Stereoselective synthesis of amphiasterin B4: Assignment of absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2010.10.098

The first asymmetric synthesis of (+)-amphiasterin B4 was completed from a known (S)-β-benzyloxy-γ-lactone. Comparison with the spectroscopic properties reported for authentic material has given a clear indication as to the absolute stereochemistry of the

Full text of DOI:10.1016/j.tetlet.2010.10.098

Tetrahedron Letters 51 (2010) 6767–6768
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of amphiasterin B4: assignment
of absolute configuration
⇑
Masaki Takahashi, Takamasa Suzuki, Jolanta Wierzejska, Tetsuya Sengoku, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric synthesis of (+)-amphiasterin B4 was completed from a known (S)-b-benzyloxy-c-
Received 29 September 2010
Revised 15 October 2010
Accepted 20 October 2010
Available online 26 October 2010
lactone. Comparison with the spectroscopic properties reported for authentic material has given a clear
indication as to the absolute stereochemistry of the natural amphiasterin B4.
Ó 2010 Elsevier Ltd. All rights reserved.
Amphiasterins are
a
novel class of cytotoxic metabolites
demonstrated for a similar system,5 this chiral building block
was readily transformed to trans-fused succinimide 2 in an overall
yield of 16% through the six-step sequence involving the highly
stereoselective hydroxylation with 2-phenylsulfonyl-3-phenylox-
aziridine.6,7 The reaction of 2 with methylmagnesium bromide re-
sulted in a regioselective nucleophilic addition to the C2 carbonyl
(IC50 <6 M, NSCLC-N6 cancer cells) originally isolated from Pla-
l
kortis quasiamphiaster, a marine sponge collected off both Carib-
bean and Indo–Pacific coral reefs.1 From a structural point of
view, amphiasterins can be classified into five groups (A–E series),
whose components differ from each other in terms of the nature of
the lateral chains. Accordingly, amphiasterins B, being comprised
of five constituent members, share a common structural motif con-
group to afford the corresponding
could be reduced using sodium borohydride in methanol due to
spontaneous equilibrium with the acyclic -ketoamide at ambient
temperature, giving rise to acyclic -hydroxyamide 3 in 72% for
c
-hydroxylactam.8 This product
sisting of an
a-hydroxymethyl-b-hydroxy-substituted
c-butyro-
c
lactone moiety and long carbon chains at the
c
-position of the
c
lactone ring (Fig. 1). Despite the obvious importance of this series
of molecules, their biological activities have not been extensively
studied due to a limited availability in nature, and their synthetic
value is still underdeveloped.2 Recently, Piva and Salim have re-
ported the first total synthesis of amphiasterin B4, a noteworthy
success based on regio- and stereoselective cyclization of racemic
epoxydiols.3 Unfortunately, however, the synthesis was performed
non-enantioselectively, and the absolute stereochemistry of this
natural product has remained unspecified, since only the relative
configurations of the stereogenic centers have been defined by
the same group. From this basis, we decided to explore an asym-
metric approach employing a chiral pool strategy for the prepara-
tion of enantiomerically pure form of this compound. In this Letter,
we report the success of our synthetic approach to (+)-amphiaster-
in B4, which allowed the definite assignment of the absolute con-
figuration of the naturally occurring material.
two-steps.9 From the synthetic viewpoint, our next objective was
conversion of the secondary hydroxy group into ketone in order
to install the long side chain via a nucleophilic addition at some
stage of the synthesis. For this purpose, we first attempted replace-
ment of the secondary amide group in 3 with an N,N-dialkylated
amide group due to the fact that oxidation of this compound re-
sults in equilibrating reversion into the starting c-hydroxylactam.
Accordingly, THP-protected substrate 4, which was prepared quan-
titatively from 3, was converted into N,N-dimethyl amide deriva-
tive 5 through NaH deprotonation and subsequent reaction with
methyl iodide. At this point it must be noted that introducing
sterically demanding substituents adjacent to the putative car-
bonyl functionality can give significant improvements in stereose-
lectivity of nucleophilic addition to the carbonyl group.10
Therefore, the benzyl protective groups of 5 were selectively
Our approach to amphiasterin B4 started with the preparation
of (S)-b-benzyloxy-c-lactone 1 chosen as an appropriate chiral
HO
OH
HO
OH
building block (Scheme 1). Conversion of dihydroxyacetone dimer
into enantiomerically pure form of 1 was accomplished by an
already published reaction protocol employing diastereomeric
separation with (S)-(À)-
O
O
O
O
n
n
amphiasterin B1; n=10
B2; n=12
amphiasterin B4; n=10
B5; n=12
a
-methylbenzylamine.4 As has been
B3; n=16
⇑
Corresponding author. Tel./fax: +81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
Figure 1. Structures of constituent members of amphiasterins B1–B5.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.098

6768
M. Takahashi et al. / Tetrahedron Letters 51 (2010) 6767–6768
OBn
In conclusion, we have reported the success in achieving the
synthesis of (+)-amphiasterin B4. The identity and stereochemistry
of this product have been unequivocally established, with the most
convincing evidence furnished by comparison with the properties
reported for authentic material. To the best of our knowledge, this
report represents the first example of asymmetric elaboration of
amphiasterin B4 as well as the initial disclosure of the absolute ste-
reochemistry of the natural amphiasterin B4.
BnO
OH
BnO
OH
O
O
4
3
a
b
1
N
O
O
2
Me
HO
5
O
O
HO
dihydroxyacetone dimer
1
2
OBn
BnO
BnO
MeHN
c
O
N
Me
O
OH
d
O
OBn
Acknowledgment
BnO
BnO
Me2N
TBDPSO
Me2N
f
g
i
OR
OTHP
OR
This research was supported by a Grant-in-aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
MeHN
O
OBn
O
OBn
O
OTBS
3; R = H
5
6; R = THP
7; R = H
h
k
e
4; R = THP
References and notes
TBDPSO
Me2N
TBDPSO
Me2N
1. Zampella, A.; Giannini, C.; Debitus, C.; D’Auria, M. V. Tetrahedron 2001, 57, 257–
263.
2. Ralifo, P.; Sanchez, L.; Gassner, N. C.; Tenney, K.; Lokey, R. S.; Holman, T. R.;
Valeriote, F. A.; Crews, P. J. Nat. Prod. 2007, 70, 95–99.
j
HO
OH
4
O
OH
C15H31
OTBS
3
1
O
2 O
5
C15H31
O
OTBS
O
3. Salim, H.; Piva, O. J. Org. Chem. 2009, 74, 2257–2260.
4. (a) Yoda, H.; Mizutani, M.; Takabe, K. Synlett 1998, 855–856; (b) Yoda, H.;
Mizutani, M.; Takabe, K. Tetrahedron Lett. 1999, 40, 4701–4702.
5. Sengoku, T.; Suzuki, T.; Kakimoto, T.; Takahashi, M.; Yoda, H. Tetrahedron 2009,
65, 2415–2423.
6. (a) Jefford, C. W.; Wang, J. B.; Lu, Z. –H. Tetrahedron Lett. 1993, 34, 7557–7560;
(b) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774–1775.
7. On the basis of simple 1H NMR spectral data, 2 was isolated as a single
enantiomer that has (3S,4S)-configuration, see Ref. 5
8. The high regioselectivity of the Grignard addition to the C2 carbonyl group
could be attributed to the complex induced proximity effect, see: (a) Beak, P.;
Meyers, A. I. Acc. Chem. Res. 1986, 19, 356–363; (b) Yoda, H.; Yamazaki, H.;
Kawauchi, M.; Takabe, K. Tetrahedron: Asymmetry 1995, 6, 2669–2672; (c)
Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang, Y. Q.; Zheng, H.; Gao, J. X.
Tetrahedron 1998, 54, 12547–12560.
8
9
(+)-amphiasterin B4
Scheme 1. Reagents and conditions: (a) see Ref. 4; (b) (i) LiHMDS, 2-phenylsul-
fonyl-3-phenyloxaziridine, THF, À78 °C; (ii) BnBr, Ag2O, EtOAc; (iii) MeNH2, THF–
MeOH (2:1); 34% (three-steps); (iv) (COCl)2, DMSO, DIPEA, CH2Cl2–THF (2:1), À78
to 0 °C; (v) BF3ÁOEt2, THF, 0 °C; 80% (two-steps); (vi) PCC, MS4Å, CH2Cl2, 0 °C to rt;
58%; (c) MeMgBr, THF, À78 to 0 °C; (d) NaBH4, MeOH, 72% (two-steps); (e) 2,3-DHP,
PTSA, CH2Cl2, 0 °C; quant; (f) MeI, NaH, THF, 0 °C; (g) (i) H2, Pd/C, EtOH; (ii) TBDPSCl,
Et3N, CH2Cl2; (iii) TBSOTf, 2,6-lutidine, CH2Cl2, À78 to 0 °C; 71% (four-steps); (h)
PTSA, MeOH; 74%; (i) PDC, MS4Å, CH2Cl2; 78%; (j) n-C15H31MgBr, CeCl3, THF, À40 to
À20 °C; 72% (93:7); (k) (i) PTSA, toluene, 60 °C ; quant; (ii) 3% HCl–MeOH; 84%.
removed by hydrogenolysis (H2, Pd/C) and the resulting primary
and secondary hydroxy functionalities were then protected as
the tert-butyldiphenylsilyl (TBDPS) and tert-butyldimethylsilyl
(TBS) ethers, respectively, to give 6 in 71% yield for four-steps.11
Removal of the THP group of 6 using p-toluenesulfonic acid
(PTSA) in methanol provided the corresponding alcohol 7 in 74%
yield, which was then subjected to PDC oxidation in dichlorometh-
ane to afford the ketone 8 in 78% yield as a single stereoisomer.12
As anticipated, the reaction of 8 with n-pentadecylmagnesium bro-
mide proceeded with remarkably high stereoselectivity in the
presence of CeCl3 at À20 °C to give a 93:7 ratio of diastereomeric
alcohols in 72% yield.13 The major stereoisomer 9, obtained
through purification by column chromatography, underwent a
PTSA-catalyzed cyclization at 60 °C to produce an almost quantita-
tive yield of the fully protected lactone without racemization. Fol-
lowing deprotection of the silyl ethers by brief exposure to HCl in
methanol, the fully synthetic amphiasterin B4 was obtained in 84%
yield as an enantiomerically pure form. The structural identity of
the synthetic and natural amphiasterin B4 was established by com-
parison of 1H and 13C NMR spectral data with literature data,14
whereas the synthetic sample showed an approximately the same
9. Yoda, H.; Kitayama, H.; Takabe, K.; Kakehi, A. Tetrahedron: Asymmetry 1993, 4,
1759–1762.
10. In fact, we observed that reaction of some Grignard reagents with dibenzyloxy-
substituted ketone derived directly from 5 (see below) gave a decreased
stereoselectivity (80:20) compared to those of structurally modified substrates
bearing much bulkier silyl substituents as will be elaborated below.
BnO
O
Me2N
O
OBn
11. An attempt to introduce the TBDPS group on the secondary hydroxy group
failed presumably due to steric congestion. Therefore, the TBS group was used
as an alternative to mask the hydroxy functionality.
12. High purity of the product was confirmed by the simplicity of the 1H and 13C
NMR spectra that were consistent with the assigned structure, suggesting no
racemization occurred in this oxidation step.
13. For example, the reaction of the dibenzyloxy-substituted ketone (see Ref. 10)
in the absence of CeCl3 resulted in a dramatic decrease of diastereoselectivity
showing opposite preference (21:79). Therefore, the addition of CeCl3 is
necessary to obtain the desired isomer 9 with greater stereoselectivity, since
this stereochemical course can be understood on the basis of a simple non-
chelation model.
14. Characterization data for (+)-amphiasterin B4: IR (NaCl) m ;
max 3436, 1733 cmÀ1
1H NMR (300 MHz, CDCl3) d 4.29 (dd, J = 9.9, 5.0 Hz, 1H, CH), 4.04 (m, 1H, CH2),
3.92 (m, 1H, CH2), 2.83 (dt, J = 9.9, 4.6 Hz, 1H, CH), 2.73 (d, J = 5.0 Hz, 1H, OH),
2.56 (br s, 1H, OH), 1.78–1.66 (m, 3H, CH2), 1.45–1.21 (m, 30H, CH2), 1.36 (s, 3H,
CH3), 0.88 (t, J = 6.6, 3H, CH3); 13C NMR (CDCl3) d 174.1 (C), 87.0 (C), 74.6 (CH),
59.3 (CH2), 49.4 (CH), 39.8 (CH2), 31.9 (CH2), 29.8 (CH2), 29.61 (CH2), 29.57
(CH2), 29.55 (CH2), 29.48 (CH2), 29.40 (CH2), 29.3 (CH2), 23.4 (CH2), 22.7 (CH2),
18.9 (CH3), 14.1 (CH3). Anal. Calcd for C21H40O4: C, 70.74; H, 11.31. Found: C,
70.61; H, 11.08.
but opposite optical rotation, [a]D +2.8 (c 0.8, CHCl3), compared to
the reported value, [
a
]
D À3.3 (c 0.3, CHCl3).1 From this, we are rea-
sonably confident that the absolute configurations of the naturally
occurring amphiasterin B4 should be assigned as 3R, 4R, and 5S.
Hence, it is obvious that the synthetic route developed could pro-
vide easy access to the optically active amphiasterin B family.