A versatile route to the tulearin class of macrolactones: synthesis of a stereoisomer of tulearin A

Article abstract of DOI:10.1021/ol900936t

A versatile synthetic approach to the tulearin class of macrolactones has been developed and deployed to make a stereoisomer of tulearin A. The knowledge gained about structure and synthesis will expedite the assignment of the stereostructure of this new

Full text of DOI:10.1021/ol900936t

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3282-3285
A Versatile Route to the Tulearin Class
of Macrolactones: Synthesis of a
Stereoisomer of Tulearin A
Alexander L. Mandel,† Ve´ronique Bellosta,† Dennis P. Curran,‡ and
Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS 10 rue Vauquelin,
75231 Paris Cedex 05, France and Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
janine.cossy@espci.fr
Received April 29, 2009
ABSTRACT
A versatile synthetic approach to the tulearin class of macrolactones has been developed and deployed to make a stereoisomer of
tulearin A. The knowledge gained about structure and synthesis will expedite the assignment of the stereostructure of this new anticancer
agent.
In 2008, Kashman et al. reported the isolation of tulearin A
(1) (Figure 1) from the marine sponge Madagascar Fascapl-
ysinopsis sp. collected in the Salary Bay north of Tulear.1a
The structure of 1 was elucidated through interpretation of
MS, IR, and various one-dimensional and two-dimensional
NMR experiments. However, the relative and absolute
stereochemistry of 1 were unknown until recently.1b Tulearin
A (1) exhibited potent antiproliferative activity against human
leukemic cell lines K562 and UT7. Activity against K562
cells was notably better; a 0.5 µg/mL solution of 1 inhibited
∼60% of proliferation vs 35% inhibition against the UT7
cells.1a
Due to its promising biological activity and lack of a three-
dimensional structure, we designed a synthetic strategy that
was capable of producing any stereoisomer of tulearin A (1).
Figure 1. Proposed two-dimensional structure of tulearin A.
These stereoisomers could be used to help assign the
stereochemistry and to provide information about the stereo-
structure/activity relationship. Here, we describe the synthesis
of the single stereoisomer of tulearin, compound 2.
Our retrosynthetic plan was to construct the complete
structure through the union of three fragments: stannane 25
(the C20-C26 fragment), an acid of type I (the C1-C12
fragment), and vinyl iodide 20 (the C13-C19 fragment)
through an esterification, ring-closing metathesis, and Stille
coupling (Figure 2).
† ESPCI ParisTech.
‡ University of Pittsburgh.
(1) (a) Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.;
Kashman, Y. Org. Lett. 2008, 10, 153–156. (b) After acceptance of our
manuscript, the relative and absolute configurations of tulearin A were
published. See: Bishara, A.; Rudi, A.; Goldberg, I.; Aknin, M.; Kashman,
Y. Tetrahedron Lett. 2009, 50, 3820–3822.
10.1021/ol900936t CCC: $40.75
Published on Web 06/25/2009
 2009 American Chemical Society

fragments could be adjusted by choice of reagents to give
any stereoisomer.
The synthesis of the C1-C12 fragment I began with
known aldehyde 42 derived from (S)-citronellal (Scheme 1).
Aldehyde 4 and phenyltetrazolylsulfonyl ester 5 were joined
in a Julia-Kociensky reaction3 (KHMDS, THF, -78 °C to
-45 °C, 69%) to provide alkene 6 with excellent E
selectivity. Sharpless asymmetric dihydroxylation4 of 6 with
AD-mix-R in the presence of methanesulfonamide (t-BuOH/
H2O 1:1, 0 °C, 96 h) gave rise to a diol that spontaneously
cyclized to form the five-membered lactone 7 exclusively
in 85% yield. Thus, the hydroxy groups at C8-C9 (tulearin
A numbering) were differentiated, and the C8 group was
protected as a p-methoxybenzyl ether [PMBOC(dNH)CCl3,
La(OTf)3, toluene, 12 h, 85%] to give lactone 8. The
p-methoxybenzyl (PMB) group was chosen because it can
later be removed in the presence of silyl protecting groups
installed on the hydroxy groups present at C3 and C9.
To cleave the lactone and introduce the double bond for
the eventual ring-closing metathesis (RCM), lactone 8 was
reduced (DIBAL-H, CH2Cl2, -78 °C, 96% yield) and the
resulting hemiacetal was treated with the methylphosphonium
ylide (MePPh3Br, n-BuLi, THF, -78 °C to +60 °C, 2 h,
80%) to give alkene 9. The liberated hydroxy group at C9
was protected with TBSOTf (2,6-lutidine, CH2Cl2, 1 h, 96%),
and the primary alcohol was deprotected selectively with
Oxone5 (MeOH, H2O, 2 h) to yield alcohol 10 (88%). The
free alcohol was then oxidized to aldehyde 11 with
Dess-Martin periodinane (CH2Cl2, 2 h, 85%). To construct
the final two stereogenic centers with the carboxylic acid
already in place, the versatile Crimmins chiral auxiliary A6
was chosen and conditions were used to provide the syn
Figure 2. Target stereoisomer 2 and retrosynthetic plan.
Both acid I and iodide 20 originate from readily available
(S)-citronellal (3), which already contains the methyl ster-
eochemistry at C5 and C15. The stereocenters at C2 and C3
come from an asymmetric aldol reaction, while the substit-
uents at C8 and C9 are installed through a Sharpless
asymmetric dihydroxylation.
The alcohol at C17 is formed through a Noyori reduction.
The carbamate is challenging because the alcohols at C8 and
C9 have to be orthogonally protected to allow its installation
before the final deprotection. We envisioned that all of the
Scheme 1. Synthesis of C1-C12 Fragment 14
Org. Lett., Vol. 11, No. 15, 2009
3283

product. Reagent A was treated with TiCl4, (-)-sparteine,
and N-methylpyrrolidinone (CH2Cl2, 0 °C) to give an enolate
intermediate that was reacted with aldehyde 11 to afford the
aldol product 12 in good yield (84%) and with good
diastereoselectivity (dr ) 94/6). After protection (TBSOTf,
2,6-lutidine, CH2Cl2) and saponification7 (LiOH, H2O2, THF),
compound 13 was transformed into acid 14 in 99% yield
(over the two steps). Thus, the C1-C12 fragment 14 was
obtained in 21.7% yield from (S)-citronellal (3) over 14 steps.
Alcohol 20, representing the C13-C19 fragment of target
2, was also prepared from (S)-citronellal (3) (Scheme 2).
Scheme 3. Endgame for the Synthesis of 2
Scheme 2. Synthesis of C13-C19 Fragment 20
Noyori reduction8 with (S,S)-Noyori catalyst B (10 mol %
in i-PrOH) gave alcohol 16 in moderate yield (48%).9
Alcohol 16 was transformed into the alkyne 18, precursor
of 20, through a facile five-step sequence (Scheme 3). To
begin, the hydroxy group in 16 was protected (TIPSCl,
imidazole, DMF), and then the double bond was oxidatively
cleaved with ozone followed by in situ reduction with NaBH4
(CH2Cl2/MeOH (3:2), -78 °C to rt) to give alcohol 17 in
85% yield (two steps). A three-step sequence10 involving
mesylation (MsCl, Et3N, CH2Cl2), iodination (NaI, THF),
and elimination (t-BuOK, THF) produced alkyne 18 in good
yield (91%). Finally, the alkyne was converted to the desired
vinyl iodide 19 through the (E)-selective hydrostannylation
(Bu3SnH, Pd(PPh3)2Cl2, THF), followed by tin-iodine
exchange with iodine (I2, CH2Cl2, 45% yield).11 Deprotection
of the C17 hydroxy group proceeded smoothly to furnish
iodide 20 (TBAF, THF) in 72% yield. Thus, the C13-C19
fragment 20 was obtained in 10.6% yield from (S)-citronellal
(3) over 11 steps.
Treatment of 3 with the propynyl Grignard reagent (THF,
-78 °C), followed by a Swern oxidation [(COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C], afforded ketone 15 in 71% yield
over the two steps.
(2) Breitenbach, R.; Chiu, C. K.-F.; Massett, S. S.; Meltz, M.; Mur-
tiashaw, C. W.; Pezzullo, S. L.; Staigers, T. Tetrahedron: Asymmetry 1996,
7, 435–422.
(3) Blakemore, P. R.; Cole, W. J.; Kocien´ski, P. J.; Morley, A. Synlett
1998, 26–28.
(4) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J.
Org. Chem. 1992, 57, 2768–2771.
(5) Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1, 1701–
1703.
(9) Catalyst B (1%) gave 16 in only 10% yield. A high catalyst loading
was used, however some starting material could still be recovered from
this reaction (39%).
(6) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894–902.
(7) Crimmins, M. T.; Slade, D. J. Org. Lett. 2006, 8, 2191–2194.
(8) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738–8739. Selectivity was confirmed by formation of a
(10) Tu, Y. Q.; Hu¨bener, A.; Zhang, H.; Moore, C. J.; Fletcher, M. T.;
Hayes, P.; Dettner, K.; Francke, W.; McErlean, C. S. P.; Kitching, W.
Synthesis 2000, 1956–1978.
1
MPA-ester and H NMR analysis. See: Seco, J. M.; Quin˜oa, E.; Riguera,
(11) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67, 2751–
2754.
R. Chem. ReV. 2004, 104, 17–118.
3284
Org. Lett., Vol. 11, No. 15, 2009

With both major fragments 14 and 20 in hand, the
fragment couplings were undertaken. Several avenues were
explored, and we present in Scheme 3 the optimum strategy
for both yield and RCM (E) to (Z) selectivity. Coupling of
acid 14 with alcohol 20 (DCC, DMAP, CSA, CH2Cl2)12
produced ester 21 in 74% yield. The RCM with Grubbs’
first-generation metathesis catalyst gave macrocyclic lactone
22 as a 1.9:1 (E/Z) mixture.13 Without separation, 22 was
deprotected with DDQ14 (CH2Cl2/H2O 20/1, rt). A single
flash chromatography purification on silica gel gave (E)-
macrocycle 23 in 43% yield (over two steps). The free C8
hydroxy group was converted to the carbamate using a milder
base that had been described15 (Cl3CONCO, CH2Cl2, then
NaHCO3, MeOH) to afford macrocycle 24 in 86% yield. The
Stille coupling with the easily prepared stannane 25, based
on conditions reported by Marshall et al.16 [Pd2(dba)3·CHCl3,
AsPh3, LiCl, NMP], proceeded in moderate yield (31%) to
provide compound 26. Finally, the latter was deprotected
with TBAF at 0 °C to minimize basic saponification of the
carbamate moiety,17 and compound 218 was recovered after
HPLC purification.19
of compound 2 tended to be similar to those of the natural
product in both chemical shifts and coupling constants, but
because the stereocenters of tulearin are somewhat isolated
from each other, further conclusions about stereochemistry
were premature.1b
In summary, a stereoisomer of tulearin A, compound 2,
has been prepared in 0.34% overall yield from (S)-citronellal
(20 steps for the longest linear sequence) in a total of 32
steps. The synthesis takes into account stereochemical
flexibility, so the work paves the way to make other isomers
and analogues of tulearin in an expeditious fashion.
Acknowledgment. We are grateful to Dr. Sable´ and Dr.
Herman from Sanofi-Aventis (Vitry sur Seine) for purifying
compound 2. We thank Mr. Bin Sui for helpful comments
´
on the manuscript and D.P.C. thanks l’Etat et la re´gion Ile-
de-France for a Chaire Blaise Pascal and NIH-NIGMS for
funding.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
Analysis of the RD data and H and 13C NMR spectra of
2 showed that it was a stereoisomer of tulearin A. The J3
coupling constant between H2 and H3 was significantly
smaller in the spectrum of the natural product (2.9 Hz) than
in isomer 2 (6.9 Hz) (the natural product has the 1,2-anti
configuration).1b Other resonances in the 1H NMR spectrum
OL900936T
(16) Marshall, J. A.; Adams, N. D. J. Org. Chem. 2002, 67, 733–740.
(17) Under the conditions used for the deprotection step, two byproducts
were formed: one appeared to be the macrocyclic lactone wherein the
carbamate was cleaved and the other compound corresponds to an allylic
rearrangement of the macrocycle producing a 22-membered ring lactone.
(18) Compound 2: Rf ∼0.21 (Hex/EtOAc 1/4); [R]20D ) +13 (c ) 0.04,
CHCl3); IR 3361, 2950, 2923, 1707, 1604, 1456, 1394, 1380, 1325, 1250,
(12) (a) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 522–524. (b) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–
2395.
1
1066, 1040, 968, 935 cm-1; H NMR (600 MHz, (CD3)2CO) δ 6.09 (d, J
(13) Other catalysts such as Grubbs second-generation and Hoveyda-
Grubbs second-generation were unreactive or, when forced, produced
byproducts. Understanding that protecting groups can also alter the outcome
of methatheses, alternately protected compounds were tried with all of the
catalysts but gave poorer selectivities and yields. See: Yamamoto, K.;
Biswas, K.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2003, 44, 3297–
3299.
) 15.5 Hz, 1H), 5.77 (dt, J ) 15.5 and 7.0 Hz, 1H), 5.72 (br s, 2H), 5.60
(td, J ) 9.3 and 5.2 Hz, 1H), 5.49 (dt, J ) 15.2 and 6.5 Hz, 1H), 5.43 (dt,
J ) 15.3 and 6.8 Hz, 1H), 5.23 (d, J ) 9.3 Hz, 1H), 4.58 (dt, J ) 6.5 and
5.1 Hz, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.61 (d, J ) 6.8 Hz, 1H), 3.52 (d,
J ) 6.2 Hz, 1H), 2.44 (papp, J ) 6.9 Hz, 1H), 2.22-1.96 (m, 6H), 1.86 (d,
J ) 1.1 Hz, 3H), 1.72-1.34 (m, 11H) 1.31 (m, 7H), 1.12 (d, J ) 7.0 Hz,
3H), 0.95 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.7 Hz, 3H), 0.88 (t, J ) 7.0
Hz, 3H); 13C NMR (125 MHz, (CD3)2CO) δ 174.2, 158.0, 138.3, 134.9,
132.6, 131.5, 129.5, 129.0, 77.5, 70.9, 70.7, 70.7, 47.6, 42.5, 41.2, 40.8,
33.9, 33.5, 33.4, 32.2, 30.1, 30.0, 30.0, 29.5, 28.6, 23.2, 20.2, 20.0, 14.3,
13.4, 13.1; HRMS [M + Na]+ calcd ) 558.3765, found 558.3757.
(19) HPLC using a Waters (USA) Xterra MS C18 7 µm reversed-phase
column measuring 7.8 mm × 300 mm with a gradient from 55% MeCN/
H2O to 95% MeCN/H2O over 25 min.
(14) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021–3028.
(15) (a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am.
Chem. Soc. 2007, 129, 6386–6387. (b) Nicolaou, K. C.; Guduru, R.; Sun,
Y.-P.; Banerji, B.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2007, 46, 5896–
5900. (c) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–
7892.
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