Asymmetric catalysis route to anti,anti stereotriads, illustrated by applications

Article abstract of DOI:10.1021/ol702989g

(Chemical Equation Presented) A short sequence based on asymmetric catalysis, chirality transfer, and an optimized carbometallation protocol gave an anti,anti stereotriad building block in six steps. Both enantiomers of the chirality source, N-methyl ephedrine, are inexpensive, and the auxiliary is recoverable. In one chiral series, the building block was converted to the B-2 intermediate in Miyashita's synthesis of scytophycin C; in the enantiomeric series, it was converted to a key intermediate for aplyronine A and to the polyketide cap for the callipeltins.

Full text of DOI:10.1021/ol702989g

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1349-1352
Asymmetric Catalysis Route to anti,anti
Stereotriads, Illustrated by Applications
Kathlyn A. Parker* and Qiuzhe Xie
Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York, 11794
kparker@notes.cc.sunysb.edu
Received December 12, 2007
ABSTRACT
A short sequence based on asymmetric catalysis, chirality transfer, and an optimized carbometallation protocol gave an anti,anti stereotriad
building block in six steps. Both enantiomers of the chirality source, N-methyl ephedrine, are inexpensive, and the auxiliary is recoverable.
In one chiral series, the building block was converted to the “B-2” intermediate in Miyashita’s synthesis of scytophycin C; in the enantiomeric
series, it was converted to a key intermediate for aplyronine A and to the polyketide “cap” for the callipeltins.
As new and promising polypropionate antibiotics are dis-
covered in nature, interest in these compounds as biological
probes and as potential therapeutics continues to expand. The
preparation of polypropionates is a challenge that has been
met by the development of a variety of new methodologies.
Nonetheless, the complexity of many target structures is such
that more efficient syntheses from inexpensive materials are
needed.
The anti,anti stereotriad is a noticeable feature of the
structures of numerous polyketide antibiotics. Among these
are macrolides isolated from aquatic organisms, primarily
from marine sponges (e.g., swinholides) but also from sea
snails (aplyronines, e.g., aplyronine A, 1a) and fresh water
cyanobacteria (scytophycins, e.g., scytophycin C, 1b),1 that
bear a stereochemically rich, N-vinyl formamide-terminated
side chain. There is speculation that the compounds isolated
from the higher marine organisms are, in fact, the metabolites
of cyanobacteria that are symbiotic with the hosts.2 These
marine macrolides alter the dynamics of the actin polymer-
ization/depolymerization process by binding globular (mono-
meric) actin (G-actin) and by severing filamentous actin
(F-actin). Perhaps, at least in part, because their action
interferes with cell division,3 these compounds are highly
cytotoxic.
The anti,anti stereotriad is also found in a second class of
marine natural products, the callipeltins. These cyclic and
acyclic peptides are notable for their unusual amino acid
residues as well as for their impressive biological activities.
(2) (a) Andrianasolo, E. H.; Gross, H.; Goeger, D.; Musafija-Girt, M.;
McPhail, K.; Leal, R. M.; Mooberry, S. L.; Gerwick, W. H. Org. Lett. 2005,
7, 1375 and references therein. (b) Luesch, H.; Harrigan, G. G.; Goetz, G.;
Horgen, F. D. Curr. Med. Chem. 2002, 9, 1791.
(3) Recent data suggest, however, that toxicity is not directly correlated
with depolymerizing activity; see: (a) Suenaga, K.; Kimura, T.; Kuroda,
T.; Matsui, K.; Miya, S.; Kuribayashi, S.; Sakakura, A.; Kigoshi, H.
Tetrahedron 2006, 62, 8278 and references therein. (b) Ojika, M.; Kigoshi,
H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.; Arakawa, M.;
Ekimoto, H.; Yamada, K. Tetrahedron 2007, 63, 3138. (c) Also of interest
in this context: Fuerstner, A.; Nagano, T.; Mueller, C.; Seidel, G.; Mueller,
O. Chem. Eur. J. 2007, 13, 1452.
(1) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237.
10.1021/ol702989g CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/04/2008

anti,anti stereotriad equivalent 3 might be elaborated from
propargyl ether 5 by way of the rearrangement product 4.
Scheme 1. Enantiomeric Stereotriad Building Block Targets
and Retrosynthetic Postulate
Figure 1. anti,anti Stereotriads in selected natural products.
This approach to the anti,anti stereotriad 3 offered two
desirable features. First, the precursor of the Wittig re-
arrangement substrate, chiral alcohol 6, should be available
by an asymmetric addition reaction in which the chiral ligand
can be easily recovered. Second, the enantiomeric stereotriad
ent-3 should be equally available by applying the same
approach in the enantiomeric series.
The practicality of our overall strategy and its utility have
now been demonstrated by the facile preparation of
Miyashita’s “B-2” (7), a building block in the synthesis of
scytophycin C (1b);8,9 aldehyde 8, an intermediate in
Paterson’s approach to aplyronine A (1a); and the TBS-
protected (for use in total synthesis) 3-hydroxy-2,4,6-
trimethylheptanoic acid 9 (TBS-Htmha), the “cap” for
callipeltins (e.g., 2).10
In callipeltins A, C, D (2), and F-L from Callipelta sp. and
Latrunculia sp.,4 and in the closely related neamphamide A
from Neamphius huxleyi,5 a (2R,3R,4R)-3-hydroxy-2,4,6-
trimethylheptanoic acid moiety acts as an N-terminal “cap”
of the peptide chain.
In order to gain easy access to polypropionate-derived
natural products, we have focused on the exploitation of the
2,3-Wittig rearrangement. In 2006, we described the stereo-
selective rearrangement of a methallyl ether of a chiral cis
allylic alcohol to produce a syn stereodiad that was subse-
quently elaborated to syn,anti stereotriad intermediates for
a discodermolide synthesis.6 The corresponding anti stereo-
diad is not cleanly available by variations of this direct
approach; however, an anti stereodiad is available by the
Wittig rearrangement of a propargyl ether of a trans allylic
alcohol.7 Therefore we considered the possibility that the
(8) For the structure determination and biological activities of scytophycin
C, see: Smith, C. D.; Carmeli, S.; Moore, R. E.; Patterson, G. M. L. Cancer
Res. 1993, 53, 1343.
(9) (a) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3579.
(b) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3583. (c)
A total synthesis of scytophycin C was also reported by Paterson, I.; Watson,
C.; Yeung, K.-S.; Ward, R. A.; Wallace, P. A. Tetrahedron 1998, 54, 11955.
(10) (a) For an elegant and efficient synthesis of TBS-Htmha in which
the source of chirality is pseudoephedrine was reported by Lipton, see: Turk,
J. A.; Visbal, G. S.; Lipton, M. A. J. Org. Chem. 2003, 68, 7841. (b) For
an earlier synthesis of the O-benzyl-protected acid, see: Zampella, A.;
D’Auria, M. V. Tetrahedron: Asymmetry 2002, 13, 1237. (c) For prepara-
tions of the (2R,3R,4S)-diastereomer, see: Zampella, A.; Sorgente, M.;
D’Auria, M. V. Tetrahedron: Asymmetry 2002, 13, 681. Guerlavais, V.;
Carroll, P. J.; Joullie, M. M. Tetrahedron: Asymmetry 2002, 13, 675.
(4) D’Auria, M. V.; Sepe, V.; D’Orsi, R.; Bellotta, F.; Debitus, C.;
Zampella, A. Tetrahedron 2007, 63, 131 and references therein. For the
total synthesis of Callipeltin D, see Cranfill, D. C.; Morales-Ramos, A. I.;
Lipton, M. A. Org. Lett. 2005, 7, 5881.
(5) Oku, N.; Gustafson, K. R.; Cartner, L. K.; Wilson, J. A.; Shigematsu,
N.; Hess, S.; Pannell, L. K.; Boyd, M. R.; McMahon, J. B. J. Nat. Prod.
2004, 67, 1407.
(6) Parker, K. A.; Cao, H. Org. Lett. 2006, 8, 3541.
(7) Tsai, D. J. S.; Midland, M. M. J. Org. Chem. 1984, 49, 1842.
1350
Org. Lett., Vol. 10, No. 7, 2008

Scheme 3. Conversion of anti Stereodiad 4 to anti,anti
Stereotriad 3 and Elaboration to Miyashita’s “B-2” 7
Figure 2. Illustrative targets.
Preparation of stereotriad building block 3 was to be based
on elaboration of the 2,3-Wittig rearrangement product 4.
Synthesis of this key intermediate began (Scheme 2) with
the addition of (E)-1-propenylzinc bromide to cyclohexane-
carboxaldehyde in the presence of (+)-N-methylephedrine
according to the method of Oppolzer.11 Allylic alcohol 6 was
obtained in 81% yield and 90% ee.12 Alkylation with
propargyl bromide afforded ether 5 in 87% yield. Application
of standard [2,3]-Wittig rearrangement conditions afforded
(E)-propargylic alcohol 4 (93% yield). The ratio of the anti/
syn diastereomers in this rearrangement product was, as
alcohols to methallyl alcohols, we studied the product
distribution of the carbometallation of 1-cyclohexyl-2-
propyn-1-ol (Table 1).14,15
Table 1. Distribution of Starting Material (SM) and Products:
CuI-Catalyzed Addition of Methylmagnesium Halide to 1-
Cyclohexyl-2-propyn-1-ol
1
judged by integration of the H NMR spectrum, 96:4.
MeMgX
X, equiv
CuI
(equiv)
SM, R-adduct,
â-adduct (%)
solvent
Scheme 2. Three-Step Preparation of the Chiral anti
Br, 2.5
Br, 4.0
Br, 4.0
Br, 4.0
Br, 4.0
Cl, 4.0
I, 4.0
0.95
2.0
3.0
2.0
2.0
2.0
2.0
THF
THF
THF
Et2O
dioxane
THF
54, 24, 22
28, 58, 14
62, 22, 16
65, 4, 31
100, 0, 0
21, 79, trace
87, 13, trace
Stereodiad
THF
Application of the most favorable protocol to substrate 4
resulted in the isolation of an 81% yield of the desired alcohol
10 along with the recovery of some starting material.
Methylation and hydroboration gave the desired synthon 3
(R ) Me). Silylation and ozonolysis demonstrated its utility
by conversion to the desired “B-2,” aldehyde 7.
An advantage of the asymmetric addition-rearrangement
approach to stereotriad-containing intermediates is that both
enantiomers of key compound 3 are readily available. For
the preparation of Paterson’s triad 8 or TBS-Htmha (9), it is
more efficient to use a synthon derived from ent-10 than
one derived from the previously prepared 10. Therefore the
five-step asymmetric synthesis was applied in the enantio-
meric series (ent-6 f ent-4 f ent-10, as in Schemes 2 and
3).
At this point, our plan was to convert alcohol 4 to the key
intermediate 3 (R ) Me) by a sequence consisting of
carbometallation with a proton quench, O-methylation, and
hydroboration (see Scheme 3). Efforts to obtain useful results
by applying the Duboudin carbometallation protocol13 to
substrate 4 afforded a low yield of the desired R-adduct 10
along with the â-adduct and recovered starting material. In
order to develop an efficient conversion of terminal propargyl
Both targets 8 and 9 were then prepared (Scheme 4).
Conversion of ent-10 to Paterson’s triad 8 was accomplished
(11) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(12) The ee was determined by Mosher ester analysis; see Supporting
Information. The chiral ligand was recovered quantitatively in purity that
was appropriate for use in further reactions.
(13) (a) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979,
168, 1-11. (b) Duboudin, J. G.; Jousseaume, B. J.; Bonakdar, A. J.
Organomet. Chem. 1979, 168, 227-232.
(14) Details will be reported in a full paper.
(15) During the course of our work, a similar study was reported for the
carbometallation of terminal, secondary propargyl alcohols in which the
substituent was a straight-chain alkyl group. See: Lu, Z.; Ma, S. J. Org.
Chem. 2006, 71, 2655.
Org. Lett., Vol. 10, No. 7, 2008
1351

15a suffered oxidative removal of the PMB group as
indicated by the appearance of p-methoxybenzaldehyde.
However, a two-step procedure with OsO4 and buffered
NaIO4 provided the aldehyde target 8.16 For elaboration of
ent-10 to the protected hydroxy trimethylheptanoic acid 9,
silylation with TBSOTf (f 13b) was followed by benzyl-
ation with benzyl trichloroacetimidate to give the fully
protected olefin 15b. Ozonolysis provided aldehyde 16 which
was subjected to the Wittig reaction. Treatment of the
trisubstituted olefin 17 with hydrogen in the presence of
palladium on carbon effected both debenzylation and satura-
tion of the double bond. Oxidation of primary alcohol 1817
gave TBS-Htmha (9).
Scheme 4. Preparation of Paterson’s Triad 8 and TBS-Htmha
9
The advantages of this approach to anti,anti stereotriad
building blocks are (1) the use of asymmetric catalysis as a
source of chirality, (2) the ready availability of catalysts for
both chiral series, (3) the functional group pattern in the
synthon (3 or ent-3) itself, which allows generation of an
aldehyde in one step in high yield, and (4) the relatively
robust protocols required for the short scheme that provides
synthon 3 or ent-3. More sophisticated applications are being
pursued.
Acknowledgment. This work was supported by the
Department of Defense Army Breast Cancer Initiative
(BC051816), and the National Science Foundation (CHE-
0131146, NMR instrumentation).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702989G
(16) Paterson, I.; Blakey, S. B.; Cowden, C. J. Tetrahedron Lett. 2002,
43, 6005.
(17) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
by silylation with TES triflate, hydroboration with 9-BBN
(f 14a), and protection with p-methoxybenzyl trichloro-
acetamidate. Under standard ozonolysis conditions, olefin
1352
Org. Lett., Vol. 10, No. 7, 2008