A highly catalytic asymmetric conjugate addition: Synthesis of the C14-C20 fragment of antibiotic TMC-151A, siphonarienal and siphonarienone

Article abstract of DOI:10.1021/ol702715q

A highly selective and general method for the synthesis of enantiopure deoxypropionates via the iterative application of Cul-Tol-BINAP-catalyzed asymmetric conjugate addition is described. This method gives access to all possible stereoisomers since both syn- and anti-deoxypropionates were obtained in high diastereoselectivities. The usefulness of the method is further exemplified by the preparation of two marine organisms, siphonarienal and siphonarienone, from commercially available trans-2-hexenoate.

Full text of DOI:10.1021/ol702715q

ORGANIC
LETTERS
2008
Vol. 10, No. 5
761-764
A Highly Catalytic Asymmetric
Conjugate Addition: Synthesis of the
C14−C20 Fragment of Antibiotic
TMC-151A, Siphonarienal and
Siphonarienone
Tze-Keong Lum, Shun-Yi Wang, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 639798
teckpeng@ntu.edu.sg
Received November 22, 2007
ABSTRACT
A highly selective and general method for the synthesis of enantiopure deoxypropionates via the iterative application of CuI-Tol-BINAP-
catalyzed asymmetric conjugate addition is described. This method gives access to all possible stereoisomers since both syn- and anti-
deoxypropionates were obtained in high diastereoselectivities. The usefulness of the method is further exemplified by the preparation of two
marine organisms, siphonarienal and siphonarienone, from commercially available trans-2-hexenoate.
The enantiopure alternating methyl-substituted unit, or deox-
ypropionate, is a common recurring motif in many deoxy-
genated polyketide-type natural products.1 Therefore, many
methods have been developed for the synthesis of such
compounds. Currently, most of the reported procedures are
based on the use of chiral auxiliaries (enolate alkylations,2
conjugate additions3), allylic substitutions,4 or substrate
control methods.5 Catalytic asymmetric methods include
Negishi’s Zr-catalyzed carboalumination,6 Burgess’s Ir-
catalyzed hydrogenation,7 and Feringa’s Josiphos-catalyzed
conjugate addition (CA).8 Conjugate addition of MeMgBr
to simple and commercially available R,â-unsaturated esters
is one of the most direct entries into these structural elements.
In addition, not only are R,â-unsaturated esters easier to
handle but also a larger scope of useful chemical transforma-
tions can be applied. In this paper, we report the iterative
(5) (a) Breit, B.; Demel, P. Tetrahedron 2000, 56, 2833-2846. (b)
Hanessian, S.; Chahal, N.; Giroux, S. J. Org. Chem. 2006, 71, 7403-7411.
(6) (a) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117,
10771-10772. (b) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5782-5787. (c) Tan, Z.; Negishi, E. Angew.
Chem., Int. Ed. 2004, 43, 2911-2914. (d) Magnin-Lachaux, M.; Tan, Z.;
Liang, B.; Negishi, E.-I. Org. Lett. 2004, 6, 1425. (e) Novak, T.; Tan, Z.;
Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005, 127, 2838-2839. (f) Liang,
B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006, 128, 2770-
2771. (g) Zhu, G.; Negishi, E. Org. Lett. 2007, 9, 2771-2774.
(1) (a) Hanessian, S.; Giroux, S.; Mascitti, V. Synthesis 2006, 7, 1057-
1076.
(2) (a) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 793-795. (b) Stoermer, D.; Caron, S.; Heathcock,
C. H. J. Org. Chem. 1996, 61, 9115-9125. (c) Myers, A. G.; Yang, B. H.;
Chen, H.; Kopecky, D. J. Synlett 1997, 457-459.
(3) (a) Nicola´s, E.; Russel, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
766-770. (b) Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org. Chem.
2004, 69, 5374-5382.
(4) (a) Spino, C.; Beaulieu, C.; Lafreniere, J. J. Org. Chem. 2000, 65,
7091-7097. (b) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43,
3790-3792.
(7) (a) Zhou, J.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 1129-
1131. (b) Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit, V.; Zhu, Y.; Burgess,
K. Chem.sEur. J. 2007, 13, 7162-7170.
10.1021/ol702715q CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/30/2008

application of CuI-Tol-BINAP-catalyzed asymmetric CA of
MeMgBr to commercially accessible R,â-unsaturated esters
to access enantiopure deoxypropionate subunits, including
the short synthesis of the C14-C20 subunit of antibiotic
TMC-151A, two related marine natural products siphonar-
ienal and siphonarienone starting from commercially avail-
able R,â-unsaturated esters.
Scheme 2. Synthesis of Deoxypropionate Units
A practical and efficient procedure for the enantioselective
conjugate addition of Grignard reagents to R,â-unsaturated
esters was previously developed.9 To demonstrate the ap-
plicability and versatility of this synthetic strategy, we
extended this method to an iterative sequence for the
introduction of contiguous enantiopure methyl moieties into
an acyclic carbon chain (Scheme 1).
Scheme 1. General Route to Deoxypropionate Units
The first methyl stereogenic center was introduced from
commercially available methyl trans-2-pentenoate using (S)-
Tol-BINAP to give methyl ester 1 in 96% ee and 67% yield
(Scheme 2).9 A one-pot DIBAL-H reduction followed by
Wittig olefination furnished a mixture of enoate isomers (E/Z
92:8) in 73% yield. Further chromatographic purification
exclusively isolated the (E)-enoate 2 in 64% yield over two
steps. The second methyl addition, under the same catalytic
conditions, afforded the syn-deoxypropionate unit 310 in more
than 99:1 diastereoselectivity and 65% yield.
95:5 diastereoselectivity and 63% yield. Thus, CA reactions
of MeMgBr to R,â-unsaturated esters producing the 1,3-syn-
stereochemistry appear to represent a “matched” case, while
those producing the 1,3-anti-diastereoselectivity represent a
“mismatched” case. It should be emphasized that even the
mismatched CA reaction is highly selective, and the selectiv-
ity is governed almost exclusively by use of the appropriate
enantiomer of Tol-BINAP ligand.
Use of the R-enantiomer of Tol-BINAP, under the same
catalytic conditions, afforded the anti-deoxypropionate 4 in
(8) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.;
Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b)
Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2004, 126, 12784-12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756. (d) Des
Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967. (e) Van
Summeren, R. P.; Moody, D. B.; Feringa, B. L.; Minnaard, A. J. J. Am.
Chem. Soc. 2006, 128, 4546-4547. (f) Harutyunyan, S. R.; Lopez, F.;
Browne, W. R.; Correa, A.; Pena, D.; Badorrey, R.; Meetsma, A.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103-9118. (g) ter
Horst, B.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2007, 5, 489-
491. (h) ter Horst, B.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2007, 9,
3013-3015. (i) Ruiz, B. M.; Geurts, K.; Ferna´ndez-Iba´n˜ez, M. A.; ter Horst,
B.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123-5126.
(9) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129, 276-
277.
Further iterations of this sequence proceeded with similarly
high diastereoselectivity. First, second stage elongation from
methyl ester 4 via the same one-pot DIBAL-H reduction-
(10) (a) Assuming an analogous reaction mechanism, syn- and anti-
stereochemistry were assigned on the basis of enantiomeric Tol-BINAP
ligands selected in each methyl addition leading to the deoxypropionate
units. (b) Diastereoselectivity was determined in 13C NMR by comparing
an average of carbon signals with respective diastereomeric mixtures of
the deoxypropionate units. See Supporting Information for more details.
762
Org. Lett., Vol. 10, No. 5, 2008

Wittig olefination protocol furnished the anti-enoate 5 in 59%
yield. Third stage methyl addition to this anti-enoate 5 using
(S)-Tol-BINAP gave the anti,anti-deoxypropionate 6 in 95:5
diastereoselectivity and 66% yield. Gratifyingly, the iterative
use of appropriate CuI-Tol-BINAP catalytic systems allowed
the access of anti,anti-deoxypropionate chirons in excellent
stereoselectivity even though the 1,3-anti-stereochemistry
was disfavored.
found in the Mediterranean Sea.12 Since these marine
natural products possess interesting biological properties,
syntheses of them have been reported. The notable synthetic
procedures include iterative aldol reactions using Evan’s
auxiliary12b and alkylations with Masamune’s chiral ben-
zopyranoisoxalidine.13 The use of a chiral ketene dimer by
Calter is noteworthy,14 while Zr-catalyzed carboalumination
developed by Negishi is also another useful method.6d More
recently, an ex-chiral pool synthesis was also reported.15
Encouraged by the excellent selectivity achieved previously
in the syn,syn-deoxypropionate 9 subunit, we proceeded to
apply the iterative use of CuI-Tol-BINAP-catalyzed asym-
metric CA in the synthesis of siphonarienal and siphonar-
ienone.
Flexibility of this synthetic route is enhanced with the
incorporation of bromine, as the enolate trapping reagent in
the third stage methyl addition, so as to allow a one-carbon
dehomologation required in subsequent steps. Other useful
transformations after the bromine enolate quenching step
include the conversion of the terminal bromohydrin into
epoxides and olefins for further useful transformations.
Starting from commercially available methyl trans-2-
hexenoate, the first methyl stereogenic center was installed
using (S)-Tol-BINAP to give methyl ester 12 in 96% ee and
68% yield (Scheme 3). After the one-pot DIBAL-H reduc-
tion-Wittig olefination protocol to (E)-enoate 13 (64%
yield), the second stage methyl addition was performed under
the same catalytic conditions to afford the syn-deoxypropi-
onate unit 14 in more than 99:1 diastereoselectivity and 66%
yield. The same elongation protocol furnished the second
(E)-enoate 15 in 58% yield.
Likewise, from the syn-deoxypropionate methyl ester 3,
second stage elongation proceeded similarly via the one-pot
DIBAL-H reduction-Wittig olefination protocol to afford
the syn-enoate 7 in 61% yield. Third stage methyl addition
to this syn-enoate 7 using (R)-Tol-BINAP furnished the syn,-
anti-deoxypropionate 8 in 94:6 diastereoselectivity and 62%
yield. Use of the S-enantiomer of Tol-BINAP afforded the
syn,syn-deoxypropionate 9 in 99:1 diastereoselectivity and
58% yield, which corresponds to the C14-C20 fragment of
antibiotic TMC-151A11 without the sugar moiety.
Siphonarienal 10 and siphonarienone 11 (Scheme 3) are
Scheme 3. Synthesis of Siphonarienal and Siphonarienone
The third and final stage methyl addition using (S)-Tol-
BINAP was modified by using neat bromine as an enolate-
trapping reagent to effect the following one-carbon deho-
mologation. Without further purification, the R-bromomethyl
ester obtained was reduced to the alcohol using DIBAL-H,
and this reduced alcohol was used without further
isolation for the next step. Treating this alcohol in THF
with zinc dust and glacial acetic acid gave the terminal
olefin 16 in 44% yield over three steps from the (E)-enoate
15. The diastereoselectivity for the third stage methyl
addition was more than 99:1 as determined in 13C NMR by
comparing this to a diastereomeric mixture of the same
terminal olefin.
A one-pot ozonolysis and Wittig olefination protocol gave
the R,â-unsaturated ester 17 in 42% yield over two steps.
No epimerization of the third methyl stereogenic center was
observed by comparing the 13C NMR to a diastereomeric
mixture of the same R,â-unsaturated ester. From the R,â-
unsaturated ester 17, a two-step DIBAL-H reduction and
IBX oxidation furnished siphonarienal 10 in 63% yield
(12) (a) Norte, M.; Cataldo, F.; Gonza´lez, A. G. Tetrahedron Lett. 1988,
29, 2879. (b) Norte, M.; Cataldo, F.; Gonzalez, A. G.; Rodriguez, M. L.;
Ruiz-Perez, C. Tetrahedron 1990, 46, 1669. (c) Norte, M.; Fernandez, J.
J.; Padilla, A. Tetrahedron Lett. 1994, 35, 3413.
(13) Abiko, A.; Masamune, S. Tetrahedron Lett. 1996, 37, 1081.
(14) (a) Calter, M. A.; Liao, W.; Struss, J. A. J. Org. Chem. 2001, 66,
7500. (b) Calter, M. A.; Liao, W. J. Am. Chem. Soc. 2002, 124, 13127.
(15) Galeyeva, Y.; Morr, M.; Baro, A.; Nimtz, M.; Sasse, F.; Laschat,
S. Synthesis 2005, 17, 2875-2880.
members of siphonarienes, a class of deoxypropionates
produced by Gastropod mollusks of the genus Siphonaria
(11) Kohno, J.; Nishio, M.; Sakurai, M.; Kawano, K.; Hiramatsu, H.;
Kameda, N.; Kishi, N.; Yamashita, T.; Okuda, T.; Komatsubara, S.
Tetrahedron 1999, 55, 7771-7786.
Org. Lett., Vol. 10, No. 5, 2008
763

over the two-step sequence. Likewise, from R,â-unsaturated
ester 17, the application of Weinreb’s ketone synthesis
using MeNHOMe‚HCl with i-PrMgCl followed by treatment
of the Weinreb amide with EtMgBr in THF gave siphar-
ienone 11 in 67% yield over two steps. Spectral data of
both compounds are in good agreement with those
reported.12c,15
marine organisms siphonarienal and siphonarienone,
from commercially available trans-2-hexenoate. Further
investigations will be directed toward understanding the
mechanism, broadening the reaction scope, and applying the
catalytic system in the total synthesis of other natural
products.
In summary, we have developed a highly selective and
general method for the synthesis of enantiopure deoxypro-
pionate units via the iterative application of CuI-Tol-BINAP-
catalyzed asymmetric CA to simple and commercially
available R,â-unsaturated esters. These results established
the excellent diastereoselectivities of all desired configura-
tions possible with this iterative protocol since both syn- and
anti-deoxypropionates were obtained in high diastereoselec-
tivities. This method is further exemplified by the preparation
of the C14-C20 subunit of antibiotic TMC-151A, two
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University, Ministry of Education and
Biomedical Research Council (A*STAR grant M47110003),
for funding of this research.
Supporting Information Available: Experimental pro-
cedures and data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 10, No. 5, 2008