Total synthesis of (-)-amathaspiramide F

Article abstract of DOI:10.1021/ol802179e

(Chemical Equation Presented) The stereoselective total synthesis of the marine alkaloid (-)-amathaspiramide F (1) was achieved from the α-hydoxy-α-ethynylsilane 2. The crucial steps in this synthesis involved not only the enolate Claisen rearrangement of

Full text of DOI:10.1021/ol802179e

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5449-5452
Total Synthesis of (-)-Amathaspiramide F
Kazuhiko Sakaguchi,* Miki Ayabe, Yusuke Watanabe, Takuya Okada,
Kazushige Kawamura, Tetsuro Shiada, and Yasufumi Ohfune*
Graduate School of Science, Department of Material Science, Osaka City UniVersity,
Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
sakaguch@sci.osaka-cu.ac.jp; ohfune@sci.osaka-cu.ac.jp
Received September 19, 2008
ABSTRACT
The stereoselective total synthesis of the marine alkaloid (-)-amathaspiramide F (1) was achieved from the r-hydoxy-r-ethynylsilane 2. The
crucial steps in this synthesis involved not only the enolate Claisen rearrangement of the r-acyloxy-r-alkenylsilane 6 for the construction of
the nitrogen-containing quaternary carbon center, but also the chemoselective formation of the azaspirohemiaminal 12 using heptamethyldisilazane
as the methylamine equivalent and the regioselective dibromination of the phenol moiety of 12 using n-Bu4NBrCl2.
Amathaspiramides A-F were isolated from a New Zealand
collection of the marine bryozoan Amathia wilsoni by Prinsep
et al. in 1999 (Figure 1).1 The structural features common
that these alkaloids would have an important biological
activity.2 However, only preliminary biological tests regard-
ing their antimicrobial, antiviral, and cytotoxic activities have
been performed for amathaspiramides A-C and E (moderate
antimicrobial and cytotoxic activities for A and E and potent
antiviral activity against Polio virus type-I for E), while those
of the other congeners have not yet been reported probably
due to only minute quantities being available from the marine
sources. Only one example for the total synthesis of
amathaspiramide F (1) has been reported by Trauner et al.3
Their unique structure together with unanswered questions
surrounding their biological activity prompted us to synthe-
size these alkaloids. In this paper, we describe the total
synthesis of 1 via the enolate Claisen rearrangement of an
R-acyloxy-R-alkenylsilane as a key step.
Figure 1. Amathaspiramides.
(2) For several biologically active natural products containing cyclic
spirolactam or hemiaminal structure, see the following examples. Massadine:
(a) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata, K.;
van Soest, R. W. M.; Fusetani, N Org. Lett. 2003, 5, 2255–2257. Azaspirene:
(b) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada,
H. Org. Lett. 2002, 4, 2845–2848. Axinellamine: (c) Urban, S.; Leone, P. A.;
Carroll, A. R.; Fechner, G. A.; Smith, J.; Hopper, J. N. A.; Quinn, R. J. J.
Org. Chem. 1999, 64, 731–735. Pseurotin A: (d) Komagata, D.; Fujita, S.;
Yamashita, N.; Saito, S.; Morino, T. J. Antibiot. 1996, 49, 958–959.
Synerazol: (e) Ando, O.; Satake, H.; Nakajima, M.; Sato, A.; Nakamura,
T.; Kinoshita, T.; Furuya, K.; Haneishi, T. J. Antibiot. 1991, 44, 382–389.
(3) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 4556–
4559.
to these alkaloids are characterized by a novel aza-spirobi-
cyclic framework that consists of three contiguous chiral
centers in which one of the amino groups is attached to the
quaternary carbon center, a cyclic hemiaminal moiety, and
11,13-dibrominated aromatic ring. These structures suggest
(1) Morris, B. D.; Prinsep, M. R. J. Nat. Prod. 1999, 62,
688–693.
10.1021/ol802179e CCC: $40.75
Published on Web 10/31/2008
2008 American Chemical Society

and subsequent formation of a spirohemiaminal unit with
methylamine. The dibromination to the aromatic ring of A
involves a critical problem in the choice of the phenoxy
protecting group. Our preliminary studies indicated that the
electrophilic brominaton of the methoxy derivative did not
provide the desired 4′,6′-dibromo derivative but a 6′-
monobromo compound.7 Further attempts to introduce the
4′-bromo group were not successful at all, suggesting that a
highly reactive phenol is needed for the dibromination of
A. Thus, methoxymethyl group, readily removable under
mild acidic conditions, was chosen for the protecting group
of the phenol moiety.
The optically active R-acyloxy-R-alkenylsilane has re-
ceived significant attention because of its chirality as well
as functional group transferring properties from the R- to
γ-position through a metal-catalyzed cationic rearrangement4
or an electrocyclic rearrangement of the enolate derived from
its acyloxy group.5 In particular, the ZnCl2-assisted ester-
enolate Claisen rearrangement6 of the R-acyloxy-R-alkenyl-
silanes having various N-protected R-amino acids as the
acyloxy group produced the vinylsilane-containing R-sub-
stituted R-amino acids with the complete transfer of the
original chirality, e.g., the (S,E)- and (S,Z)-R-alkenylsilane
produced the (2S,3R)- and (2S,3S)-vinylsilane, respectively
(eq 1).5a
The synthesis began with the preparation of the enolate
Claisen precursor, (S,Z)-R-acyloxysilane 6, from the
readily available racemic R-hydroxy-R-ethynylsilane 2
(Scheme 2).8 The palladium-catalyzed Sonogashira cou-
Scheme 2
We considered that this method is applicable for the
stereoselective construction of the consecutive C5 and C9
chiral centers of 1. We envisioned that (S,Z)-R-acyloxysilane
E, prepared from the R-hydroxy-R-ethynylsilane 2, would
undergo the ZnCl2-assisted enolate Claisen rearrangement
to give (2S,3R)-C via a chairlike transition state as shown
in Scheme 1. This can be converted into the azaspirohemi-
Scheme 1
pling of 2 with the MOM-protected 3-iodophenol under
standard conditions afforded the desired coupling product
3 (73%). The oxidation of 3 using Jones reagent or other
chromium reagents was rather troublesome when forming
the desired silyl ketone 4 in moderate yields due to the
significant loss of the TBDMS group. On the other hand,
this group was found to be stable under the Mukaiyama
oxidation conditions (NCS and catalytic PhSNH-t-Bu) to
give 4 in 81% yield without any loss of the TBDMS
group.9 The enantioselective reduction of 4 by (+)-DIP-
aminal A by the following sequence of transformations: (1)
cleavage of the terminal olefin followed by the construction
of the pyrrolidine B and (2) cleavage of the vinylsilane group
(7) In the preliminary studies, it was found that the electrophilic
bromination of the 3′-methoxy derivative 18 [NBS (2 equiv), DMF, rt, 18
h] gave only the 6′-monobrominated product 19 in 84% yield (Supporting
Information). At elevated temperature, the reaction was sluggish, and no
4′,6′-dibrominated product was obtained.
(4) (a) Sakaguchi, K.; Higashino, M.; Ohfune, Y. Tetrahedron 2003,
59, 6647–6658. (b) Sakaguchi, K.; Yamada, T.; Ohfune, Y. Tetrahedron
Lett. 2005, 46, 5009–5012. (c) Sakaguchi, K.; Okada, T.; Yamada, T.;
Ohfune, Y. Tetrahedron Lett. 2007, 48, 3925–3928.
(5) (a) Sakaguchi, K.; Suzuki, H.; Ohfune, Y. Chirality 2001, 13, 357–
365. (b) Morimoto, Y.; Takanishi, M.; Kinoshita, T.; Sakaguchi, K.; Shibata,
K. Chem. Commun. 2002, 42–43. (c) Sakaguchi, K.; Yamamoto, M.;
Kawamoto, T.; Yamada, T.; Shinada, T.; Shimamoto, K.; Ohfune, Y.
Tetrahedron Lett. 2004, 45, 5869–5872. (d) Sakaguchi, K.; Yamamoto, M.;
Watanabe, Y.; Ohfune, Y. Tetrahedron Lett. 2007, 48, 4821–4824.
(6) The ZnCl2-assisted dianionic enolate Claisen rearrangement of the
N-protected R-amino acid allyl ester was originally developed by Kazmaier:
Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998–999.
(8) Sakaguchi, K.; Fujita, M.; Suzuki, H.; Higashino, M.; Ohfune, Y.
Tetrahedron Lett. 2000, 41, 6589–6592.
(9) Matsuo, J.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron
2003, 59, 6739–6750.
5450
Org. Lett., Vol. 10, No. 23, 2008

Cl10 gave the optically pure (S)-R-hydroxysilane 3 (87%,
>95% ee). The (S,Z)-olefin 5 was prepared by the Pd-
catalyzed hydrostanylation of (S)-3 followed by an acidic
treatment (66%, two steps).11,12 The esterification of 5 with
racemic Boc-homoallylglycine was effected by using EDCI
in the presence of the catalytic DMAP to give the (S,Z)-R-
acyloxysilane 6 in 90% yield.
Next, we examined the enolate Claisen rearrangement of
(S,Z)-6 for the construction of the C5 and C9 stereocenters.
The treatment of (S,Z)-6 with LDA (4 equiv) in the presence
of ZnCl2 smoothly proceeded to give the desired (2S,3R)-
isomer 7 as an inseparable mixture of its diastereomer13
(83%, dr 7:1 by 1H NMR) (Scheme 3).14 The stereochemistry
group with a trifluoroacetyl (TFA) group gave 10 (91%),
which, upon ozonolysis, afforded the aldehyde 11 (dr 7:1).
The minor diastereomer was removed at this stage by flash
chromatography to give diastereomerically pure (2S,3R)-11
(73%).
For completion of the total synthesis of 1, the unexploited
spirohemiaminal formation and dibromination of the aromatic
group remained to be solved. The initial attempt for
construction of the spirohemiaminal was the treatment of
11 with excess methylamine in MeOH. The reaction gave
the desired spirohemiaminal 12 as the exclusive diastereomer
in 32% yield but was not reproducible. Control experiments
using 5 equiv of methylamine revealed that the reaction gave
a mixture of products consisting of the desired 12 (24%),
spirolactone 1316 (18%), butenolide 14 (22%), and lactam
15 (12%) (Scheme 4).17 It was assumed that the attack of
Scheme 3
Scheme 4
a Conditions: (1) OsO4 (0.05 equiv), NMO (2 equiv), 1,4-dioxane-H2O,
(3:1), rt, 16 h; (2) NaIO4 (1.7 equiv), t-BuOH-pH 6.7 buffer (3:2), rt, 3 h;
(3) NaBH3CN (1.7 equiv), AcOH, 70 °C, 1 h.
the methylamine on the proton attached to the R-position of
the carbonyl group resulted in the formation of the retro-
Michael products 14 and 15, since further treatment of each
product under the same reaction conditions remained un-
changed. Based on these results, we postulated that the
sterically bulky heptamethyldisilazane instead of the methy-
lamine would prevent the undesired ꢀ-elimination reaction.
In fact, the treatment with excess heptamethyldisilazane gave
12 in 50% yield and was reproducible. Only 15 was the
byproduct (12%) isolated from the reaction mixture (Scheme
5). The relative stereochemistry of 12 including the hydroxy
group at C8 was assigned as shown in Scheme 5 by the NOE
experiments. Prior to examining the dibromination of 12,
we observed that the bromination of the phenol derivative
10 with NBS (DMF, 0 °C) gave the 2′,4′,6′-tribrominated
product as the exclusive product indicating that NBS or Br2
is not a suitable reagent for the 4′,6′-dibromination of 12.18
Thus, we chose tetrabutylammonium dichlorobromate (n-
of the products was determined by converting them into the
corresponding spirolactams 12 (vide infra). The fact that
(2S,3R)-7 was obtained as the major diastereomer suggested
that the chairlike transition state D (Scheme 1) is the
preferential pathway for this transformation. The mixture was
converted to the R-substituted proline 8 by the following
sequence of reactions: (1) chemoselective dihydroxylation
of the terminal olefin with OsO4, (2) oxidative cleavage of
the resulting diol with NaIO4, and (3) reductive amination
with NaBH3CN in AcOH (67%, three steps from 7). The
silyl group was removed under acidic conditions to avoid
the troublesome oxidative cleavage of the vinylsilane
group.15 This reaction gave the protection-free phenol
derivative 9 in 88% yield. Reprotection of the resulting amino
(10) (a) Sonderquist, E. J.; Anderson, C. L.; Miranda, E. I.; Rivera, I.
Tetrahedron Lett. 1990, 31, 4677–4680. (b) Dahr, R. K. Aldrichim. Acta
1994, 27, 43–51.
(11) Liron, F.; Garrev, P. L.; Alami, M. Synlett 1999, 246–234
.
(15) It is reported that the ozonolysis of the vinylsilane does not give
the corresponding aldehyde; see: (a) Bu¨chi, G.; Wu¨est, H. J. Am. Chem.
Soc. 1978, 100, 294–295. (b) Murakami, M.; Sakita, K.; Igawa, K.;
Tomooka, K. Org. Lett. 2006, 8, 4023–4046.
(12) Hydrogenation of 3 using the Lindlar catalyst did not give any olefin
product even at high pressure (5 atm). The use of Pd/C produced the
corresponding alkane.
(13) The absolute configuration of the minor isomer was not
determined.
(16) The spirolactone 13 was obtained as a single diastereomer. The
relative stereochemistry of 13 was not determined.
(14) The reaction without ZnCl2 resulted in the decreased yield of 7
(28%).
(17) Lower amounts of methylamine (2 equiv) resulted in the decreased
yield of 12 (<20%).
Org. Lett., Vol. 10, No. 23, 2008
5451

undesired tribromide. Finally, etherification of the phenol
moiety of 16 afforded the N-TFA protected amathaspiramide
F (17) (84%), which was Trauner’s synthetic intermediate.3
The TFA group was removed by LiBH4 to give the
(-)-amathaspiramide F (1) (53%).20 The spectroscopic data
of the synthetic (-)-1 were in good agreement with those
of the natural product.
Scheme 5
In summary, the stereoselective total synthesis of (-)-
amathaspiramide F (1) was achieved from the R-hydoxy-R-
ethynylsilane 2 in 17 steps (1.3% overall yield). The synthesis
is highlighted by the stereoselective construction of the
consecutive C5 and C9 stereogenic centers by the ester
enolate Claisen rearrangement, novel azaspirohemiaminal
formation using the sterically bulky heptamethyldisilazane
to avoid the undesired ꢀ-elimination, and 4′,6′-dibromination
of the 3′-substituted phenol with n-Bu4NBrCl2. The synthesis
of the other congeners (A-E) as well as the biological
evaluation of 1 is currently in progress in our laboratories.
Acknowledgment. This study was financially supported
by a Grant-in-Aid (16201045, 19201045, and 16073214) for
Scientific Research from the Japan Society of the Promotion
of Science (JSPS) and the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Bu4NBrCl2) that is reported by Negoro et al.19 to be an
effective reagent for the electrophilic o,p-dibromination of
phenols as a mild source of bromonium chloride. The
reaction of 12 using n-Bu4NBrCl2 (2.5 equiv) in CH2Cl2 at
0 °C for 3 h smoothly proceeded to give the desired 4′,6′-
dibrominated product 16 in 59% yield without forming the
Supporting Information Available: Full experimental
details and characterization data of all the synthetic products
are available. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) Electrophilic 4,6-dibromination of 3-substituted phenol: (a) Osuna,
M. R.; Agurrie, G.; Somanathan, R.; Molins, E. Tetrahedron: Asymmetry
2002, 13, 2261–2266. (b) Hashimoto, A.; Jacobson, A. E.; Rothman, R. B.;
Dersch, C. M.; George, C.; F-Anderson, J. L.; Rice, K.C. Bioorg. Med.
Chem. 2002, 10, 3319–3329.
OL802179E
(20) The optical rotation of the synthetic (-)-1 showed [R]28 -39.0
D
(c 0.30, MeOH), which is in good agreement with that of the synthetic 1
(19) Negoro, T.; Wada, M.; Someya, M. Bull. Fac. Educ. Wakayama
UniV. Natur. Sci. 1998, 48, 1–7.
reported by Trauner [[R]25 -41.0 (c 0.50, MeOH)],2 while the natural
D
sample was recorded as [R]D -10.0 (c 0.0023, MeOH).1
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Org. Lett., Vol. 10, No. 23, 2008