Total synthesis of aigialomycin D: Surprising chemoselectivity dependence on alkyne structure in nickel-catalyzed cyclizations

Article abstract of DOI:10.1021/ol702961v

The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.

Full text of DOI:10.1021/ol702961v

ORGANIC
LETTERS
2008
Vol. 10, No. 5
811-814
Total Synthesis of Aigialomycin D:
Surprising Chemoselectivity
Dependence on Alkyne Structure in
Nickel-Catalyzed Cyclizations
Christa C. Chrovian, Beth Knapp-Reed, and John Montgomery*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
jmontg@umich.edu
Received December 7, 2007
ABSTRACT
The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed
macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter
was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed
when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.
Aigialomycin D (1) is a resorcinylic macrolide isolated from
the marine mangrove fungus Aigialus parVus.1 This com-
pound is part of a larger family of natural products that
possess a 14-membered macrolide core structure fused to a
benzenoid unit.2 Extensive studies have examined the ability
of the resorcinylic macrolides to degrade oncogenic proteins
by targeting the heat shock protein 90 (Hsp90),3 and other
members of the class function as potent kinase inhibitors.4
Aigialomycin D (1) itself has been reported to display
antimalarial activity (IC50: 6.6 µg/mL against P. falciparum)
as well as cytotoxicity [IC50: 3.0 µg/mL for human epider-
moid carcinoma (KB cells), 1.8 µg/mL for African green
monkey kidney fibroblast (Vero cells)].1 This array of
interesting biological properties has stimulated considerable
synthetic work directed toward the resorcinylic macrolides
and their analogues.
A number of attractive total syntheses of aigialomycin D
have been reported, in which assembly of the 14-membered
ring was accomplished by ring closing metathesis5 or by
macrolactonization.6 Our interest in the synthesis of aigia-
(4) (a) Ninomiya-Tsuji, J.; Kajino, T.; Ono, K.; Ohtomo, T.; Matsumoto,
M.; Shiina, M.; Mihara, M.; Tsuchiya, M.; Matsumoto, K. J. Biol. Chem.
2003, 278, 18485. (b) Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.;
Patrick, D. R.; Huber, H. E.; Goetz, M. A.; Hensens, O. D.; Zink, D. L.;
Vilella, D.; Dombrowski, A. W.; Lingham, R. B.; Huang, L. Y. J. Antibiot.
1999, 52, 1077. (c) Tanaka, H.; Nishida, K.; Sugita, K.; Yoshioka, T. Jpn.
J. Cancer Res. 1999, 90, 1139.
(5) (a) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413. (b) Yang,
Z. Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J.
Am. Chem. Soc. 2004, 126, 7881. (c) Barluenga, S.; Dakas, P. Y.; Ferandin,
Y.; Meijer, L.; Winssinger, N. Angew. Chem., Int. Ed. 2006, 45, 3951.
(1) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kangsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(2) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
(3) (a) Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper,
P. W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260. (b) Richter, K.; Buchner,
J. J. Cell. Physiol. 2001, 188, 281. (c) Schulte, T. W.; Akinaga, S.; Soga,
S.; Sullivan, W.; Stensgard, B.; Toft, D.; Neckers, L. M. Cell Stress
Chaperones 1998, 3, 100.
10.1021/ol702961v CCC: $40.75
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Published on Web 02/07/2008

lomycin D stems from our development of a catalytic
macrocyclization of ynals7,8 as well as our more recent studies
toward developing intermolecular diastereoselective cou-
plings of alkynyl silanes and R-silyloxy aldehydes.9,10
Merging these two developments from our laboratory sug-
gested that a diastereoselective macrocyclization of substrate
2 to afford product 3 could be used as a key feature in an
efficient total synthesis of aigialomycin D (1) (Scheme 1).
Scheme 2. Preparation of a Cyclization Substrate
Scheme 1. Retrosynthetic Strategy
With structure 2 in hand, we examined macrocyclization
with Et3SiH as reducing agent (5.0 equiv), Ni(COD)2 (25
mol %), IMes‚HCl (25 mol %), and t-BuOK (25 mol %)
(eq 1). Whereas conversion was sluggish in THF, addition
To pursue the line of work proposed above, we prepared
the known resorcinylic iodide 4 (Scheme 2).11 Protection as
the bis-methoxymethyl ether, followed by ester hydrolysis
and Mitsunobu esterification with alcohol 5 produced
compound 6 in 70% isolated yield. Alkenyl boronic acid 8
was then prepared from the known diol 712 by bis-silylation,
followed by treatment of the protected alkyne with cat-
echolborane and catalytic 9-BBN.13 Palladium-catalyzed
cross-coupling of boronic acid 8 with aryl iodide 6 afforded
9 in 90% yield.13b,c Compound 9 thus serves as a common
intermediate for strategies involving macrocyclization of
either a terminal alkyne or alkynyl silane. Preparation of the
alkynyl silane cyclization precursor 2 was accomplished by
treatment of 9 with LDA and TMSCl, followed by selective
monodeprotection with HF‚pyridine and Dess-Martin oxi-
dation.
of water to give a 99:1 THF:water solvent system promoted
substrate consumption at 60 °C.14 Under these conditions,
no evidence for macrocyclization was obtained; however, a
new product was observed that maintained the alkynyl silane
unit but involved disappearance of the aldehyde. Upon
evaluating the COSY, HMQC, and NOE data, it became
apparent that the major product of the cyclization was
compound 10, formed in 50% yield, with an anti relationship
of the newly formed cyclopentane diol unit and the E-
configuration of the newly formed trisubstituted alkene.
Product 10 is not derived from a reductive cyclization as
typically seen in nickel-catalyzed processes involving tri-
ethylsilane. Instead, the product is analogous to the known
nickel-catalyzed silyl triflate-promoted couplings of alde-
hydes and alkenes that involve loss of HOTf (with neutral-
ization by triethylamine) during the coupling event.15,16 This
(6) Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron:
Asymmetry 2006, 17, 1066.
(7) Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem.
Soc. 2005, 127, 13156.
(8) For other studies of ynal macrocyclizations, see: (a) Colby, E. A.;
O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297. (b)
Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 10682. (c) Oppolzer,
W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593. (d) Oppolzer, W.;
Radinov, R. N.; El-Sayed, E. J. Org. Chem. 2001, 66, 4766.
(9) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441.
(10) For diastereoselective internal alkyne-aldehyde couplings: (a)
Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7,
2937. (b) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc.
2005. (c) For applications in macrolide synthesis: Bahadoor, A. B.;
Micalizio, G. C. Org. Lett. 2006, 8, 1181. (d) Belardi, J. K.; Micalizio, G.
C. Org. Lett. 2006, 8, 2409.
(11) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991,
56, 2883.
(12) Maezaki, N.; Kojima, N.; Sakamoto, A.; Tominaga, H.; Iwata, C.;
Tanaka, T.; Monden, M.; Damdinsuren, B.; Nakamori, S. Chem. Eur. J.
2003, 9, 389.
(14) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299.
(15) For observation of metallacycle generation from an aldehyde, alkene,
and silyl triflate: Ogoshi, S.; Oka, M.-A.; Kurosawa, H. J. Am. Chem. Soc.
2004, 126, 11802.
(16) For development of the catalytic coupling of aldehydes, alkenes,
and silyl triflates: (a) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005,
127, 14194. (b) Ho, C.-Y.; Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc.
2006, 128, 5362. (c) Ng, S.-S.; Ho, C.-Y.; Jamison, T. J. Am. Chem. Soc.
2006, 128, 11513. (d) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed.
2007, 46, 782.
(13) (a) Arase, A.; Hoshi, M.; Mijin, A.; Nishi, K. Synth. Commun. 1995,
25, 1957. (b) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am.
Chem. Soc. 1985, 107, 972. (c) Frank, S. A.; Chen, H.; Kunz, R. K.;
Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691.
812
Org. Lett., Vol. 10, No. 5, 2008

non-reductive cyclization mode utilizing a silyl hydride rather
than silyl triflate is, to our knowledge, unprecedented. One
possibility is that triethylsilane modification to an electro-
philic silylating agent involving the trace water additive
occurs under the reaction conditions,14,17 which then promotes
a cyclization directly analogous to the silyl triflate procedure
previously described (Scheme 3).16 Coordination of Ni(0)
model systems involving the intermolecular coupling of
alkynyl silanes with R-silyloxy aldehydes. From our previous
study, nickel-catalyzed couplings of aldehyde 15 with alkyne
16 bearing an unbranched alkyl chain (R1 ) H) afforded
high yields of 17 with exceptional diastereoselectivity.9
However, as the examples illustrate (Scheme 4), even modest
Scheme 4. Study of Intermolecular Alkynyl Silane Couplings
Scheme 3. Mechanism of the Formation of 10
branching at the homopropargylic position led to consider-
ably lower yields, with substrates oxygenated at that position
being particularly poor substrates. Given these results, and
knowing that the internal styrene of substrate 2 was capable
of undergoing undesired five-membered-ring cyclization, we
abandoned attempts to effect the desired alkynyl silane
macrocyclization.
Although we knew from our prior studies that terminal
alkynes undergo intermolecular couplings with R-silyloxy
aldehydes with considerably lower diastereoselection than
alkynyl silanes, we nonetheless opted to examine a terminal
alkyne macrocyclization since that material was easily
accessible from our studies described above. To pursue this
strategy, selective monodesilylation of 9 with HF‚pyridine
followed by Dess-Martin oxidation afforded compound 18
in good yield (Scheme 5). Cyclization of 18 with Ni(COD)2
to the aldehyde and styrene unit of 2, with the silyloxy unit
positioned in a pseudo-equatorial position, would result in
structure 11. Oxidative cyclization would produce metalla-
cycle 12, most likely promoted by silyl activation of the
aldehyde.15,18 Ni-O bond dissociation to 13, followed by
bond rotation and â-hydride elimination, would afford
product 10.
Alternatively, direct involvement of unmodified triethyl-
silane in the reaction mechanism would require extrusion of
H2 during the cyclization event (Scheme 3). Formation of
metallacycle 12, followed by σ-bond metathesis with
Et3SiH would result in nickel hydride 14. syn-â-Hydride
elimination of 14 would afford the observed E-alkene of pro-
duct 10 and a nickel dihydride species, which could produce
H2 upon regeneration of the catalytically active Ni(0) species.
The importance of the precise aromatic ring functional group
arrangement has not been established, and the generality of
this transformation remains to be determined.19 Details of
the mechanism of the formation of 10 including the nature
of the active silyl species are under study.
Scheme 5. Macrocyclization of a Terminal Alkyne
Given the failure of the alkynyl silane of 2 to participate
in the desired macrocyclization, we examined a few simple
(17) A tentative possibility is that triethylsilane undergoes nickel-
catalyzed conversion to triethylsilanol in the presence of water to generate
the Et3SiX species depicted in Scheme 3. Control experiments illustrated
that Et3SiOH is slowly produced under the reaction conditions in the absence
of substrate 2.
(18) (a) For a detailed study of the role of the acceleration of oxidative
cyclizations by Lewis acids see: Hratchian, H. P.; Chowdhury, S. K.;
Gutie´rrez-Garc´ıa, V. M.; Amarasinghe, K. K. D.; Heeg, M. J.; Schlegel,
H. B.; Montgomery, J. Organometallics 2004, 23, 4636. (b) For an earlier
suggestion of Lewis acid catalysis of metallacycle generation see: Kimura,
M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.;
Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 397.
and IMes (25 mol % each) in THF afforded the desired
macrocycle 19 in 61% isolated yield as a 1:1 mixture of
(19) Simple intermolecular reductive couplings of benzaldehyde with
either styrene or allyl benzene are not promoted by either Et3SiH in wet
THF or Et3SiOH in dry THF with use of the catalyst and reaction conditions
used in the production of 10.
Org. Lett., Vol. 10, No. 5, 2008
813

diastereomers. Similar chemical yield and diastereoselectivity
for formation of 19 were observed with the 99:1 THF:water
solvent composition that afforded the five-membered-ring
10 from alkynyl silane 2. Deprotection of the diastereomeric
mixture with 0.5 M HCl afforded aigialomycin D (1) in 46%
yield and epimeric structure 20 in 44% yield after preparative
HPLC separation. Synthetic data for 1 were identical in all
respects with data previously reported for synthetic and
natural material.1,5,20
In summary, the total synthesis of aigialomycin D has been
accomplished by a short sequence involving a nickel-
catalyzed ynal macrocyclization. Initial attempts to ac-
complish ring closure via an alkynyl silane macrocyclization
uncovered a surprising styrene-aldehyde five-membered-
ring cyclization using triethylsilane as a promoter for a non-
reductive transformation. These studies shed light on the
scope of macrocyclizations involving different classes of
alkynes and suggest interesting new cyclization modes
available for Ni(0)/trialkylsilane reagent combinations.
Acknowledgment. Support for this work was provided
by the National Institutes of Health (GM 57014). Professor
Samuel Danishefsky (Sloan-Kettering Institute and Columbia
University) is thanked for providing copies of spectra of syn-
thetic aigialomycin D. Hasnain A. Malik (University of
Michigan) is thanked for helpful discussions and for examin-
ing the control experiments described in footnotes 17 and
19.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Additional synthetic manipulations of compounds derived from 19
were performed for the confirmation of structure 20. See the Supporting
Information for details.
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