De novo formal synthesis of (-)-apicularen A via an iterative asymmetric hydration sequence

Article abstract of DOI:10.1021/ol062595u

(Chemical Equation Presented) A de novo approach to the formal total synthesis of the macrolide natural product (-)-apicularen A has been achieved in 18 steps'from achiral starting materials. Both the absolute and relative stereochemistries of apicularen A were introduced by a Sharpless asymmetric dihydroxylation, a π-allyl-palladium catalyzed reduction, a stereoselective reduction, and a base-promoted transannulation to install the C-9 stereocenter.

Full text of DOI:10.1021/ol062595u

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6087-6090
De Novo Formal Synthesis of
)-Apicularen A via an Iterative
(−
Asymmetric Hydration Sequence
Miaosheng Li and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received October 21, 2006
ABSTRACT
A de novo approach to the formal total synthesis of the macrolide natural product (
starting materials. Both the absolute and relative stereochemistries of apicularen A were introduced by a Sharpless asymmetric dihydroxylation,
-allyl-palladium catalyzed reduction, a stereoselective reduction, and a base-promoted transannulation to install the C-9 stereocenter.
−)-apicularen A has been achieved in 18 steps from achiral
a
π
Since its isolation and structural determination by Jansen and
co-workers,1 apicularen A has attracted significant interest
due to its extremely potent antitumor activity. Apicularen A
showed remarkable cytotoxicities against nine human cancer
lines at quite low concentration (IC50 ∼ 0.1-3 ng/mL). This
activity persisted even with the multidrug resistant line, KB-
VI (IC50 ∼ 0.4 ng/mL).1b Recently, the mode of action for
the apicularens was demonstrated to occur via the selective
inhibition of the mammalian V-ATPases,2 which are respon-
sible for regulating the intracellular pH. Interestingly,
although apicularen A and B were equipotent inhibitors of
V-ATPases, apicularen A is ∼100 times more toxic to cancer
cells.1b This switch in activity controlled by glycosylation
has peaked our interest in the synthesis of both apicularen
A and B, as well as other glycosylated potential prodrugs
(Scheme 1).
attention of the synthetic community. To date, several total
syntheses of apicularen A have been completed,3 along with
several formal total syntheses and various efforts to the
unique bicyclic ring system.4 Whereas all of the previous
syntheses of the apicularen A derived their asymmetry by a
resolution or from the chiral pool, we were interested in a
de novo asymmetric approach that would use asymmetric
catalysis to install the four stereocenters in apicularen A from
achiral starting materials. Herein, we describe our successful
efforts to implement this strategy for the de novo formal
total synthesis of apicularen A.
Retrosynthetically, we envisioned apicularen A (1) and
apicularen B (2) as being derived from the known macrolide
Scheme 1. Biological Activity of (-)-Apicularen A and B2b
In addition to its fascinating biological activities, the
structural novelty of apicularen A has also attracted the
(1) (a) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075-1080. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913-919.
(2) (a) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
J. J. Pharmacol. Exp. Ther. 2001, 297, 114-120. (b) Huss, M.; Sasse, F.;
Kunze, B.; Jansen, R.; Steinmetz, H.; Ingenhorst, G.; Zeeck, A.; Wieczorek,
H. BMC Biochem. 2005, 6, 13.
10.1021/ol062595u CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/29/2006

3 and the amide side chain 4, which have been successfully
used by Maier for the synthesis of 1.5 In our strategy (Scheme
2), the macrolide 3 could be derived from macrolactone 5,
which in turn could be obtained by cross metathesis of
styrene 6 and alkene 7. The homoallylic alcohol stereochem-
istry in the differentially protected tetraol 7 was planned to
step approach was developed (Scheme 3). The route featured
the KAPA-promoted alkyne zipper reaction8 and the Ph3P-
promoted ynoate to dienoate isomerization, developed by
Trost.9 Treatment of the lithium acetylide of 10 with
paraformaldehyde gave a good yield (87%) of a propargylic
alcohol, which when exposed to the KAPA reagent readily
isomerized to the terminal heptynol 11 (79%). The primary
alcohol in 11 was easily protected as a benzyl ether (KH/
BnBr, 92%), and the terminal alkyne was carboxylated (n-
BuLi/ClCO2Et, 93%) to give ynoate 12. Exposure of
alkynoate 12 to the Rychnovsky variant of the Trost
isomerization (Ph3P/PhOH) cleanly gave dienoate 9 in
excellent yield (95%) and near perfect double bond stereo-
selectivity.
Scheme 2. Retrosynthesis of (-)-Apicularen A (1)
Scheme 3. Synthesis of Dienoate 9 and Its Bishydration
be introduced by the diastereoselective introduction of an
allyl group to the benzylidene-protected triol 8.6 Previously,
we have been successful at preparing protected 3,5-dihydroxy
esters from 2,4-dienoates.6,7 Thus, we envisioned using this
four-step asymmetric bishydration protocol for the prepara-
tion of benzylidene acetal 8 from dienoate 9.
To access useful quantities of dienoate 9, an efficient five-
We next turned to our three-step asymmetric hydration
protocol (dihydroxylation, carbonate formation, and pal-
ladium-catalyzed reduction) to convert dienoate 9 into
δ-hydroxyenoate 14. In practice, dienoate 9 was dihydroxy-
lated under the Sharpless conditions to give a diol, which
(3) (a) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron
Lett. 2001, 42, 1217-1220. (b) Nicolaou, K. C.; Kim, D. W.; Baati, R.
Angew. Chem., Int. Ed. 2002, 41, 3701-3704. (c) Su, Q.; Panek, J. S. J.
Am. Chem. Soc. 2004, 126, 2425-2430. (d) Petri, A. F.; Bayer, A.; Maier,
M. E. Angew. Chem., Int. Ed. 2004, 43, 5821-5823.
(4) (a) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J.
K. Tetrahedron Lett. 2001, 42, 5549-5552. (b) Lewis, A.; Stefanuti, I.;
Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol. Chem. 2003, 1,
104-116. (c) Graetz, B. R.; Rychnovsky, S. D. Org. Lett. 2003, 5, 3357-
3360. (d) Ku¨hnert, S.; Maier, M. E. Org. Lett. 2002, 4, 643-646. (e) Hilli,
F.; White, J. M.; Rizzacasa, M. A. Tetrahedron Lett. 2002, 43, 8507-
8510. (f) Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289-
1292.
(6) (a) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 2777-2780.
(b) Tosaki, S. Y.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett. 2003,
5, 495-498. (c) Smith, C. M.; O’Doherty, G. A. Org. Lett, 2003, 5, 1959-
1962.
(7) (a) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049-1052.
(b) Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 3987-3990.
(8) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891-
892. (b) Kimmel, T.; Becker, D. J. Org. Chem. 1984, 49, 2494-2496.
(9) (a) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659-2660.
(b) Trost, B.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933-7935.
(5) Although Maier’s endgame seemed ideal for our purpose, his use of
a stoichiometric amount of (CF3CO2)2Hg to set the transannular ether bridge
in macrolide 3 (see ref 3d) was viewed as needing to be replaced with an
environmentally more benign yet equally stereoselective process.
6088
Org. Lett., Vol. 8, No. 26, 2006

was cyclized into carbonate 13 in good overall yield (78%).
Exposure of carbonate 13 to the palladium(0)-catalyzed
reduction conditions (HCO2H/Et3N) provided δ-hydroxy
enoate 14 in good yield (90%). With the initial chiral center
introduced in δ-hydroxy enoate 14, the remaining double
bond was diastereoselectively hydrated and protected to form
the benzylidene acetal 8 using Evans’ procedure (PhCHO/
t-BuOK, 59%).10 The ester 8 was then converted into
Weinreb amide 16 (ClMgN(OMe)Me) in 89% yield (Scheme
3).11
high yield (88%).12 Finally, the alcohol in 18 was protected
as a benzyl ether to provide the cross metathesis precursor
7.
Scheme 5. Synthesis of Salicylate 23 via Cross-Metathesis
Reaction
Scheme 4. Synthesis of Intermediate 7 via Stereoselective
Reduction or Asymmetric Allylation
We next looked at the synthesis of styrene fragment 6
(Scheme 5). Selective monomethylation13 of commercially
available salicylic acid 21 (DBU/MeI, 82%) was followed
by treatment of the remaining phenol group with Tf2O to
give triflate 22 (89%). The Molander14 trifluoroborate variant
of the Suzuki-Miyaura15 coupling was then used to convert
the triflate 22 to the styrene 6 (91%).
The merging of the two alkenes 6 and 7 via an olefin cross
metathesis reaction was then investigated. Treatment of 6
(2 equiv) and 7 with the second-generation Grubbs reagent
(5% Grubbs II)16 provided the cross metathesis product 23
in good yield (86%) and high trans stereoselectivity (Scheme
5).
In preparation for the macrolactone assembly (Scheme 6),
the benzylidene protection group in 23 was removed with
mildly acidic conditions (4:1 AcOH/H2O, 80 °C) to form
diol 24 (82%).17 Then, the methyl ester 24 was hydrolyzed
with LiOH.18 Applying a modified Yamaguchi lactonization19
procedure to the seco acid 25 selectively produced the 12-
membered macrolactone 6 (67%) over the 10-membered ring.
With the macrolactone established, we next looked for an
Exposure of Weinreb amide 16 to allylmagnesium chloride
cleanly formed the ketone 17 in 86% yield (Scheme 4).
Reduction of the ketone under various conditions resulted
in different ratios of diastereomers 18 and 19. Our optimized
conditions used L-selectride, which produced homoallylic
alcohols 18 and 19 in a ratio of 7:1. The two diastereomers
18 and 19 were separable by careful chromatography. The
undesired isomer 19 can be recycled by a Dess-Martin
oxidation back to ketone 17 (94%). Alternatively, treatment
of aldehyde 20, which was formed by Dibal-H reduction of
ester 8 (92%), with the Leighton reagent formed the desired
homoallylic alcohol 18 in high diastereoselectivity (97:3) and
(12) Previous approaches to apicularen A used the Brown AllylBIpc2
reagent; see: refs 3b, 3c, 4b, and 4f. We have found that the Leighton
reagent works equally well in terms of stereochemical outcome and allows
for a significantly simpler product isolation procedure. See: Kubota, K.;
Leighton, J. Angew. Chem., Int. Ed. 2003, 42, 946-948.
(13) Mal, D. Synth. Commun. 1986, 16, 331-335.
(14) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107-109.
(15) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(17) Efforts to lactonize diol 24 under various basic conditions (NaH,
KH, or t-BuOK) caused either decomposition of the starting material or no
reaction.
(10) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-
2453.
(11) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. Tetrahedron Lett. 1995, 36, 5461-5464.
(18) Petri, A. F.; Kuhnert, S. M.; Scheufler, F.; Maier, M. E. Synthesis
2003, 6, 940-955.
(19) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993. (b) Mulzer, J.; Mareski, P.
A.; Buschmann, J.; Luger, P. Synthesis 1992, 1, 215-234.
Org. Lett., Vol. 8, No. 26, 2006
6089

conditions and in good yield (83%).22 The desired target
macrolide 3 was physically (mp, optical rotation) and
spectroscopically (1H NMR, 13C NMR, IR, and MS) identical
to the material previously reported by Maier.3d
Scheme 6. Completion of the Formal Synthesis of
(-)-Apicularen A
In conclusion, a short formal de novo asymmetric synthesis
of apicularen A has been developed. This highly enantio-
and diastereocontrolled route illustrates the utility of our
dienoate asymmetric hydration strategy for natural product
synthesis. In addition, this approach features a cross me-
tathesis reaction, a Yamaguchi lactonization, and a base-
mediated transannular etherification. Further application of
this approach to the synthesis of other members of this class
of compounds and biological testing are ongoing.
Acknowledgment. We are grateful to Dr. Joseph Dough-
erty (WVU) for initial exploratory work, to the NIH
(GM63150) and NSF (CHE-0415469) for the support of our
research program, and to NSF-EPSCoR (0314742) for a 600
MHz NMR and an LTQ-FT mass spectrometer at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds
can be found in the Supporting Information. This material
is available free of charge via the Internet at http://pubs.acs.org.
alternative to the Maier transannular etherification.3d After
numerous fruitless investigations, including Au(I)20 and Pt-
(II)21 catalysts, we eventually found that the tetrahydropyran
could be formed under basic (t-BuOK, 1 equiv) conditions.
Significantly, only one diastereomer was formed under these
OL062595U
(22) The high diastereoselectivity associated with this transannular
cyclization (5 to 3) has precedent in the work of Rizzacasa. See refs 4e
and 4f. Our results suggest the possibility of an olefin migration preceding
cyclization, in the Rizzacasa model study, instead of the proposed 6-endo-
dig cyclization. See ref 4e.
(20) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966-6967.
(21) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536-9537.
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Org. Lett., Vol. 8, No. 26, 2006