Stereoselective Synthesis of the C25-C36 Segment of Arenicolides A and B: Determination of the Configuration of the Trisubstituted Epoxide

Article abstract of DOI:10.1021/ol902750e

Chemical Equation Presentation Two diastereomerlc epoxides 4a and 4b corresponding to the C₂₅-C₃₆ fragment of arenicolides A and B were synthesized in a stereoselective manner involving the Pd(0)-catalyzed stereospecific methoxy substitution reaction of epoxy unsaturated ester 6 with B(OMe)₃ as the key step. Comparison of the ¹H NMR spectra of the synthetic compounds with that of arenicolide A revealed that the configuration of the epoxide in arenicolides A and B is 30R and 31R

Full text of DOI:10.1021/ol902750e

ORGANIC
LETTERS
2
010
Vol. 12, No. 5
08-911
Stereoselective Synthesis of the
9
C -C Segment of Arenicolides A
2
5
36
and B: Determination of the
Configuration of the Trisubstituted
Epoxide
†
†
†
‡
Shinji Nagumo, Taeko Nakano, Kyomi Hata, Megumi Mizukami, and
,†
Masaaki Miyashita*
Department of Applied Chemistry, Kogakuin UniVersity, Nakano 2665-1,
Hachioji, Tokyo 192-0015, Japan, and Hokkaido Pharmaceutical UniVersity,
School of Pharmacy, Katsuraoka 7-1, Otaru 047-0264, Japan
bt13149@ns.kogakuin.ac.jp
Received November 29, 2009
ABSTRACT
Two diastereomeric epoxides 4a and 4b corresponding to the C25-C36 fragment of arenicolides A and B were synthesized in a stereoselective
manner involving the Pd(0)-catalyzed stereospecific methoxy substitution reaction of epoxy unsaturated ester 6 with B(OMe) as the key step.
3
1
Comparison of the H NMR spectra of the synthetic compounds with that of arenicolide A revealed that the configuration of the epoxide in
arenicolides A and B is 30R and 31R.
Marine organisms have been known to produce a wide
variety of secondary metabolites to adapt themselves to
the environment of the ocean. Searching for new com-
pounds from these metabolites can often provide us with
a good opportunity to find a promising candidate for drug
development. In the course of their active research, Fenical
and co-workers isolated salinosporamide A, a potent
proteasome inhibitor, from the fermentation broth of
were discovered by the same group in the fermentation
broth of Salinospora arenicola and arenicolide A (1)
exhibited cytotoxicity against human colon adenocarci-
2
noma cell lines. The absolute structures of 1-3 were
determined based on spectroscopic analyses and chemical
degradation (Figure 1), although the configuration of the
methyl group at the C12 position and that of the trisub-
stituted epoxide in arenicolides A and B (1 and 2) have
yet remained undetermined. Evidently, the arenicolides
are a new type of polyene macrolide composed of a 26-
membered lactone ring containing three characteristic
conjugated (E,E)-diene units and three or four sets of an
1
marine actinomycete Salinispora. The new molecule is
currently in phase I of human clinical trials for cancer.
Recently, three new compounds, arenicolides A-C (1-3),
†
Kogakuin University.
Hokkaido Pharmaceutical University.
‡
(
1) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
(2) Williams, P. G.; Miller, E. D.; Asolkar, R. N.; Jensen, P. R.; Fenical,
W. J. Org. Chem. 2007, 72, 5025.
Jensen, P. R.; Fenical, W. Angew, Chem., Int. Ed. 2003, 42, 355.
1
0.1021/ol902750e  2010 American Chemical Society
Published on Web 01/29/2010

unsaturated ester A, easily obtainable from commercially
available (E)-2-hexen-1-ol, would be stereoselectively
converted to unsaturated ester B bearing a syn-vicinal
hydroxy-methoxy structure, by means of the Pd(0)-
catalyzed stereospecific alkoxy substitution reaction of A
4
with B(OMe)
3
, which was recently developed by us. The
unsaturated ester B would be transformed into two
diastereomeric epoxy alcohols C and D, from which the
targeted compounds 4a and 4b would be derived via a
similar synthetic reaction sequence, respectively.
The synthesis of the two requisite fragments 4a and 4b
was performed according to Scheme 2. Thus, the chiral epoxy
Figure 1
.
Structures of arenicolides A (1), B (2), and C (3).
Scheme 2. Synthesis of Intermediate 13a
extremely rare vicinal hydroxy-methoxy structure, and a
side chain bearing a trisubstituted epoxide (arenicolides
A and B) or a fully substituted tetrahydrofuran ring
(
arenicolide C), in which fourteen asymmetric carbon
atoms are included in total.
Very recently, Lee and co-workers have reported the
synthesis of a C26-C36 segment bearing (30R, 31R)-
epoxide, although the configuration of the epoxide in the
3
arenicolides has not been clarified by their synthesis.
The quite unique structures of the arenicolides, as well
as their distinctive biological properties, prompted us to
start a synthetic study on these natural products. To this
end, we initially set about to determine the configuration
of the trisubstituted epoxide in arenicolides A and B (1
and 2).
To determine the configuration of the epoxide unam-
biguously, we planned to synthesize two diastereomeric
epoxides 4a and 4b corresponding to the C25-C36 segment
in 1 and 2 (Scheme 1). In this regard, a chiral R-epoxy
alcohol 5 prepared from (E)-2-hexen-1-ol, by the Katsuki-
Sharpless asymmetric epoxidation, was subjected to the
Dess-Martin oxidation followed by a Wittig reaction to
furnish epoxy unsaturated ester 6 in 87% yield. The key syn-
methoxy substitution reaction of 6 at the γ-position was
5
successfully performed by a combination of Pd(OAc)
3 3
furyl) , and B(OMe) in THF giving rise to the desired syn-
2
, P(2-
4
Scheme 1
.
Strategy for the Synthesis of Two Diastereomeric
δ-hydroxy-γ-methoxy unsaturated ester 7 in 72% isolated
yield. Reduction of 7 with DIBAL-H in hexane produced
diol 8 in 99% yield, which underwent epoxidation with
m-CPBA to afford a nearly 1:1 inseparable mixture of
diastereomers 11a and 11b in 94% combined yield. On the
other hand, protection of the alcohol 7 with a TBS group
followed by reduction of the ester 9 with DIBAL-H gave
allylic alcohol 10 in 94% yield. Subsequent epoxidation of
Epoxides 4a and 4b
1
2 2
0 with m-CPBA in CH Cl stereoselectively occurred from
6
the opposite side of the TBS group giving rise to 12a as a
single product, which was then converted to epoxy unsatur-
(
3) Lee, J. L.; Han, S.-J.; Lee, D.-H. Bull. Korean Chem. Soc. 2009,
0, 1443.
4) Yu, X.-Q.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.; Tanino,
3
(
K.; Miyashita, M. Angew, Chem., Int. Ed. 2008, 47, 750.
(
(
5) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
6) Maruyama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.; Miyazawa, M.;
Miyashita, M. Tetrahedron Lett. 1998, 39, 4517.
Org. Lett., Vol. 12, No. 5, 2010
909

7
ated ester 13a by the Dess-Martin oxidation followed by
a Wittig reaction in 80% overall yield.
Scheme 4. Synthesis of C25-C36 Segments 4a and 4b
To determine the stereochemistry of the two epoxides, the
mixture of 11a and 11b was initially subjected to oxidation
8
with TEMPO and BAIB followed by a Wittig reaction to
afford a mixture of epoxy unsaturated esters 14a and 14b,
which was fortunately separated by silica gel column
chromatography. First, the R-epoxy unsaturated ester 14b
was converted to acetonide 16 by a two-step reaction
3 4
sequence: (1) reductive epoxide-opening with [Pd(PPh ) ]
9
and BH
3
-NHMe
2
in CH
2
Cl
2
in the presence of AcOH and
C(OMe) and
(
2) acetonization of R-syn-diol 15 with Me
2
2
1
0
13
PPTS. The C NMR spectrum of 16 exhibited peaks due
to the methyl groups on the acetonide at 29.75 and 18.97
ppm, and a peak due to the acetal carbon atom at 98.86 ppm,
which clearly indicated that the stereochemistry of the
1
1
acetonide in 16 was syn (Scheme 3). On the other hand,
Scheme 3. Determination of the Stereochemistry of the Epoxide
by the same two-step reaction sequence: (1) Dess-Martin
oxidation and (2) Wittig reaction. The subsequent crucial
Pd(0)-catalyzed reductive epoxide-opening reaction of 19a
1
2
and 19b with HCOOH nicely occurred at the γ-position,
giving rise to the desired products 20a and 20b, respec-
tively. Finally, removal of the TBS group with aqueous
AcOH and reduction of the resulting dihydroxy ester with
DIBAL-H furnished the two targetted compounds 4a and
4
b, respectively, corresponding to the C25-C36 segment
in 1 and 2.
The synthetic fragments 4a and 4b showed remarkable
1
differences in their 400 MHz H NMR spectra in CDCl
3
,
particularly, with respect to the chemical shifts of the
protons at the C29, C31, C32, and C33 positions as shown
in Table 1. Namely, the chemical shifts of the protons at
the C29, C31, C32, and C33 positions in 4a are very close to
those of arenicolide A, whereas those of 4b are obviously
different from the latter, inter alia, the chemical shifts of
the protons at the C29, C31, and C33 positions. Although
each coupling constant of the particular protons in 4a is
apparently different from that in arenicolide A, it is
presumed that the presence of four vicinal hydroxy-
methoxy structures and two additional hydroxyl groups
and an epoxide in the natural product might make
extremely difficult the measurements of their coupling
constants in the densely close chemical shifts. Thus, we
concluded that the configuration of the trisubstituted
epoxide in arenicolides A and B (1 and 2) is (30R,31R)
by comparison of the chemical shifts of the protons at
protection of the alcohol 14b with a TBS group furnished
1
3b in 79% yield.
With the two requisite epoxy unsaturated esters 13a and
3b in hand, we next focused on the synthesis of 20a and
0b corresponding to the C25-C36 fragment. These
1
2
conversions were carried out according to Scheme 4. Thus,
reduction of 13a and 13b with DIBAL-H in THF followed
5
by the Katsuki-Sharpless epoxidation of the resulting
allyl alcohols with (D)-(-)-tartrate afforded diepoxides 18a
and 18b in high yields, respectively, which were converted
to diepoxy unsaturated esters 19a and 19b, respectively,
(
(
7) Dess, P. B.; Martin, J. C. J. Am. Chem. Soc. 1978, 100, 300.
8) Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
9) David, H.; Dupuis, L.; Guillerez, M. G.; Guib e´ , F. Tetrahedron Lett.
000, 41, 3335.
10) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
(
2
(
4
2, 3772.
(
11) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
3
1, 945. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
8, 3511.
(12) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am.
Chem. Soc. 1989, 111, 6280.
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910
Org. Lett., Vol. 12, No. 5, 2010

1
3
Table 1. The Characteristic Peaks in the 400 MHz H NMR Spectra (CDCl ) of 4a, 4b, and Arenicolide A (1)
2
4a [ppm]
4b [ppm]
arenicolide A [ppm]
C29-H
C31-H
C32-H
C33-H
3.37 (br t, J ) 6.1 Hz)
2.96 (d, J ) 8.5 Hz)
3.00 (dd, J ) 8.5, 3.9 Hz)
3.70 (br m)
3.78 (t, J ) 4.8 Hz)
3.32 (d, J ) 8.0 Hz)
3.00 (dd, J ) 8.0, 2.0 Hz)
3.55 (m)
3.39 (dd, J ) 11.0, 2.5 Hz)
3.04 (s)
3.07 (d, J ) 3.9 Hz)
3.68 (dt, J ) 8.3, 3.9 Hz)
the C29, C31, C32, and C33 positions in 4a, 4b, and
arenicolide A.
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science and Technology, Japan
(a Grant-in-Aid for Scientific Research (B) (No. 19350027)
and Advanced Promotion Research Program for Education
of Graduate School) is gratefully acknowledged.
In conclusion, we synthesized the two diastereomeric
epoxides 4a and 4b corresponding to the C25-C36 fragment
of arenicolides A and B (1 and 2) in a stereoselective
manner and the configuration of the epoxide in 1 and 2
was determined to be 30R and 31R by comparison of the
Supporting Information Available: Detailed experimen-
1
1
tal procedures, full characterization, and copies of H and
H NMR spectra of the synthetic compounds with that of
1
3
C NMR spectra of new compounds. This material is
arenicolide A (1). Further synthetic studies toward total
synthesis of arenicolides A-C are in progress in our
laboratory.
available free of charge via the Internet at http://pubs.acs.org.
OL902750E
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