Transition-metal-catalyzed synthesis of aspergillide B: An alkyne addition strategy

Article abstract of DOI:10.1021/ol300200m

A catalytic enantioselective formal total synthesis of aspergillide B is reported. This linchpin synthesis was enabled by the development of new conditions for Zn-ProPhenol catalyzed asymmetric alkyne addition. This reaction was used in conjunction with ruthenium-catalyzed trans-hydrosilylation to affect the rapid construction of a late-stage synthetic intermediate of aspergillide B to complete a formal synthesis of aspergillide B in a highly efficient manner.

Full text of DOI:10.1021/ol300200m

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1322–1325
Transition-Metal-Catalyzed Synthesis
of Aspergillide B: An Alkyne
Addition Strategy
Barry M. Trost* and Mark J. Bartlett
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received January 25, 2012
ABSTRACT
A catalytic enantioselective formal total synthesis of aspergillide B is reported. This linchpin synthesis was enabled by the development of new
conditions for Zn-ProPhenol catalyzed asymmetric alkyne addition. This reaction was used in conjunction with ruthenium-catalyzed trans-
hydrosilylation to affect the rapid construction of a late-stage synthetic intermediate of aspergillide B to complete a formal synthesis of
aspergillide B in a highly efficient manner.
The aspergillides are a family of bioactive natural pro-
ducts originally derived from the marine fungus aspergillus
ostianus.1 Aspergillide A, B, and C, shown in Figure 1,
share common macrolactone and pyran motifs but differ
with respect to the stereochemistry at C3 and the unsatura-
tion present in the pyran ring.2
(human promyelocytic leukemia), MDA-MB-231 (human
breast carcinoma), and HT1080 (human fibrosarcoma) cell
lines.3 These properties, along with the challenging struc-
tural features present, have motivated a number of groups
to pursue the synthesis of aspergillides AꢀC.4,5 Our interest
in the aspergillides stems from the potential application of
our zinc-catalyzed asymmetric alkynylation and ruthenium-
catalyzed trans-hydrosilylation-desilylation methodologies
ꢀ
(3) Dıaz-Oltra, S.; Angulo-Pachon, C. A.; Murga, J.; Falomir, E.;
Carda, M.; Marco, J. A. Chem.;Eur. J. 2011, 17, 675.
(4) For previous syntheses of aspergillide B, see: (a) Nagasawa, T.;
Kuwahara, S. Biosci. Biotechnol. Biochem. 2009, 73, 1893. (b) Dıaz-
ꢀ
Oltra, S.; Angulo-Pachon, C. A.; Kneeteman, M. N.; Murga, J.; Carda,
M.; Marco, J. A. Tetrahedron Lett. 2009, 50, 3783. (c) Liu, J.; Xu, K.; He,
J.; Zhang, L.; Pan, X.; She, X. J. Org. Chem. 2009, 74, 5063. (d) Fuwa,
H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848. (e) Mueller
Hendrix, A. J.; Jennings, M. P. Tetrahedron Lett. 2010, 51, 4260. (f)
Kanematsu, M.; Yoshida, M.; Shishido, K. Angew. Chem., Int. Ed. 2011,
50, 2618. (g) Kanematsu, M.; Yoshido, M.; Shishido, K. Tetrahedron
Lett. 2011, 52, 1372 and also ref 2a.
(5) For previous syntheses of aspergillides A and C, see: Nagasawa,
T.; Kuwahara, S. Org. Lett. 2009, 11, 761. Panarese, J. D.; Waters, S. P.
Org. Lett. 2009, 11, 5086. Sabitha, G.; Reddy, D. V.; Rao, A. S.; Yadav,
J. S. Tetrahedron Lett. 2010, 51, 4195. Kobayashi, H.; Kanematsu, M.;
Yoshida, M.; Shishido, K. Chem. Commun. 2011, 47, 7440. Kanematsu,
M.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2011, 52, 1372. Izuchi,
Y.; Kanomata, N.; Koshino, H.; Hongo, Y.; Nakata, T.; Takahashi, S.
Tetrahedron: Asymmetry 2011, 22, 246. Nagasawa, T.; Nukada, T.;
Figure 1. Aspergillide family of natural products.
These compounds exhibit cytotoxicity toward a
number of different cancer cell lines including, HL-60
(1) Kito, K.; Ookura, S. Y.; Namikoshi, M.; Ooi, T.; Kusumi, T. Org.
Lett. 2008, 10, 225.
(2) The structures of aspergillide A and B were revised in 2009 as a
result of synthetic work by Hande and Uenishi. (a) Hande, S. M.;
Uenishi, J. Tetrahedron Lett. 2009, 50, 189. The revised structures were
later confirmed when X-ray crystal structures of the corresponding
m-bromobenzoates were reported. (b) Ookura, R.; Kito, K.; Saito, Y.;
Kusumi, T.; Ooi, T. Chem. Lett. 2009, 38, 384.
ꢀ~
ꢀ
Kuwahara, S. Tetrahedron 2011, 67, 2882. Zuniga, A.; Perez, M.;
ꢀ
ꢀ
Gonalez, M.; Gomez, G.; Fall, Y. Synthesis 2011, 20, 3301. Srihari, P.;
Sridhar, Y. Eur. J. Org. Chem. 2011, 6690.
r
10.1021/ol300200m
Published on Web 02/22/2012
2012 American Chemical Society

(Scheme 1) to provide access to two chiral allylic alcohol
moieties that would ultimately lead to an efficient synthesis
of aspergillide B.
reactions require the use of 2.8 equiv of alkyne and
2.95 equiv of Me2Zn to obtain high levels of enantioselec-
tivity.8 At the outset, we recognized that the use of a super-
stoichiometric amount of alkyne (ꢀ)-9 was particularly
inefficient, given that this chiral intermediate is prepared
using a multistep synthesis. Consequently, the use of a
stoichiometric quantity of alkyne in ProPhenol-catalyzed
alkynylations was investigated.
Scheme 1. Sequential Application of Asymmetric Alkynylation
and Ru-Catalyzed Hydrosilylation
Using 1.2 equiv of alkyne (()-9,9 alkynylation of ali-
phatic aldehyde 11a resulted in only a 22% yield of the
desired product in 54% ee (entry 1, Table 1).10 The
traditional superstoichiometric conditions provided only
modest improvements in yield and enantioselectivity
(entreis 2, 3). Low yields of the desired product 12a were
primarily a consequence of competing aldol reactions.11
The predominance of this side reaction led to the hypoth-
esis that incomplete formation of the alkynylzinc nucleo-
phile may be leaving significant amounts of basic
dimethylzinc in the reaction mixture. Consequently, we
examined a number of additives and methods that have
been shown to facilitate the formation of alkynylzinc
nucleophiles.12 The use of N-methylimidazole (NMI),
DMSO, and DMF resulted in lower yields of the desired
product, 12a (entries 4ꢀ6). Increasing the alkyne/
Me2Zn/(S,S)-4 premix time and catalyst loading provided
improved yields of propargylic alcohol 12b (entries 7, 8).
While the excess alkyne could be recovered quantitatively,
this inefficiency along with the moderate yield and enan-
tioselectivity prompted the investigation of the analogous
unsaturated aldehyde, 11c. The ProPhenol-catalyzed ad-
dition of (()-9 to11c provideda muchimproved 84%yield
and 95% ee (entry 9). Reducing the stoichiometry of the
alkyne to either 1.2 or 1.0 equiv provided a lower yield,
although excellent ee was maintained in both cases (entries
10, 11). The moderate yield was presumably a consequence
of poor reactivity, and a solution to this problem was
This alkyne-based strategy envisioned to synthesize
aspergillide B is outlined in Scheme 2. Retrosynthetic
Scheme 2. Retrosynthetic Analysis of Aspergillide B
disconnection of the macrolactone leads back to diester
6, a late-stage intermediate used in a previous synthesis.4d
Diastereoselective formation of the pyran ring was ex-
pected to arise from intramolecular oxy-Michael addition
of the C8 hydroxyl group and the pendant R,β-unsaturated
ester in 7. It was anticipated that the two chiral allylic
alcohol moieties could be prepared using Ru-catalyzed
hydrosilylation of the corresponding propargylic alcohols.
Lastly, asymmetric alkyne addition would be used to
access the aforementioned propargylic alcohols via sepa-
rate addition of (S)-hept-6-yn-2-yl benzoate ((ꢀ)-9) and
methyl propiolate (10) to each end of a butane dialdehyde
equivalent 11 which is serving as a linchpin.
The invention of the ProPhenol ligand 4 has led to the
development of a number of catalytic enantioselective
transformations, including a direct aldol reaction.6 The
ProPhenol ligand also facilitates the addition of a variety
of alkynes to aryl and R,β-unsaturated aldehydes in
excellent yield and enantioselectivity.7 Typically, these
(8) For a recent review on the enantioselective addition of alkynes to
aldehydes, see: Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351,
963.
(9) (()-9 was prepared in 4 steps from 3-methyl cyclohexenone. See
Supporting Information for experimental details. Le Drain, C.; Greene,
A. E. J. Am. Chem. Soc. 1982, 104, 5473.
(10) The major method which can avoid such excesses is that of
Carreira, but sometimes that too will require them. See: Frantz, D.;
€
Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806. Frantz,
€
D.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
33, 373. Anand, N.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605.
Reber, S.; Knoepfel, T. F.; Carreira, E. M. Tetrahedron 2003, 6813. Also
see Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524. Yue, Y.;
Turlington, M.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 8681 and ref
12c.
(11) The cross aldol side reaction produces a complex mixture of
oligomers. The aldol side product A was isolated in 19% yield as a
mixture of diastereomers from entry 1 (Table 1). HRMS-ESI (m/z):
[MþH]þ calculated for C34H61O6Si2, 621.4001; found, 621.3996.
(6) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2009, 122, 12003. For
subsequent applications of this ligand, see: Trost, B. M.; Hitce, J. J. Am.
Chem. Soc. 2009, 131, 4572 and references cited therein.
(7) (a) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8. (b) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am.
Chem. Soc. 2010, 132, 5186.
(12) For selected discussions on the use of additives to facilitate
alkynylzinc formation, see: (a) Gao, G.; Xie, R.-G.; Pu, L. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5417. (b) Yang, F.; Xi, P.; Yang, L.; Lan, J.;
Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457. (c) Du, Y.; Turlington, M.;
Zhou, X.; Pu, L. Tetrahedron Lett. 2010, 51, 5024.
Org. Lett., Vol. 14, No. 5, 2012
1323

found in the use of fumaraldehyde dimethyl acetal (11d).
The inductive effects of the dimethyl acetal create a more
Scheme 3. Proposed Mechanism for ProPhenol-Catalyzed
Alkyne Addition
Table 1. Optimization of Alkyne Addition
from undesired aldol side reactions and typically only
produce moderate yields of the desired propargylic alco-
hol. Methyl propiolate, a more acidic alkyne, has been
shown to give significantly higher yields in addition to
enolizable aldehydes under the standard conditions.15
The synthesis of aspergillide B commenced with the
preparation of chiral alkyne (ꢀ)-9 (Scheme 4),16 taking
Scheme 4. Preparation of Alkyne (ꢀ)-9
a All reactions were run on 0.1625 mmol scale using the standard
ProPhenol alkynylation procedure and at a concentration of 0.5 M with
respect to alkyne unless otherwise noted. b Isolated yield. c Enantiomeric
excess determined by chiral HPLC analysis. d Enantiomeric excess
determined by 1H NMR analysis of the corresponding (S)-methyl
mandelate. e Reaction performed with (ꢀ)-9 on a 0.45 mmol scale.
TPPO = triphenylphosphine oxide, NMI = N-methylimidazole.
a ee determined by chiral HPLC analysis of (ꢀ)-9.
electrophilic aldehyde, and as a result, the desired pro-
pargylic alcohol 12d was obtained in 82% yield (entry 12).
The results in Table 1 provide a number of new insights
into the proposed reaction mechanism for ProPhenol-
catalyzed alkyne addition (Scheme 3). Incomplete forma-
advantage of the Noyori asymmetric hydrogenation17 of
ynone 14 and the alkyne zipper reaction of 16 to 17.
Alkynylation of fumaraldehyde dimethyl acetal (11d)18
using just 1 equiv of alkyne (ꢀ)-9 and 10 mol % of the
(S,S)-ProPhenol ligand provided 12d in 82% yield and
90% de (Scheme 5).19 Alkyne trans-hydrosilylation
using benzyldimethylsilane (BDMS-H) and 2 mol %
1
tion of the alkynylzinc nucleophile was confirmed by H
NMR analysis of a standard premix with 1-octyne, Me2Zn
and (S,S)-4 in toluene-d8.13 Despite the entropically fa-
vored release of methane gas, deprotonation of the term-
inal alkyne was not observed in the absence of the
ProPhenol ligand. The presence of significant amounts of
dimethylzinc in the reaction mixture appears to have little
effect on the outcome of alkyne additions to R,β-unsatu-
rated aldehydes.14 However, enolizable aldehydes suffer
(15) Trost, B. M.; Burns, A. C.; Bartlett, M. J.; Tautz, T.; Weiss,
A. H. J. Am. Chem. Soc. 2012, 134, 1474.
(16) Parenty, A.; Campagne, J.-M.; Aroulanda, C.; Lesot, P. Org.
Lett. 2002, 4, 1663.
(17) Matsumara, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738.
(18) Fumaraldehyde dimethyl acetal (11d) was prepared in one step
from commercially available fumaraldehyde bis(dimethyl acetal).
Coppola, G. M. Synthesis 1984, 1021.
(19) For examples of the few methodologies capable of efficient
Zn-catalyzed asymmetric alkynylation with <1.2 equiv of alkyne, see:
Kojima, N.; Nishijima, S.; Tsuge, K.; Tanaka, T. Org. Biomol. Chem. 2011,
9, 4425. Anand, N.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(13) Approximately 28% conversion to the alkynylzinc species was
observed based on integration of the peaks at 0.29 (s, 3H, CH3ZnCtC)
and ꢀ0.58 ppm (s, 6H, (CH3)2Zn).
(14) Minor amounts of methyl addition side products have been
isolated in only a small number of cases; see ref 7a for details.
1324
Org. Lett., Vol. 14, No. 5, 2012

Scheme 5. First Alkyne Addition in the Synthesis of Aspergillide B
Scheme 6. Formal Synthesis of Aspergillide B
a dr determined by chiral HPLC analysis.
(77% brsm) over 2 steps.24 Compound 6 can be trans-
formed into aspergillide B in 3 additional steps.4d
In summary, an enantioselective formal total synthesis
of aspergillide B has been accomplished using sequential
Zn-catalyzed alkyne addition and Ru-catalyzed trans-
hydrosilylationꢀdesilylation to access E-alkenes. The
hydrosilylationꢀdesilylation protocol not only pro-
vides the E-geometry but also allows chemoselective
differentiation of the two double bonds in a susequent
hydrogenation step. The development of new conditions
for the Zn-ProPhenol catalyzed alkynylation has resulted
in excellent yield and enantioselectivity using just 1 equiv
of alkyne. Further research into the use of enolizable
aldehydes in this methodology is currently underway.
of Cp*Ru(CH3CN)3PF6 provided vinyl silane 18, regio-
selectively.20 Hydrosilylation of propargylic alcohols
under these conditions typically results in silylation at the
β-position. The dramatic reversal in regioselectivity is
thought to be a consequence of a coordinative interaction
between ruthenium and the electron-poor alkene. The
presence of the silicon on one of the double bonds provides
a key for their differentiation toward hydrogenation. The
disubstituted olefin of allylic alcohol 18 was then chemo-
selectively hydrogenated using Wilkinson’s catalyst and silyl
protected to give 19.21 Hydrolysis of the dimethyl acetal was
performed under mild acid-catalyzed conditions, providing
the desired aldehyde 20 for the second alkyne addition.
ProPhenol-catalyzed addition of methyl propiolate (10)
to aldehyde 20 provided the desired propargylic alcohol
21 in 71% yield as a 5.2:1 mixture of diastereomers
(Scheme 6).22 Protection of the propargylic alcohol was
followed by a chemoselective alkyne reduction using our
hydrosilylation/protodesilylation protocol for formation
of E-double bonds.23 The basic reaction conditions used
for this transformation resulted in spontaneous intramo-
lecular oxy-Michael addition. Consequently, the desired
2,6-anti tetrahydropyran 6 was isolated in 38% yield
Acknowledgment. We thank the National Science
Foundation (CHE-0846427) and the National Institutes
of Health (GM-33049) for their generous support of our
programs. M.J.B. thanks Victoria University of Welling-
ton for the provision of a Ph.D. scholarship. We also thank
Unicore for a generous gift of ruthenium salts.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
(20) Trost, B. M.; Ball, Z. T.; Joge, T. Angew. Chem., Int. Ed. 2003,
115, 3537. Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644.
(21) Young, J. F.; Osborn, J. A.; Jardine, F. H.; Wilkinson, G. Chem.
Commun. 1965, 131. O’Connor, C.; Wilkinson, G. J. Chem. Soc. A 1968,
2665.
(24) The 2,6-syn diastereomer could not be observed by 1H NMR of
the crude reaction mixture. Given that 88% yield of 6 was obtained, the
diastereomeric ratio is >7.3:1, anti/syn.
(22) Diastereomeric ratio was determined by 1H NMR of the cyclized
compound 6.
€
(23) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124,
7922.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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