Efficient and selective synthesis of siphonarienolone and related reduced polypropionates via Zr-catalyzed asymmetric carboalumination

Article abstract of DOI:10.1021/ol0497483

Siphonarienolone (1) has been synthesized from siphonarienal (3) in 66% over four steps. Synthesis of 3, in turn, has been achieved in two steps (85% combined yield) from 4, prepared from 3-buten-1-ol in seven steps (23% combined yield). Also, a two-step

Full text of DOI:10.1021/ol0497483

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1425-1427
Efficient and Selective Synthesis of
Siphonarienolone and Related Reduced
Polypropionates via Zr-Catalyzed
Asymmetric Carboalumination
Marina Magnin-Lachaux, Ze Tan, Bo Liang, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received February 12, 2004
ABSTRACT
Siphonarienolone (1) has been synthesized from siphonarienal (3) in 66% over four steps. Synthesis of 3, in turn, has been achieved in two
steps (85% combined yield) from 4, prepared from 3-buten-1-ol in seven steps (23% combined yield). Also, a two-step conversion of 3 into
siphonarienone (2) is reported.
Siphonarienolone (1) is a member of the siphonarienes, a
class of polypropionates produced by mollusks of the genus
Siphonaria. It was isolated and tentatively identified in 1988
by Norte et al.1 Its first total synthesis, however, was achieved
only in 2002,2 and this work also revised its stereochemistry
at C4. In view of an efficient and general method for the
synthesis of reduced polypropionates via Zr-catalyzed asym-
metric carboalumination developed recently by us,3 its ap-
plication to the synthesis of siphonarienolone (1) and a couple
of other structurally related siphonarienes, i.e., siphonar-
ienone (2)4 and siphonarienal (3),5 was undertaken. It was
envisioned that siphonarienal (3) would serve as aconvenient
intermediate for the synthesis of 1 and 2 (Scheme 1).
All previous syntheses of 1-3 and other related siphonar-
ienes2,4b,5b,6 have employed (2S,4S,6S)-2,4,6-trimethyl-1-
nonanol (4) and/or the corresponding aldehyde (5) as key
intermediates. Their syntheses, in turn, have been most
frequently achieved via asymmetric C-C bond formation
in the R position of chiral carboxamides, exemplified by
those of Evans,7 and of related nucleophiles such as chiral
imines.6 Some notable examples of the use of this method
include the synthesis of siphonarienone (2) via 5 by
Masamune4b and that of pectinatone via 5 by Enders.6
Although nonstereoselective, an earlier synthesis of sipho-
narienal (3) by Norte4a is also noteworthy. All of these
syntheses involved three steps for generation of each
additional asymmetric carbon center with stoichiometric
amount or even excesses of chiral carboxamides and related
(1) Norte, M.; Cataldo, F.; Gonza´lez, A. G. Tetrahedron Lett. 1988, 29,
2879.
(2) Calter, M. A.; Liao, W. J. Am. Chem. Soc. 2002, 124, 13127.
(3) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc. Natl. Acad. Sci.,
U.S.A. in press.
(4) (a) Norte, M.; Cataldo, F.; Gonzalez, A. G.; Rodriguez, M. L.; Ruiz-
Perez, C. Tetrahedron 1990, 46, 1669. (b) Abiko, A.; Masamune, S.
Tetrahedron Lett. 1994, 35, 1081.
(5) (a) Norte, M.; Ferna´ndez, J. J.; Padilla, A. Tetrahedron Lett. 1994,
35, 3413. (b) Calter, M. A.; Liao, W.; Struss, J. A. J. Org. Chem. 2001, 66,
7500.
(6) Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823
(7) Evans, D. A.; Dowe, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290.
10.1021/ol0497483 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/25/2004

Scheme 1
Scheme 2
reagents. Thus, the synthesis of 4 and/or 5 containing three
asymmetric carbon centers typically requires approximately
10 steps from readily available compounds. Another aspect
common to these procedures is the need for reduction of
carboxylic acid derivatives to aldehyde or alcohols in each
three-step cycle. A recently reported ingenious method,2,5b
which is catalytic in chiral auxiliary for C-C bond formation,
involved asymmetric cyclic dimerization of methylketene and
ring opening with racemic 2-methylpentanal to construct the
entire carbon framework of 5 with the desired stereochem-
istry in one step in 35% yield. Subsequent functional
modification over five steps in 42% combined yield led to
the synthesis of 5 in 15% overall yield in six steps.
Conversion of 5 into siphonarienal (3) was then achieved in
three additional steps in 69% combined yield. Thus, 3 was
synthesized in 10% overall yield in nine steps.
The Zr-catalyzed asymmetric carboalumination method we
have recently developed8 has provided (2S,4S,6S)-2,4,6-
trimethyl-1-nonanol (4) of g50/1 dr (13C NMR and >99%
ee by Mosher analysis) in 23% overall yield over seven (or
six isolation) steps from 3-buten-1-ol, as shown in Scheme
2.3 This novel protocol that is totally discrete from any other
methods features the following. (1) (3S)-3-Methyl-1-hexanol
(6) of 90% ee was prepared from 3-buten-1-ol in one step.3
(2) The alcohol thus obtained was used without enantiomeric
separation to prepare (2S,4S)-2,4-dimethyl-1-heptanol (7) of
6.7/1 dr, which, after column chromatography (1/50 EtOAc/
hexanes), provided pure 7 (dr g40/1 by 13C NMR and g98%
ee by Mosher analysis) in 50% yield from 3-buten-1-ol over
four (or three isolation) steps.3 (3) A three-step protocol
consisting of iodination, Pd-catalyzed vinylation, and Zr-
catalyzed asymmetric carboalumination-oxidation furnished,
after column chromatography, pure 43 of g50/1 dr in 46%
combined yield over three steps (or 23% combined yield over
seven (or six isolation) steps from 3-buten-1-ol).
for 1 h.10 The reaction mixture was quenched with CF3COOH
at 0 °C in THF to give siphonarienal (3) in 85% yield over
two steps (Scheme 2), dr g 50/1. Thus, the overall yield of
3 based on 3-buten-1-ol over nine (or seven isolation) steps
is 20%. Its spectral data are in good agreement with those
reported previously.5
Conversion of siphonarienal (3) into siphonarienolone (1)
was achieved in four steps, as summarized in Scheme 3. (2S)-
2-Benzoyloxy-3-pentanone,11 prepared from ethyl (S)-lactate,
was treated with B-chlorodicyclohexylborane and Me2NEt
in ether (-78 to 0 °C, 2 h). The reaction of 3 with the above-
generated enolborane was carried out at -78 °C for 1 h and
then at -20 °C (freezer) for 10 h. The resultant mixture was
treated at 0 °C with MeOH, a buffer (pH 7) solution of NaH2-
PO4 and Na2HPO4, and 30% H2O2 to oxidize any organobo-
ranes. After the standard workup and column chromatogra-
phy (5 to 8% EtOAc in hexanes), 8 was obtained in 82%
yield. Protection of the OH group of 8 with TBSOTf and
2,6-lutidine in 99% yield was followed by removal of the
BzO group with SmI212 and MeOH in THF to give 9 in 94%
yield. Attempted removal of the TBS group with TBAF in
Oxidation of 4 with (COCl)2 (1.2 equiv), DMSO (2.4
equiv), and Et3N (3 equiv)9 produced the corresponding
aldehyde 5. Without isolation-purification, it was treated
with 1.3 equiv of Et3SiCH(Me)CHdNCy, where Cy is
s
cyclohexyl, and BuLi (1.2 equiv) in THF at -78 to 20 °C
(8) (a) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771.
(b) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577. (c) Huo,
S.; Negishi, E. Org. Lett. 2001, 3, 3253. (d) Huo, S.; Shi, J.; Negishi, E.
Angew. Chem., Int. Ed. 2002, 41, 2141. (e) Negishi, E. In Catalytic
Asymmetric Synthesis II; Ojima, I., Ed.; Wiley-VCH: New York, 2000; p
165. (f) Negishi, E.; Huo, S. Pure Appl. Chem. 2002, 74, 151.
(10) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 1, 7.
(11) (a) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett.
1994, 35, 9083. (b) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. (c)
Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217.
(9) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(12) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
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Org. Lett., Vol. 6, No. 9, 2004

Scheme 3
Scheme 4
trimethyl-2-octenal (10), which has been employed as a key
intermediate in a recent synthesis of (3S,4S,5E,7S,9R)-
3,5,7,9-tetramethyl-1,5-undecadien-4-ol (11) (Scheme 4),
further demonstrates the high efficiency and general ap-
plicability of the Zr-catalyzed asymmetric carboalumination-
based method for the synthesis of reduced polypropionates
and complex natural products containing such fragments. In
the above-mentioned synthesis of (+)-sambutoxin,11c for
example, 10 was prepared in 11 or 12 steps by using two
chiral reagents, i.e., methyl (2R)-3-hydroxy-2-methylpropi-
onate and a chiral (E)-crotonamide, in stoichiometric quanti-
ties. Thus, its synthesis from 3-buten-1-ol in six (or four
isolation) steps without using any chiral materials in sto-
ichiometric quantities or any enantiomeric separation amounts
to a substantial simplification, and similar simplifications
appear to be feasible also in many other cases.
THF at 23 °C was unsuccessful. On the other hand, treatment
of 9 with HF-pyridine13 in THF at 23 °C in a Teflon tube
afforded, after column chromatography (8 to 20% EtOAc
in hexanes), an 87% yield of the desired siphonarienolone
(1): g50/1 dr; [R]D ) + 11° (c 0.3, CHCl3), lit.1 [R]D )
+19.6° (c 0.9, CHCl3). The yield of 1 (g50/1 dr) from 3
was 66% over four steps. Since 3 was synthesized in 20%
yield over nine (or seven isolation) steps (vide supra), the
overall yield of 1 from 3-buten-1-ol is 13% over 13 (or 11
isolation) steps. The previously reported conversion of 5 into
12 was achieved in four steps in 40% combined yield via a
totally different route, the overall yield of 1 from racemic
2-methylpentanal being 6% in 10 steps.
Conversion of siphonarienal (3) into siphonarienone (2)
was simply achieved by the reaction of 3 with EtMgBr in
88% yield, followed by oxidation with Dess-Martin perio-
dinane in 90% yield (isomeric purity g 99%). Its spectral
data are in good agreement with those reported for 2.4
3-Buten-1-ol has also been converted to (2R,4R)- and
(2S,4R)-2,4-dimethyl-1-hexanol in 49 and 40% yields, re-
spectively, by the four-step procedure shown in Scheme 2.3
Conversion of (2S,4R)-1-hexanol into (2E,4S,6R)-2,4,6-
Acknowledgment. We thank the National Institutes of
Heath (GM36792) and Purdue University for support of this
research. Boulder Scientific Co. has kindly provided as-
sistance in the procurement of Zr compounds.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
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