Polyol synthesis with β-Oxyanionic alkyllithium Reagents: Syntheses of aculeatins A, B, and D

Article abstract of DOI:10.1021/ol901623h

Synthesis of ketone aldol products using a non-aldol route was developed. The β-phenylthio alcohols were prepared from optically pure oxiranes. Deprotonation and reductive lithiation generated the key intermediate, a β-oxyanionic alkyllithium reagent. Addition to a Weinreb amide produced the β-hydroxy ketone In >90% yield using only 1.5 equiv of the phenylthio alcohol. Stereoselective reduction of the ketone led to either the syn-or anti-1,3-diol. This simple, convergent sequence was used to prepare aculeatins A, B, and D from a common intermediate

Full text of DOI:10.1021/ol901623h

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4220-4223
Polyol Synthesis with ꢀ-Oxyanionic
Alkyllithium Reagents: Syntheses of
Aculeatins A, B, and D
Viengkham Malathong and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received July 15, 2009
ABSTRACT
Synthesis of ketone aldol products using a non-aldol route was developed. The ꢀ-phenylthio alcohols were prepared from optically pure
oxiranes. Deprotonation and reductive lithiation generated the key intermediate, a ꢀ-oxyanionic alkyllithium reagent. Addition to a Weinreb
amide produced the ꢀ-hydroxy ketone in >90% yield using only 1.5 equiv of the phenylthio alcohol. Stereoselective reduction of the ketone
led to either the syn- or anti-1,3-diol. This simple, convergent sequence was used to prepare aculeatins A, B, and D from a common intermediate.
Ketone aldol reactions are very useful for the construction of
polyacetate and polypropionate natural products.1 They allow
Scheme 1.
Aldol Product from ꢀ-Oxyanionic Alkyllithium Reagents3
carbon chains to be joined together to make much larger
structures and are often the key disconnection in the retrosyn-
thesis.2 We recently reported an alternative sequence (Scheme
1) in which a ꢀ-oxyanionic alkyllithium reagent (2) was
prepared and added to a Weinreb amide (3) to produce a
ꢀ-hydroxy ketone (4). The sequence was used to prepare most
of the carbon skeleton of amphidinol 3.3 This strategy nicely
complements the traditional aldol sequence and offers several
advantages, including the direct introduction of the stereogenic
center from a chiral building block. Other groups have begun
to adopt this method.4 One limitation is the use of a large excess
of the alkyllithium reagent (3-4 equiv). In this Letter, we have
(1) (a) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237–4313.
(b) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506–
7525.
reinvestigated the generation of ꢀ-oxyanionic alkyllithium
reagents and demonstrated that with normal precautions to
exclude moisture, as little as 1.5 equiv of the alkyllithium
precursor results in excellent yield of the coupled product. The
utility of the improved procedure was demonstrated in a unified
synthetic approach to aculeatins A, B, and D.
(2) For recent examples of strategic aldol reactions in synthesis, see:
(a) Evans, D. A.; Kvaerno, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.;
Mulder, J. A.; Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am.
Chem. Soc. 2008, 130, 16295–16309. (b) Dunetz, J. R.; Julian, L. D.;
Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 16407–16416.
(c) Bock, M.; Dehn, R.; Kirschning, A. Angew. Chem., Int. Ed. 2008, 47,
9134–9137. (d) Lu, L.; Zhang, W.; Carter, R. G. J. Am. Chem. Soc. 2008,
130, 7253–7255. (e) Lanners, S.; Norouzi-Arasi, H.; Salom-Roig, X. J.;
Hanquet, G. Angew. Chem., Int. Ed. 2007, 46, 7086–7089.
(3) Huckins, J. R.; De Vicente, J.; Rychnovsky, S. D. Org. Lett. 2007,
9, 4757–4760.
The ꢀ-oxyanionic alkyllithium reagents have been prepared by
(4) Kartika, R.; Gruffi, T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047–
5050.
10.1021/ol901623h CCC: $40.75
Published on Web 08/19/2009
 2009 American Chemical Society

a number of methods that include mercury-lithium exchange5 and
reductive lithiation of chlorohydrins,6 oxiranes,7 and ꢀ-phenylthio
alcohols.8 A few complex ꢀ-oxyanionic alkyllithium reagents have
been prepared by reduction of oxiranes,7,9 but these reagents have
not been used widely in synthesis. The ꢀ-phenylthio alcohols
are typically prepared by nucleophilic opening of oxiranes;
thus the most direct route to the alkyllithium reagents would
be by direct reduction of oxiranes.
reduced and added to aldehydes with excellent results,7 in
our hands they did not add to a Weinreb amide efficiently.
Table 1. Optimized Coupling Between ꢀ-Oxyanionic
Alkyllithium and Electrophiles
Reductive lithiation and coupling of a model oxirane is
presented in Scheme 2. The reductive lithiation of oxirane 5
Scheme 2
.
Aldol Products Formed by Reductive Lithiation of
Oxiranes
generated ꢀ-oxyanionic alkyllithium 6, which coupled only
poorly with the Weinreb amide 7 to give the expected
product in 34% yield. Both Cohen7b and Yus7c reported good
yields for reductive lithiation of oxiranes followed by
addition to aldehydes. Presumably the issue is not with the
generation of the anion but rather with the coupling efficiency
with the much less reactive Weinreb amide under these
conditions.10 We considered the possibility that added
thiophenol might catalyze the reduction of the oxirane or
stabilize the alkyllithium agent. The addition of 20 mol %
of thiophenol to the reaction did neither and actually resulted
in a lower yield of product. Although oxiranes have been
a Compound 9 (100 mg) was titrated with n-BuLi with 1,10-phenan-
throline as an indicator at 0 °C. The alkoxide was reduced with LiDBB at
-78 °C for 1 h, followed by addition of the electrophile and stirring for
12 h. Isolated yields are reported and ranges are given for multiple runs.
b The mixture was stirred for 2 h after addition of the electrophile. c The
syn- and anti-diols were isolated as a 47:53 mixture of diastereomers.
Lithiation of ꢀ-phenylthio alcohols was much more effective,
Table 1. The model phenylthio alcohol 9 was prepared from
oxirane 5 using catalytic LiClO4.11 The alcohol 9 was dissolved
in THF with 1,10-phenanthroline and titrated with n-BuLi to
prepare the alkoxide and to remove all traces of water. The
reductive lithiation was carried out with LiDBB (lithium 4,4′-
di-tert-butylbiphenylide, Freeman’s reagent)12 at -78 °C in
THF. The first entries in Table 1 show the addition to Weinreb
amide 7. With 1.5 equivalents of 9, the product 8 was isolated
in excellent yield. Reducing the ratio of phenylthio alcohol 9
and Weinreb amide 7 to 1:1 gave 68-85% of the product, a
surprisingly good outcome.13 One reaction using the phenylthio
(5) (a) Barluenga, J.; Fananas, F. J.; Yus, M. J. Org. Chem. 1979, 44,
4798–4801. (b) Barluenga, J.; Fananas, F. J.; Yus, M. J. Org. Chem. 1981,
46, 1281–1283.
(6) (a) Barluenga, J.; Florez, J.; Yus, M. J. Chem. Soc., Chem. Commun.
1982, 1153–1154. (b) Barluenga, J.; Florez, J.; Yus, M. J. Chem. Soc., Perkin
Trans. 1 1983, 3019–3026. (c) Najera, C.; Yus, M.; Seebach, D. HelV. Chim.
Acta 1984, 67, 289–300.
(7) (a) Bartmann, E. Angew. Chem., Int. Ed. 1986, 25, 653–655. (b)
Cohen, T.; Jeong, I. H.; Mudryk, B.; Bhupathy, M.; Awad, M. M. A. J.
Org. Chem. 1990, 55, 1528–1536. (c) Bachki, A.; Foubelo, F.; Yus, M.
Tetrahedron: Asymmetry 1996, 7, 2997–3008. (d) Dorigo, A. E.; Houk,
K. N.; Cohen, T. J. Am. Chem. Soc. 2002, 111, 8976–8978. (e) Grobelny,
Z. Eur. J. Org. Chem. 2004, 2004, 2973–2982.
(8) (a) Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett. 1997, 38,
4837–4840. (b) Foubelo, F.; Gutierrez, A.; Yus, M. Synthesis 1999, 503–
514.
(10) Reductive lithiation of oxirane 5 with LiDBB and quenching with
1.5 equiv of isobutyraldehyde resulted in 59% of compound 12. In a side-
by-side reaction, quenching the alkyllithium with 1.0 equiv of Weinreb
amide resulted in <20% of ketone 8, accompanied by a significant amount
of allylbenzene.
(11) Azizi, N.; Saidi, M. R. Catal. Commun. 2006, 7, 224–227.
(12) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–
1930.
(9) (a) Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo, F.; Yus, M.
Tetrahedron: Asymmetry 2000, 11, 493–517. (b) Falvello, L. R.; Foubelo,
F.; Soler, T.; Yus, M. Tetrahedron: Asymmetry 2000, 11, 2063–2066. (c)
Yus, M.; Soler, T.; Foubelo, F. Tetrahedron: Asymmetry 2001, 12, 801–
810. (d) Yus, M.; Maci, B.; Guˆmez, C.; Soler, T.; Falvello, L. R.; Fanwick,
P. E. Tetrahedron 2005, 61, 3865–3871
.
Org. Lett., Vol. 11, No. 18, 2009
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alcohol 9 as the limiting reagent only gave 56%, but this result
could certainly be improved upon. The use of a morpholine
amide 10 was also effective, but resulted in slightly diminished
yields compared with the Weinreb amide. Aldehydes are much
better electrophiles, and generated the 1,3-diol 12 in 92% yield
using phenylthio alcohol 9 as the limiting reagent. As expected,
the 1,3-diol was produced as a 1:1 mixture of diastereomers,
underscoring the need for an alternative strategy to introduce the
second stereogenic center. Using a modest excess (1.5 equiv) of
the phenylthio alcohol led to >90% yields of the desired aldol
product.
The aculeatins A-D have attracted significant attention
from synthetic chemists. They were isolated by Heilmann
from the rhizomes of Amomum aculeatum and were reported
to have significant antiprotozoal and antiplasmodial activity.14
In addition, they show low to submicromolar activity against
KB cell lines, and aculeatin A was found to be active against
MCF-7 (human breast cancer cells) using an in vivo hollow
fiber assay.15 The synthesis of racemic aculeatin A and B
was first reported by Wong,16 followed by enantioselective
syntheses by Marco.17 Synthesis of aculeatin D was first
reported by Baldwin.18 A number of other syntheses have
followed, all of which use a final phenol oxidation to
assemble the spirocyclic system.19 The aculeatins are inter-
esting synthetic targets and promising lead compounds in a
number of important therapeutic areas.
Figure 1. Structures and unified retrosynthetic analyses of aculeatins
A, B, and D.
the planned syntheses are Weinreb amide 16 and the optically
pure phenylthio alcohol 17.
The retrosynthetic analysis of the aculeatins is presented
in Figure 1. Aculeatin A and B are epimeric at the acetal
center, with A having the thermodynamically favored
configuration.17b Similarly, aculeatin D is thermodynamically
disfavored with respect to its C6 epimer. The final step is a
biomimetic cyclization using a dithiane in place of the C6
ketone.16 syn-1,3-Diol 13 is the precursor to A and B,
whereas anti-1,3-diol 14 is the precursor to aculeatin D. Both
diols share a common 2R-configuration (aculeatin number-
ing), and they will be derived from the common intermediate
15 by stereoselective reduction. The key building blocks for
Synthesis of the building blocks and an initial attempt at the
coupling reaction are shown in Scheme 3. Dithiane 18 was
Scheme 3
.
Synthesis of Aculeatin Precursors and an Attempted
Coupling Reaction
(13) The reaction was quenched with NH4Cl (aq) and did not show any
indication of racemization or retro-aldol side reactions. When the reaction
was quenched with MeOH-d4, we observed partial deuteration at the
positions adjacent to the ketone but not at the benzylic position. Traces of
retro-aldol product may be present, but apparently the forward aldol reaction
is unfavorable. In cases where the yields of 8 were modest, most of the
unreacted Weinreb amide 7 was recovered.
(14) (a) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. HelV.
Chim. Acta 2000, 83, 2939–2945. (b) Heilmann, J.; Brun, R.; Mayr, S.;
Rali, T.; Sticher, O. Phytochemistry 2001, 57, 1281–1285. (c) Salim, A. A.;
Su, B.-N.; Chai, H.-B.; Riswan, S.; Kardono, L. B. S.; Ruskandi, A.;
Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. Tetrahedron Lett.
2007, 48, 1849–1853.
(15) Chin, Y.-W.; Salim, A. A.; Su, B.-N.; Mi, Q.; Chai, H.-B.; Riswan,
S.; Kardono, L. B. S.; Ruskandi, A.; Farnsworth, N. R.; Swanson, S. M.;
Kinghorn, A. D. J. Nat. Prod. 2008, 71, 390–395.
prepared by Wong’s procedure.19d,16 Formation of the Weinreb
amide20 and protection of the phenol led to the coupling
partner 16. The optically pure hydroxy phenylthio alcohol
17 was prepared by epoxidation of 1-pentadecene, followed
by Jacobsen kinetic resolution.21 The thiophenol addition was
catalyzed by LiClO4 to give optically pure22 phenylthio
alcohol 17 in 34% overall yield. The initial coupling
experiments, using the conditions reported in Table 1, gave
none of the desired aldol product and returned both the Weinreb
(16) Wong, Y.-S. Chem. Commun. 2002, 686–687.
(17) (a) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2005, 46, 8407–8410. (b) Alvarez-Bercedo, P.; Falomir,
E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62, 9641–9649.
(18) Baldwin, J. E.; Adlington, R. M.; Sham, V. W. W.; Marquez, R.;
Bulger, P. G. Tetrahedron 2005, 61, 2353–2363.
(19) (a) Chandrasekhar, S.; Rambabu, C.; Shyamsunder, T. Tetrahedron
Lett. 2007, 48, 4683–4685. (b) Peuchmaur, M.; Wong, Y.-S. Synlett 2007,
2902–2906. (c) Peuchmaur, M.; Wong, Y.-S. J. Org. Chem. 2007, 72, 5374–
5379. (d) Peuchmaur, M.; Saidani, N.; Botte, C.; Marechal, E.; Vial, H.;
Wong, Y.-S. J. Med. Chem. 2008, 51, 4870–4873. (e) Ramana, C. V.;
Srinivas, B. J. Org. Chem. 2008, 73, 3915–3918. (f) Suresh, V.; Selvam,
J. J. P.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2008, 19,
1509–1513. (g) Zhen, Z.-B.; Gao, J.; Wu, Y. J. Org. Chem. 2008, 73, 7310–
7316.
(20) (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. J. Tetrahedron Lett. 1995, 36, 5461–5464.
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amide 16 and the phenylthio alcohol 17. Recovery of 17 indicated
that the reductive lithiation reaction had failed.
coordination with the sulfur atoms may reduce the selectivity.
Eventually we found that Evans’ catecholborane procedure27
was effective on the deprotected phenol and generated the
syn-1,3-diol 13 with 5:1 dr. Oxidative deprotection and
cyclization using Wu’s buffered conditions gave aculeatin
A (38%) and aculeatin B (20%).19g The small amount of
The failure of the lithiation reaction led us to reoptimize the
conditions for the coupling. The obvious difference between the
reactive phenylthio alcohol 9 and the unreactive 17 was the long
alkyl chain in 17. We hypothesized that the lipophilic alkoxide
formed by deprotonation of 17 was not available for reduction,
possibly because it separated into a different phase or perhaps
formed micelles in the THF solution. In an effort to avoid the
hypothesized phase separation, we investigated different solvents
Scheme 5. Synthesis of Aculeatin A and B
and additives.23 The lithiation was successful when the reaction
was conducted in a 1:1 mixture of THF and hexanes, Scheme 4.
Scheme 4. Synthesis of Aculeatin D
aculeatin D and its epimer were separated by chromatography
at this stage. The NMR data for synthetic aculeatins A, B,
and D were all identical to the literature data, and the optical
rotations were consistent with the assigned configurations.
The ꢀ-oxyanionic alkyllithium addition to a Weinreb amide
is a practical segment-coupling reaction to assemble ꢀ-hydroxy
ketones. The aculeatins A, B, and D were prepared from a
common intermediate using this method. This coupling reaction
enables convergent synthesis of polyol chains and will be a
valuable tool in natural product synthesis.
Addition of Weinreb amide 16 in THF resulted in a final solvent
mixture of 70:30 THF/hexanes and delivered the aldol adduct 15
in 60-79% yield using 1.5 equiv of phenylthio alcohol 17.24
Ketone 15 is the common intermediate for all three aculeatins. Anti
reduction using Evans’ method25 and deprotection led to anti-1,3-
diol 14 as a 10:1 dr in very good yield. The final oxidative
cyclization was conducted under citrate-buffered conditions19g to
generate aculeatin D in 30% yield, accompanied by the separable
C6 epimer in 35% yield. Without the added buffer, only the C6
epimer was produced.19g Aculeatin D was prepared in 7 steps from
1-pentadodecane.
Acknowledgment. This work was supported by the
National Institute of General Medicine (GM-043854) and
by a generous gift from the Schering-Plough Research
Institute. The S. T. Li foundation also provided financial
support. V.M. thanks the Department of Education (GAANN)
for a predoctoral fellowship.
Supporting Information Available: Characterization data
and experimental procedures for all compounds described.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The synthesis of aculeatin A and B is shown in Scheme
5. Attempts to reduce 15 to the syn-diol using Narasaka’s
conditions (EtOBEt2, NaBH4)26 led to very slow and unse-
lective reduction of the ketone. The steric crowding from
the dithiane may slow the addition, and competing boron
OL901623H
(23) Toluene/THF mixtures were also effective. Other additives (LiCl,
HMPA) did not lead to any coupled product .
(24) The coupling of Weinreb amide 16 was attempted without the
TBS protecting group, but neither the phenol nor the phenoxide was
sufficiently soluble in the THF/hexanes mixture to react with the
alkyllithium reagent.
(21) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936–938. (b) Schaus, S. E.; Brandes, B. D.; Larrow,
J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
(25) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
(26) (a) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233–2338. (b)
Chen, K.-M.; Hardtman, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155–158.
(22) Compound 17 {[R]24 -27.2 (c 0.99, CHCl3)} was found to be a
D
single enantiomer (>98% ee) by 1H NMR analysis of the R and S Mosher’s
ester derivatives.
(27) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190–5192.
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