A formal synthesis of the C1-C9 fragment of amphidinolide C employing the tamaru reaction

Article abstract of DOI:10.1021/ol100959a

Homoallylation of aldehydes with isoprene and triethylborane catalyzed by Ni(acac)₂ gave hydroxyalkenes in good yield with excellent regio- and stereoselectivity. Cross metathesis of the hydroxyalkenes with methyl acrylate using second-generation Grubbs catalyst and copper(I) iodide afforded α,β-unsaturated esters, which underwent cyclization in the presence of DBU to produce tetrahydrofurans with the correct relative configuration for the C1-C9 fragment of amphidinolides C, C2, and F.

Full text of DOI:10.1021/ol100959a

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2954-2957
A Formal Synthesis of the C1-C9
Fragment of Amphidinolide C Employing
the Tamaru Reaction
Mahesh P. Paudyal, Nigam P. Rath, and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, One
UniVersity BouleVard, St. Louis, Missouri 63121
cspill@umsl.edu
Received April 27, 2010
ABSTRACT
Homoallylation of aldehydes with isoprene and triethylborane catalyzed by Ni(acac)2 gave hydroxyalkenes in good yield with excellent regio-
and stereoselectivity. Cross metathesis of the hydroxyalkenes with methyl acrylate using second-generation Grubbs catalyst and copper(I)
iodide afforded r,ꢀ-unsaturated esters, which underwent cyclization in the presence of DBU to produce tetrahydrofurans with the correct
relative configuration for the C1-C9 fragment of amphidinolides C, C2, and F.
The symbiotic marine dinoflagellate Amphidinium sp., iso-
lated from the cells of aceol flatworms Amphiscolops sp.,
produces a structurally diverse group of macrolide natural
products.1 This group of macrolides, named amphidinolides,
contains over 30 compounds, and the majority of them
possess some level of cytotoxicity.
Amphidinolide C (1) (Scheme 1), isolated from the Y-5
strain of Amphidinium sp., is one of the most cytotoxic
members of the amphidinolide family.2 Embedded within
this macrolide are two 2,5-trans tetrahydrofuran rings and
12 stereocenters. Amphidinolide C was shown to possess
cytotoxicity against murine lymphoma L1210 (IC50 0.0058
µg/mL) and human epidermoid carcinoma KB (IC50 0.0046
µg/mL) in vitro. Interestingly, amphidinolides C2 (2) and F
(3), which vary only in the structure of the side chain, are
close to 1000-fold less active.
targets for synthesis. The syntheses of several fragments of
these molecules have been reported, but they have yet to
succumb to total synthesis.3
Our retrosynthetic analysis (Scheme 1) for amphidinolide
C divides the molecule into four different subunits; the
northern (C18-25), the southern (C1-C9), and the western
(C10-C17) subunits and the side chain (C26-C34). In this
paper, we describe the synthesis of the tetrahydrofuran (THF)
ring of C1-C9 fragment of amphidinolides C, C2, and F.
The C1-C9 fragment of amphidinolide C contains a 2,3,5-
trisubstituted tetrahydrofuran with a methyl substituent at the
3-position (4-position in amphidinolide C numbering). The
stereochemical relationship between the substituents is 2,5-
and 2,3-trans and 3,5-cis. Similar 3-methyl-substituted
tetrahydrofuran moieties are found in several other natural
products, e.g., monensin A,4 amphidinolides T15 and T3,6
tetronasin,7 gambieric acid,8 and gymnodimine.9
Due to their unique structure and noteworthy biological
activity, amphidinolides C (1), C2 (2), and F (3) have become
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T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59, 1613. (d) Armstrong,
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Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363.
10.1021/ol100959a  2010 American Chemical Society
Published on Web 06/07/2010

Scheme 1. Retrosynthetic Analysis of Amphidinolide C
A particular challenge is finding a method to install the
The known homoallylation of benzaldehyde was used to
initiate a model study. The reaction of benzaldehyde with
isoprene catalyzed by Ni(acac)2 and promoted by triethylbo-
rane yielded homoallyl alcohol 4 with a 1,3 anti/syn ratio of
>15:1 (Scheme 3).10a Palladium-catalyzed cyclization/meth-
oxycarbonylation of the hydroxyalkene 4 using modified
Semmelhack conditions11 gave the tetrahydrofuran 6 in 68%
yield with a 2,5-trans/cis ratio of 9:1.
methyl group in an efficient manner. A retrosynthetic analysis
(Scheme 2) reveals that unfolding of the tetrahydrofuran ring
results in an unsaturated alcohol with a 1,3-anti relationship
between the methyl and hydroxyl groups. In the forward
sense, the tetrahydrofuran can be formed by the addition of
Scheme 2. Retrosynthetic Analysis of the C1-C9 Fragment
Scheme 3. Synthesis of Tetrahydrofuran Ring
the alcohol across the double bond. The cis orientation of
R1 and the methyl group in the transition state for cyclization
would direct the developing stereocenter at position 2 trans
relative to the existing stereocenters (positions 3 and 5),
resulting in the required 2,5-trans tetrahydrofuran ring.
Substituted 1,3-anti unsaturated alcohols can be prepared
very efficiently from appropriately functionalized aldehydes
using the highly diastereoselective nickel-catalyzed homoal-
lylation chemistry reported by Tamaru et al.10 Herein, we
report the results of the Tamaru reaction with a series of
novel electrophiles with specific application to the synthesis
of the C1-C6 tetrahydrofuran fragment from amphidiolides
C, C2, and F.
Alternatively, cross metathesis of the hydroxyalkene 4 with
methyl acrylate in the presence of second-generation Grubbs
catalyst and copper(I) iodide12 gave the R,ꢀ-unsaturated
methyl ester 5 in 79% yield. Cyclization of 5 with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)13 in CH2Cl2 gave 2,5-
trans-tetrahydrofuran 6 as a single diastereomer in an
(10) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem.
Soc. 1998, 120, 4033. (b) Tamaru, Y.; Kimura, M.; Fujimatsu, H.; Ezoe,
A.; Shibata, K.; Shimizu, M.; Matsumoto, S. Angew. Chem., Int. Ed. 1999,
30, 397. (c) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. J. Am.
Chem. Soc. 2006, 128, 8559. (d) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru,
Y. Angew. Chem., Int. Ed. 2001, 40, 3600.
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Tetrahedron Lett. 1995, 36, 7093.
Org. Lett., Vol. 12, No. 13, 2010
2955

excellent 93% yield. Thus, using either method, the required
2,5-trans-tetrahydrofuran with correct relative configuration
for the C1-C9 fragment of amphidinolide C was achieved.
The next challenge was to identify a suitable aldehyde that
contained, or that had suitable functionality for introducing,
the 1,2-anti diol found at positions 7 and 8 of ampidinolide
C. Initial efforts focused on the hemiacetal derivatives of
erythronolactone.
catalyzed cyclization/methoxycarbonylation of major isomer
9b failed to yield the tetrahydrofuran 14b. Therefore, the
alternate chain extension and cyclization method was ex-
amined. Cross-metathesis of both the minor isomer 9a and the
major isomer 9b with methyl acrylate gave R,ꢀ-unsaturated
methyl esters 13a and 13b, respectively (Scheme 5). Cyclization
Homoallylation of the bis-tert-butyldimethylsilyl (TBS)-
protected hemiacetal 8 provided two diastereomers 9a and
9b in 63% combined yield with 1:6 diastereoselectivity
(Scheme 4). The diastereomers were separated by silica gel
column chromatography. The major diastereomer 9b was
crystalline and could be recrystallized to give X-ray quality
crystals.
Scheme 5. Cross Metathesis and Cyclization
Scheme 4. Homoallylation of Erythrolactol
of 13a and 13b using DBU afforded the tetrahydrofurans 14a
and 14b. Some migration of silyl group was observed during
the cyclization process. The TBS group migrated from the
secondary 14 to the primary position 15 (Scheme 5).16
In order to avoid protecting group migration and perhaps
effect a more favorable stereochemical outcome, an alternate
protecting group was examined. Homoallylation of acetonide-
protected hemiacetal 11 (Scheme 4) gave a mixture of
diastereomers 12a and 12b in a 1:3 ratio. The diastereomers
were separable by repeated silica gel column chromatogra-
phy. Cross metathesis of the major diastereomer 12b with
methyl acrylate (Scheme 6) followed by cyclization with
DBU gave 17 in 80% yield.
The crystal structure of major diastereomer 9b (see the
Supporting Information) clearly shows that the silyloxy
groups at C2 and C3 are anti and the hydroxyl and methyl
groups at C4 and C6 are anti. However, the silyloxy at C3
and the hydroxy at C4 have the wrong relative configuration
(anti), and thus, the minor isomer 9a has the correct relative
(3,4-syn) and absolute configuration required for amphidi-
nolide C.
The observed diastereofacial selectivity was much higher
than expected for the homoallylation reaction. In the limited
number of chiral aldehydes investigated by Tamaru et al.,
the diastereofacial selectivity with respect to the aldehyde
was typically very low (1:1 to 1.6:1).10c The formation of
the major isomer 9b appears to follow the trend observed
by Evans et al. in the aldol reactions of a series of alkoxy
and bisalkoxy aldehydes.14 A Cornforth model15 was used
to explain stereochemical outcome of the addition of the
enolate to the aldehyde.
Scheme 6. Cross Metathesis and Cyclization
Undaunted by this setback, the cyclization of both dia-
stereomers 9 was investigated. The Semmelhack palladium-
(13) Abbineni, C.; Sasmal, P. K.; Mukkanti, K.; Iqbal, J. Tetrahedron
Lett. 2007, 48, 4259.
To compare the configuration of the tetrahydrofurans 17
and 14b obtained from the acetonide-protected hemiacetal
11 and the TBS-protected hemiacetal 8, the protecting groups
were removed (Scheme 7). The TBS groups were cleaved
using HF/pyridine in MeOH, which provided the triol 18 in
(14) Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128,
9433.
(15) (a) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem.
Sec. 1959, 112. (b) Burgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem.
Soc. 1973, 95, 5065. (c) Burgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G.
Tetrahedron 1974, 30, 1563.
2956
Org. Lett., Vol. 12, No. 13, 2010

70% yield. The acetonide group was removed using Am-
berlyst 15 resin in MeOH to give the triol 18 in 60% yield.
The 1H and 13C spectra of the triol 18 obtained by
deprotection of both 14b and 17 were identical, suggesting
that the tetrahydrofuran obtained from both hemiacetals have
the same configuration.
Scheme 8. Homoallylation, Cross Metathesis, and Cyclization
Scheme 7. Deprotection of TBS and Acetonide Groups
Next, our attention turned to epoxy aldehydes. Epoxides
are versatile functional groups that can be opened with water
to reveal a diol or oxidatively cleaved to obtain an aldehyde.
As a consequence, epoxycinnamaldehyde 19 was selected
as the next substrate for homoallylation. Oxidation of
commercially available (2R,3R)-3-phenylglycidol (epoxy-
cinnamyl alcohol)17 gave (2R,3R)-3-phenylglycidal 19 in
73% yield. Homoallylation of 19 gave a separable mixture
of diastereomers 20 in a 2.5:1 ratio and 63% combined yield
(Scheme 8). The absolute configuration of the diastereomers
was determined by the Mosher ester method.18 The major
isomer 20a possessed the correct configuration for the
tetrahydrofuran ring of amphidinolide C.
Aldehyde 23b has been elaborated into the C1-C9
fragment of amphidinolide C by Roush and co-workers.3a
Therefore, the synthesis of tetrahydrofuran alcohol 24b and
aldehyde 23b constitute a formal synthesis of the C1-C9
fragment of amphidinolide C. The aldehyde 23b was
prepared in five steps from the commercially available phenyl
glycidol in 12% overall yield. Roush reported two routes to
C1-C9 fragments. The first approach gave a C1-C9
fragment in 13 steps in <7% yield (17 from commercial
materials). A second more efficient approach proceeded via
aldehyde 23b, which was formed in 10 steps from com-
mercial materials in 21% overall yield. We have provided a
shorter synthesis of 23b, but with a lower overall yield.
Cross metathesis of 20a with methyl acrylate (or ethyl
acrylate) gave R,ꢀ-unsaturated methyl (or ethyl) ester 21a
(or 21b) which on cyclization with DBU gave 22a (or 22b)
as a single isomer. Cleavage of the epoxide in tetrahydrofuran
22a (or 22b) with NaIO4 in acetonitrile/water (2:1)19 gave
aldehyde 23a (or 23b), which could be isolated or subse-
quently reduced in situ with NaBH4 in MeOH to afford
alcohol 24a (or 24b) in 64% overall yield (Scheme 8). The
enantiomers of alcohol 24a could be separated by GC on a
chiral stationary phase. The alcohol (24a) derived from the
nonracemic glycidol had an enantiomeric excess of >95%.
Acknowledgment. This work was supported by Grant No.
R01-GM076192 from the National Institute of General
Medical studies. We are also grateful to the National Science
Foundation for a grant to purchase the X-ray diffractometer
(CHE-9309690). We thank Prof. R. E. K. Winter and Mr.
Joe Kramer of the Department of Chemistry and Biochem-
istry, University of MissourisSt. Louis, for mass spectra.
1
The tetrahydrofuran aldehyde 23b and alcohol 24b had H
and 13C NMR spectra and optical rotation matching those
reported by Roush and co-workers.3a
(16) (a) Ogilvie, K. K.; Entwistle, D. W. Carbohydr. Res. 1981, 89,
203. (b) Mulzer, J.; Schollhorn, B. Angew. Chem., Int. Ed. 1990, 29, 431.
(c) Wuts, P. G. M.; Bigelow, S. S. J. Org. Chem. 1988, 53, 5023. (d) Crich,
D.; Ritchie, T. J. Carbohydr. Res. 1990, 197, 324, and references cited
therein.
Supporting Information Available: Detailed experimen-
tal procedure and spectral data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Chow, K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126.
(18) (a) Mosher, H. S.; Dale, J. A. J. Am. Chem. Soc. 1973, 95, 512.
(b) Kubota, T.; Tsuda, M.; Kobayashi, Y. Tetrahedron 2003, 59, 1613. (c)
Hammerschmidt, F.; Li, Y. F. Tetrahedron 1994, 50, 10253.
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B. Tetrahedron Lett. 2008, 49, 2764.
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