496

1
496
M. P. Lisboa et al.
LETTER
(18) Procedure and Data for C16–C24 Fragment 2
(
(
11) King, A. O.; Okukado, N.; Negishi, E. I. J. Chem. Soc.,
Chem. Commun. 1977, 683.
To a solution of vinyl iodide 14 (20 mg, 0.062 mmol) in
12) Cheon, C.-G.; Kim, W.-S.; Smith, A. B. III. Org. Lett. 2005,
CH Cl (3 mL) was added imidazole (8 mg, 0.12 mmol) and
2
2
7
, 3569.
TBSCl (11 mg, 0.074 mmol) at r.t. The reaction mixture was
(
(
13) Sun, B.; Xu, X. Tetrahedron Lett. 2005, 46, 8431.
14) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; John Wiley and Sons: New York, NY,
stirred overnight and quenched with NH Cl. The solution
4
was extracted with CH Cl (3×) and the solvent evaporated
2
2
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (EtOAc–hexanes =
5:95) to yield vinyl iodide 2 as a colorless oil (23 mg, 85%).
1
994.
(
15) (a) Hirayama, L. C.; Dunham, K. K.; Singaram, B.
Tetrahedron Lett. 2006, 47, 5173. (b) For previous
application in synthesis, see: Francais, A.; Leyva, A.;
Etxebarria-J, G.; Ley, S. V. Org. Lett. 2010, 12, 340.
16) (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978,
2
5
[α]D 15.9 (c 5.32, CH Cl ). IR (thin film): 3467 (br), 2954,
2
2
–
1 1
2928, 2856, 1462, 1379, 1252, 1050, 832, 773, 666 cm . H
NMR (400 MHz, CDCl ): δ = 6.00 (d, J = 7.3 Hz, 1 H), 5.32–
3
(
5.36 (m, 1 H), 4.19 (d, J = 6.2 Hz, 2 H), 3.62–3.68 (m, 1 H),
2.28–2.40 (m, 2 H), 2.12–2.20 (m, 1 H), 1.86 (d, J = 0.9 Hz,
3 H), 1.68–1.78 (m, 2 H), 1.60 (s, 3 H), 1.47 (d, J = 4.1 Hz,
2 H), 0.89 (s, 9 H), 0.84 (d, J = 6.8 Hz, 3 H), 0.06 (s, 6 H).
1
00, 2252. (b) Wipf, P.; Lim, S. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1068.
(17) (a) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000, 2, 2687.
1
3
(b) Romero-Ortega, M.; Colby, D. A.; Olivo, H. F.
C NMR (100 MHz, CDCl ): δ = 145.3, 135.1, 126.6, 71.3,
3
Tetrahedron Lett. 2002, 43, 6439. (c) Quéron, E.; Lett, R.
Tetrahedron Lett. 2004, 45, 4527.
60.1, 44.7, 43.5, 35.5, 25.9, 24.0, 18.4, 16.1, 13.3, –5.1. ESI-
+
HRMS: m/z calcd for C H O ISiNa [M + Na ]: 461.1348;
1
8
35
2
found: 461.1343.
Synlett 2012, 23, 1493–1496
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