A macrocyclic β-iodoallenolate intermediate is key: Synthesis of the ABD core of phomactin A

Article abstract of DOI:10.1021/ol3017116

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid triggered cyclization of a β-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor.

Full text of DOI:10.1021/ol3017116

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4082–4085
A Macrocyclic β‑Iodoallenolate
Intermediate Is Key: Synthesis of the
ABD Core of Phomactin A
Jennifer Ciesielski, Kevin Cariou, and Alison J. Frontier*
Department of Chemistry, University of Rochester, Rochester, New York 14627,
United States
frontier@chem.rochester.edu
Received June 21, 2012
ABSTRACT
An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid triggered cyclization of a β-
iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and
high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate
for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual
strategy, rings A and B are both fashioned within a macrocyclic precursor.
The phomactinnatural products(Figure1) wereisolated
from Phoma sp. [SANK 11486], a marine fungus that
grows on the shell of a crab Chinoecetes opilioi, off the
coast of Fukui prefecture, Japan.1
aggregation and inhibiting the binding of platelet-activat-
ing factor to its receptor.2,3 PAF is a highly potent phos-
pholipid, and it is thought to be involved in a number of
inflammatory and respiratory diseases.2 Phomactin A is
the most structurally intricate member of the family and
has thus triggered a variety of creative synthetic strategies
(2) (a) Braquit, P.; Touqui, L.; Shen, T. Y.; Vargaftig, B. B. Pharm.
Rev. 1987, 39, 97. (b) Cooper, K.; Parry, M. J. Ann. Rep. Med. Chem.
1989, 24, 81.
(3) Phomactin A induced platelet aggregation (IC50 = 10 μM) and
inhibited the binding of platelet-activating factor to its receptor (IC50 =
2.3 μM) (see ref 1a).
(4) For recent reviews on total syntheses and approaches to the
phomactins, see: (a) Goldring, W. P. D.; Pattenden, G. Acc. Chem.
Res. 2006, 39, 354. (b) Cole, K. P.; Hsung, R. P. ChemTracts 2003, 16,
811. For total syntheses of phomactin A, see: (c) Goldring, W. P. D.;
Pattenden, G. Chem. Commun. 2002, 1736. (d) Tang, Y.; Cole, K. P.;
Buchanan, G. S.; Li, G.; Hsung, R. P. Org. Lett. 2009, 11, 1591. (e)
Buchanan, G. S.; Cole, K. P.; Tang, Y; Hsung, R. P. J. Org. Chem. 2011,
76, 7027. (d) Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y; You, L.;
Hsung, R. P. Tetrahedron 2011, 67, 10105. (g) Mohr, P. J.; Halcomb,
R. L. J. Am. Chem. Soc. 2003, 125, 1712. For approaches to phomactin
A, see: (h) Seth, P. P.; Totah, N. I. Org. Lett. 2000, 2, 2507. (i) Teng, D.;
Wang, B.; Augatis, A. J.; Totah, N. I. Tetrahedron Lett. 2007, 48, 4605.
(j) Chemler, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001, 3, 2949.
(k) Mi, B.; Maleczka, R. E. Org. Lett. 2001, 3, 1491. (l) Shapland,
P. D. P.; Thomas, E. J. Tetrahedron 2009, 65, 4201 and references cited
therein. (m) Schwartz, K. D.; White, J. D. Org. Lett. 2011, 13, 248. (n)
Huang, S.; Du, G.; Lee, C. J. Org. Chem. 2011, 76, 6534. (o) You, L. F.;
Hsung, R. P.; Bedermann, A. A.; Kurdyumov, A. V.; Tang, Y.;
Buchanan, G. S.; Cole, K. P. Adv. Synth. Catal. 2008, 350, 2885.
Figure 1. Phomactins A, D, and G.
Interestingly, the phomactins were found to be platelet-
activating factor (1-O-alkyl-2(R)-(acetylglyceryl)-3-phos-
phorylcholine, PAF) antagonists, inducing platelet
(1) (a) For the isolation of phomactin A, see: Sugano, M.; Sato, A.;
Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.; Hanzawa, H.
J. Am. Chem. Soc. 1991, 113, 5463. (b) For the isolation of phomactins B,
B1, B2, and D, see: Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.;
Haruyama, H.; Yoda, K.; Hata, T. J. Org. Chem. 1994, 59, 564. (c)
For the isolation of phomactins E, F, and G, see: Sugano, M.; Sato, A.;
Iijima, Y.; Furuya, K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188.
(d) For the isolation of phomactin C, see: Chu, M.; Patel, M. G.; Gullo,
V. P.; Truumees, I.; Puar, M. S. J. Org. Chem. 1992, 57, 5817.
r
10.1021/ol3017116
Published on Web 08/02/2012
2012 American Chemical Society

over the past decade.4 It is characterized by a tetracyclic
framework comprised of a bicyclo[9.3.1]pentadecane core,
six stereocenters (three of which are quaternary), a reduced
furanochroman, and an oxadecalin.
Scheme 2. Synthetic Strategy
Our synthetic approach was focused on building the
oxadecalin core of phomactin A from a macrocyclic pre-
cursor. To achieve this task, we intended to employ a
β-iodoallenolate cyclization recently developed in our
laboratory.5 As shown in Scheme 1, 1,4-addition of iodide
to alkynone 1 generates β-iodoallenolate intermediate 2,
which can be selectively converted into either cyclohexenyl
alcohol 3 or oxadecalin 4, depending on the Lewis acid.6,7
In this communication we describe the execution of this
transformation within a carefully crafted 12-membered
macrocycle, as a strategy for the synthesis of the frame-
work of members of the phomactin family, including the
tricyclic core of phomactin A.
Scheme 1. β-Iodoallenolate Cyclization
Scheme 3. Synthesis of Vinyl Iodide 9
The synthetic strategy is centered on cyclization of
macrocycle 5 to produce target alcohol 6, which contains
not only the framework of the phomactins but also a
vinyl iodide moiety that could act as a versatile linchpin
(Scheme 2). An oxy-Michael ring closure of cyclohexenyl
alcohol 6 would then give tricycle 7, containing the ABD
ring system of phomactin A. Macrocycle 5 could come
from a NozakiÀHiyamaÀKishi reaction with linear pre-
cursor 8, which, in a convergent manner, would come from
the β-alkyl Suzuki coupling of vinyl iodide 9 and olefin 10.
The synthesis of the vinyl iodide 9 commenced with
known nerol derived aldehyde 11 (Scheme 3).8 Then, using
the OhiraÀBestmann9 modification of the SeyferthÀGilbert
homologation,10 aldehyde 11 was transformed into terminal
alkyne 12. Alkylation with methyl iodide followed by regio-
selective silylcupration afforded vinyl silane 14 in high yield.11
Iododesilylation of vinyl silane 14 was achieved using
the conditions developed by Zakarian (N-iodosuccinimide
(NIS), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 2,6-
lutidine).12 Thus, the desired vinyl iodide 9 was generated in
four steps and 63% overall yield from aldehyde 11.
The key challenge for the synthesis of olefin 10 was
the diastereoselective installation of the C7 tertiary center
adjacent to the C6 all-carbon quaternary center (Figure 1).
To achieve this, we relied on the enantioselective
(5) Ciesielski, J.; Canterbury, D. P.; Frontier, A. J. Org. Lett. 2009,
11, 4374.
(6) For the formation of β-iodoallenolate intermediates from alky-
nones and alkynyl esters and their subsequent intermolecular addition to
aldehydes, see: (a) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett.
ꢀ
1986, 27, 4767. (b) Deng, G. H.; Hu, H.; Wei, H. X.; Pare, P. W. Helv.
Chim. Acta 2003, 86, 3510. (c) Lee, S. I.; Hwang, G. S.; Ryu, D. H.
ꢀ
Synlett 2007, 59. (d) Wei, H. X.; Gao, J. J.; Li, G. G.; Pare, P. W.
Tetrahedron Lett. 2002, 43, 5677. (e) Wei, H. X.; Hu, J. L.; Purkiss,
ꢀ
D. W.; Pare, P. W. Tetrahedron Lett. 2003, 44, 949.
(10) (a) Seyferth, D.; Hilbert, P.;Marmor, R. S. J. Am. Chem. Soc. 1967,
89, 4811. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(11) (a) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc.,
Perkin Trans. 1 1981, 2527. (b) Nakamura, E.; Mori, S. Angew. Chem.,
Int. Ed. 2000, 39, 3751. (c) Fleming, I.; Newton, T. W. J. Chem.
Soc., Perkin Trans. 1 1984, 1805. (d) Barbero, A.; Pulido, F. J. Acc.
Chem. Res. 2004, 37, 817.
(7) For the use of β-iodoallenolate intermediates in total synthesis,
see: (a) Lee, S. I.; Hwang, G. S.; Shin, S. C.; Lee, T. G.; Jo, R. H.; Ryu,
D. H. Org. Lett. 2007, 9, 5087. (b) Sloman, D. L.; Bacon, J. W.; Porco,
J. A. J. Am. Chem. Soc. 2011, 133, 9952.
(8) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui,
Y.; Abe, S.; Kotake, Y. Angew. Chem., Int. Ed. 2007, 46, 4350.
(9) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mueller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(12) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10,
1727.
Org. Lett., Vol. 14, No. 16, 2012
4083

palladium-catalyzed cycloisomerization protocol devel-
oped by Mikami.13 Accordingly, enyne 15 was converted
into compound 16, with excellent yield and enantioselec-
tivity (Scheme 4). Then, conjugate reduction of the R,β-
unsaturated ester was accomplished by using Buchwald’s
procedure to afford compound 17 in 63% yield as a 12:1
mixture of diastereomers.14 The ester was then reduced
and protected as an acetate, and the absolute and relative
configuration of compound 18 was confirmed by X-ray
crystallography of the corresponding p-nitrobenzoate
derivative.15 Regioselective opening of the tetrahydrofuran
moiety using NaI and AcCl gave rise to iodide 19.16
The selectivity can be attributed to iodide attack at the
least hindered, more reactive allylic carbon, which is
expected to be more favorable than attack at the neo-
pentylic carbon. Radical reduction of the alkyl iodide with
n-Bu3SnH and subsequent cleavage of the acetates with
K2CO3 in methanol provided the diol. Finally, protection
of both alcohols with tert-butyldimethylchlorosilane
(TBSCl) gave the desired olefin 10 in 43% overall yield
over eight steps.
Dess-Martin periodinane (DMP) gave macrocyclization
precursor 8.
Iodoalkyne 8 was cyclized to afford the corresponding
macrocycle via an intramolecular NozakiÀHiyamaÀKishi
Cr(II)/Ni(II) coupling (Scheme 5).18 Oxidation of the
resulting alcohol with MnO2 gave the desired ketone 23
in a 3.6:1.0 ratio of Z and E isomers.19 Fortunately, these
isomers were easily separable via flash chromatography.
After separationof the E- and Z-isomers, the Z-isomer was
desilylated using a HFÀpyridine solution in tetrahydro-
furan. Oxidation of the primary alcohol with the LeyÀ
Griffith reagent20 afforded aldehyde 5 in just four steps
from iodoalkyne 8.
Next, we examined the β-iodoallenolate cyclization with
aldehyde 5 (Scheme 6). The first attempts with the condi-
tions previously reported (BF3 OEt2 and TiCl4; Scheme 1)
3
failed to provide the corresponding oxadecalin or even the
cyclohexenyl alcohol. These conditions gave either com-
plex mixtures or degradation, indicating that these condi-
tions were too harsh. So, we turned our attention to MgI2,
a milder Lewis acid.6e,7b,21 β-Iodoallenolate 24 was then
generated in the presence of MgI2 and cyclized smoothly to
afford cyclohexenyl alcohol 6, in a 60% yield as a single
diastereomer. The relative stereochemistry of the alcohol
was assigned by NOE analysis.22
Scheme 4. Synthesis of Olefin 10
Cyclohexenyl alcohol 6 could serve as an intermediate
for the synthesis of multiple members of the phomactin
family (Figure 1). This versatility is a notable feature of our
synthetic approach to the phomactins. In this study, we
focused on generating the tricyclic core of phomactin A.
Mitsunobu inversion of the alcohol with p-nitrobenzoic
acid using diethyl azocarboxylate (DEAD) and triphenyl-
phosphine generated compound 26, whose structure was
assigned by X-ray crystallography (Scheme 7). Removal of
the p-nitrobenzoate ester followed by treatment of cyclo-
hexenyl alcohol 25 with tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf) and 2,6-lutidine in toluene
triggered an oxy-Michael addition, producing tricycle 7.
This oxadecalin derivative possesses all the stereogenic
centers of the A, B, and D rings of phomactin A and was
assembled using a highly diastereoselective synthetic
strategy.
Coupling of 9 and 10 was accomplished by hydrobora-
tion of olefin 10 with 9-borabicyclo[3.3.1] nonane (9-BBN)
followed by in situ β-alkyl Suzuki coupling17 with vinyl
iodide 9 to furnish compound 20 in good yield (Scheme 5).
Desilylation of the coupling product followed by selective
monoprotection of the primary alcohol with TBSCl gave
neopentylic alcohol 21. Oxidation with pyridinium chloro-
chromate (PCC) and subsequent homologation with
the OhiraÀBestmann reagent produced alkyne 22. Then,
the p-methoxybenzyl ether was oxidatively cleaved with
DDQ, and the terminal alkyne was iodinated with NIS in
the presence of silver nitrate. Finally, oxidation with the
(18) (a) Elliott, M. R.; Dhimane, A. L.; Hamon, L.; Malacria, M.
Eur. J. Org. Chem. 2000, 155. (b) For a comprehensive review of this
€
reaction, see: Furstner, A. Chem. Rev. 1999, 99, 991. (c) For a review on
the asymmetric version of this reaction, see: Hargaden, G. C.; Guiry,
P. J. Adv. Synth. Catal. 2007, 349, 2407.
(19) E/Z isomerization has been observed during the oxidation of
allylic alcohols to R,β-unsaturated ketones with MnO2: (a) Xiao, S.;
Prestwich, G. D. Synth. Commun. 1990, 20, 3125. (b) Tojo, G.; Fernandez,
M. I. Oxidation of Alcohols to Aldehydes and Ketones: A Guide to Current
Common Practice; Springer: New York, 2006; p 308. However, isomer-
ization during the NozakiÀHiyamaÀKishi coupling cannot be ruled
out.
(13) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed.
2001, 40, 249.
(14) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
(20) Ley, S.; Norman, J.; Griffith, W.; Marsden, S.; Jung, M. E.
Synthesis 1994, 639.
(21) For examples of MgI2 used in a β-iodoallenolate reaction, see:
2003, 125, 11253.
ꢀ
(a) Wei, H.; Chen, D.; Xu, X.; Li, G.; Pare, P. W. Tetrahedron: Asymmetry
(15) See Supporting Information for further details and the X-ray
structure.
2003, 14, 971. (b) Sharma, V.; McLaughlin, M. L. J. Comb. Chem. 2010, 12,
ꢀ
327. (c) Wei, H.; Hu, J.; Jasoni, R. L.; Li, G.; Pare, P. W. Helv. Chim. Acta
(16) Oku, A.; Harada, T.; Kita, K. Tetrahedron Lett. 1982, 23, 681.
(17) For a comprehensive review on this reaction, see: Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544.
2004, 87, 2359.
(22) See Supporting Information for NOE data and details concern-
ing the structure assignment of compound 6.
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Org. Lett., Vol. 14, No. 16, 2012

Scheme 5. Synthesis of Macrocycle 5
Scheme 6. β-Iodoallenolate Cyclization with Macrocycle 5
Scheme 7. Synthesis of the Core of Phomactin A
In summary, we have developed a novel enantio-
selective approach to the central core of the phomactins
and synthesized the ABD ring system of phomactin A.
The strategy features the efficient cyclization of a
β-iodoallenolate intermediate, generating the AD ring
system of the phomactin skeleton within a 12-membered
macrocycle.
Acknowledgment. We are grateful to the Lavoisier
Program for a postdoctoral fellowship (K.C.) and the
National Institute of Health (NIGMS R01 GM079364)
for funding this work. We are also grateful to Dr. Alice
Bergmann (University of Buffalo) and Dr. Furong Sun
(University of Illinois, UrbanaÀChampaign) for car-
rying out high-resolution mass spectroscopy and to Dr.
William Brennessel (University of Rochester) for solving
structures by X-ray crystallography. The authors thank
Dr. Daniel Canterbury (University of Rochester) and
Dr. David Lebœuf (University of Rochester) for helpful
discussions.
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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