Total syntheses of all the amathaspiramides

Article abstract of DOI:10.1002/anie.201109221

Six in one blow: Total syntheses of all the amathaspiramide alkaloids have been accomplished. Rapid construction of the diazaspiro[3.3]nonane core combined with regio- and diastereoselective reduction of the cyclic imide moiety with DIBAL established the route to the common structural motif. The late-stage reduction of the lactam to an imine functionality mediated by Schwartz's reagent was the key to the streamlined syntheses. Copyright

Full text of DOI:10.1002/anie.201109221

Angewandte
Chemie
DOI: 10.1002/anie.201109221
Natural Product Synthesis
Total Syntheses of All the Amathaspiramides**
Koji Chiyoda, Jun Shimokawa, and Tohru Fukuyama*
In memory of David Y. Gin
In pursuit of the scalable synthesis of highly functionalized
natural products with a diverse spectrum of accessible
congeners, we considered it conceptually challenging to
synthesize amathaspiramides A (1)–F (6) owing to their
amathaspiramide F, an 8S member, by the Trauner[3] and
Ohfune groups.[4] At the outset of our synthetic study, we
envisioned establishing a scalable and versatile synthetic
route to all amathaspiramides whose pyrrolidine moieties
range over the cyclic imine (5), and secondary (3, 6) and
tertiary amines (1) to unsubstituted (4) and N-methyl g-
lactam (2). Therefore, a systematic access is required for
establishing the configuration at C-8 and the variable
oxidation states of the spiro pyrrolidine units starting from
a common intermediate.
diverse substructures within
a uniform core skeleton
(Figure 1). Prinsep and co-workers isolated these natural
As shown in Scheme 1, our approach is based on the idea
that each member of the amathaspiramides can be derived
from the common intermediate 7 by sequential reduction. We
Figure 1. Amathaspiramide alkaloids.
products in 1999 from a New Zealand collection of the marine
bryozoan Amathia wilsoni.[1] The structural motif of these
compounds is characterized by the densely functionalized
diazaspiro[3.3]nonane framework equipped with an intrigu-
ingly stable N-acyl hemiaminal at C-8, a benzylic center at C-9
linked to a dibromomethoxyphenyl group, and a variable
pyrrolidine moiety connected through the tetrasubstituted
spiro center at C-5. Among these compounds, amathaspir-
amides A and E exhibit antiviral activity against poliovirus
type 1, cytotoxicity to BSC-1 cells, and antimicrobial activity
toward Bacillus subtilis.[1] Furthermore, a recent report has
proved structurally similar compounds to be promising b-turn
mimetics.[2] Despite these valuable aspects, the limited avail-
ability of natural samples has hampered further investigations
on these molecules and their analogues. Of these six
compounds, total synthesis has been reported for only
Scheme 1. Retrosynthetic analysis.
envisioned that Schwartzꢀs reagent, [Cp2Zr(H)Cl] (Cp =
C5H5), could play a key role in the crucial reduction of the
lactam moiety to the cyclic imine,[5] which could then be
reduced to the corresponding secondary amine. Additionally,
hitherto unexplored stereochemical control of the unusually
stable 8R N-acyl hemiaminal moiety in amathaspiramides A–
E could be possible by the regioselective reduction of the C-8
carbonyl group of the cyclic imide in 7 from the sterically less
crowded face. Combined with the known method for the
generating products with the 8S configuration,[3,4] we rea-
soned that all the amathaspiramides with variable spiro
pyrrolidine substructures and C-8 configurations of the N-acyl
hemiaminal could be synthesized from 7. The g-lactam moiety
in 7, which possesses a tetrasubstituted stereogenic center at
C-5, could be derived from carboxylic acid 8 by means of
a Curtius rearrangement and subsequent lactam cyclization.
g-Lactone 9 was thus envisioned as the starting point for the
sequential introduction of the carboxyl group and the three-
carbon alkyl chain onto the a-position of the lactone.
[*] K. Chiyoda, Dr. J. Shimokawa, Prof. Dr. T. Fukuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[**] Financial support for this work was provided by Grants-in-Aid
(21790009 and 20002004) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109221.
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Our synthesis commenced with the one-step preparation
of butenolide 12 from commercially available 3’-methoxy-
phenacyl bromide (10) by means of SN2 substitution with 11
followed by an intramolecular Horner–Wadsworth–Emmons
reaction (Scheme 2).[6] The copper-catalyzed asymmetric
We next focused on the introduction of two bromine
atoms on the aromatic ring. As Ohfune et al. reported,
dibromination is problematic after the construction of the
core structure of amathaspiramides.[4] In fact, introduction of
the second bromine atom at the position ortho to the methoxy
group was difficult by treatment with bromine even in
combination with ordinary acid sources. After extensive
experimentation, we could successfully and selectively intro-
duce two bromine atoms at the ortho and para positions using
bromine in the presence of both zinc chloride and formic
acid.[8] It should be noted that the second bromide could not
be introduced using either zinc chloride or formic acid alone,
indicating the formation of the more powerful hypobromous
formate.[9]
We next aimed at constructing the 8R N-acyl hemiaminal
moiety. According to the reports by the Trauner[3] and Ohfune
groups,[4] cyclization of the N-methyl amide to the aldehyde
selectively gave the S hemiaminal, indicating the S isomer to
be thermodynamically more stable at the N-acyl hemiaminal.
We envisioned that reduction of the cyclic imide from the less
hindered face is likely to establish the 8R stereochemistry,
assuming that the C-8 stereocenter would be sufficiently
stable for further manipulations. Cyclic imide 7 was synthe-
sized in one pot from 18 in 44% yield by aminolysis of the
lactone with methylamine in methanol followed by oxidation
with PDC.
With cyclic imide 7 in hand, we proceeded to form the N-
acyl hemiaminal moiety by a regio- and stereoselective partial
reduction of the imide moiety (Table 1). Although initial
attempts using NaBH4 reduced the imide, reduction occurred
only at the C-6 carbonyl group to give 19 (Table 1, entry 1).
Almost the same result was obtained by employing the Luche
conditions (Table 1, entry 2), L-Selectride (entry 3), or
LiAlH4 at lower temperature (entry 4). After extensive
examination of various reductive conditions, DIBAL was
found to facilitate the desired regio- and stereoselective
transformation (Table 1, entry 5). Accordingly, the desired 8R
hemiaminal was successfully obtained in 52% yield without
formation of the S isomer. The change in the regioselectivity
Scheme 2. Construction of the spiro bicyclic structure. Reagents and
conditions: a) K2CO3, THF, 508C, 62%; b) CuCl (10 mol%), (S)-
DTBM-SEGPHOS (1.0 mol%), NaOtBu, PMHS, tBuOH, THF, RT, 72%
98% ee; c) LHMDS, THF, À788C; CbzCl, 90%; d) methyl acrylate (15),
K2CO3, DMF, 708C, 90%; e) H2 (1 atm), Pd/C, MeOH, RT; f) (COCl)2,
DMF (cat.), CH2Cl2, 08C to RT; evaporation; NaN3, acetone–H2O;
g) 1,4-dioxane, 1008C; HCl aq., reflux, 77% (3 steps); h) Br2
(3.0 equiv), ZnCl2 (4.0 equiv), HCO2H (10 equiv), CH2Cl2, 84%;
i) MeNH2, MeOH, THF, reflux; evaporation; PDC, Celite, CH2Cl2, RT,
44%. DTBM-SEGPHOS=(S)-(+)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxy-
phenyl)phosphino]-4,4’-bi-1,3-benzodioxole, PMHS=polymethylhydro-
siloxane, LHMDS=lithium hexamethyldisilazide, CbzCl=benzyl
chloroformate, PDC=pyridinium dichromate.
Table 1: Reduction of the cyclic imide moiety in 7.
reduction of the unsaturated lactone was performed accord-
ing to Lipshutzꢀs method.[7] The desired chiral lactone 13 with
98% ee was obtained on a 20 g scale in 72% yield, thereby
establishing the latent C-9 configuration at the benzylic
position. To introduce the quaternary center to the a-position
of the carbonyl group, the lithium enolate of 13 was reacted
with CbzCl to afford cyclic malonate 14. This was subse-
quently subjected to a Michael addition with methyl acrylate
(15) in the presence of a catalytic amount of K2CO3 to
selectively afford 16. The crucial tetrasubstituted spiro center
at C-5 was subsequently constructed by a Curtius rearrange-
ment. Thus, benzyl ester 16 was subjected to hydrogenolysis
and the resultant acid was converted to the acyl azide in two
steps. Subsequent Curtius rearrangement was performed in
1,4-dioxane at 1008C to give the intermediate isocyanate,
which was successfully hydrolyzed in an aqueous medium to
afford g-lactam 17 without appreciable formation of a urea
byproduct.
Entry
Reagent
T
Solvent
4
19
[8C]
[%][f]
[%][f]
1[a]
2[b]
3[c]
4[d]
5[e]
NaBH4
0
0
À78
À78
À78
MeOH
MeOH
THF
THF
CH2Cl2
0
0
0
0
52
98
86
67
80
0
NaBH4, CeCl3·7H2O
L-Selectride
LiAlH4
DIBAL
[a] Conditions: NaBH4 (2.0 equiv), MeOH, 08C, 10 min. [b] Conditions:
NaBH4 (4.0 equiv), CeCl3·7H2O (4.0 equiv), MeOH, 08C, 50 min.
[c] Conditions: l-Selectride (4.0 equiv), THF, À788C, 50 min. [d] Con-
ditions: LiAlH4 (2.0 equiv), THF, À788C, 50 min. [e] Conditions: DIBAL
(2.3 equiv), CH2Cl2, À788C, 20 min. [f] Yield of the isolated product.
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could be explained in terms of the reduction of the inductive
effect and increase of the steric bulk of the g-lactam as a result
of the formation of the nitrogen–aluminum bond caused by
DIBAL. The subtle change in the environment of the C-6
carbonyl enhanced the relative reactivity of the C-8 carbonyl,
resulting in its reduction from the less hindered side to give
the 8R hemiaminal 4. The 8R hemiaminal showed surprising
stability, which allowed conventional handling and even
purification on silica gel. Amathaspiramide D (4) was thus
synthesized from 7 in 52% yield on a 5 g scale. An X-ray
crystallographic analysis of synthetic 4 confirmed, for the first
time, the unambiguous structure of the amathaspiramide
alkaloids bearing a 8R N-acyl hemiaminal moiety.[10]
mixture, the 8S isomer amathaspiramide F (6) was isolated in
82% yield.
Since the C-8 N-acyl hemiaminal moiety in 4 is stable
under weakly acidic conditions and labile to isomerization
under basic conditions, it should be protected for the
introduction of the N-methyl group of amathaspiramide B
(2; Scheme 4). Among the various protecting groups exam-
ined, an ethoxyethyl (EE) group was chosen because of the
ease of deprotection under mildly acidic conditions. After
protection of the hydroxy group of 4, methylation was
performed by treatment with MeI and Cs2CO3 to give, after
workup with aqueous HCl, amathaspiramide B (2) in 75%
yield.
We envisioned that amathaspiramide D (4) could serve as
a versatile precursor for the synthesis of all the other
amathaspiramides. Toward this end, it was necessary to
reduce the g-lactam moiety without affecting the other
functional groups in the molecule. Consequently, we focused
on the use of Schwartzꢀs reagent, [Cp2Zr(H)Cl], which is
known to effect the transformation of a lactam to the
corresponding cyclic imine.[5,11] To our delight, upon treat-
ment with [Cp2Zr(H)Cl], amathaspiramide D (4) was directly
reduced to the imine without affecting the tertiary amide at C-
6 and N-acyl hemiaminal at C-8, affording amathaspirami-
de E (5) in 67% yield (Scheme 3). Fortunately, the imine
moiety in 5 could be selectively reduced to the secondary
amine by treatment with NaBH3CN and AcOH in methanol
to afford amathaspiramide C (3) in 65% yield. Similarly,
reductive methylation of 5 with formaldehyde under similar
conditions furnished amathaspiramide A (1) in 78% yield.
Since amathaspiramide F (6) differs from amathaspiramide C
(3) only in the configuration of the N-acyl hemiaminal at C-8,
epimerization of the C-8 center was attempted. Under the
conventional acidic conditions, however, no epimerization
was observed, and elimination of the hydroxy group occurred
under harsher conditions. Gratifyingly, epimerization took
place under basic conditions with a catalytic amount of
Cs2CO3 in MeCN, resulting in the formation of the thermo-
dynamic mixture of the products (6/3 = 13:1). From this
Scheme 4. Total synthesis of amathaspiramide B (2). Reagents and
conditions: a) CSA (1.0 mol%), ethyl vinyl ether, CH2Cl2, RT; b) MeI,
Cs2CO3, MeCN, RT; HCl aq., THF, RT, 75% (2 steps). CSA=camphor-
sulfonic acid.
In conclusion, we have achieved the concise and efficient
total syntheses of all the known amathaspiramide alkaloids 1–
6 on 0.1 to 5 g scales. Our synthesis underscores the
importance of the mild conditions for reduction of the
amide with Schwartzꢀs reagent in the synthesis of complex
molecular frameworks; this allowed the streamlined prepa-
ration of the amide, imine, secondary amine, and tertiary
amine from a common intermediate. Regio- and stereoselec-
tive reduction of cyclic imide 7 using DIBAL as the only
effective reagent gave rise to the hitherto unavailable 8R
stereochemistry. In addition, C-8 N-acyl hemiaminal moiety
was successfully epimerized to the thermodynamically more
stable 8S isomer only under basic reaction conditions. Our
first total syntheses of amathaspiramides A (1), B (2), C (3),
D (4), E (5) with 8R stereochemistry combined with an X-ray
crystallographic analysis of 4 unequivocally confirmed the
stereochemistry of these molecules. Further syntheses of
analogues of the amathaspiramides and biological studies are
underway.
Received: December 28, 2011
Published online: January 27, 2012
Keywords: alkaloids · amathaspiramide · reduction ·
.
spiro compounds · total synthesis
Scheme 3. Total syntheses of amathaspiramides A, C, E, F. Reagents
and conditions: a) [Cp2Zr(H)Cl] (2.0 equiv), THF, À308C to RT, 67%;
b) NaBH3CN, AcOH, MeOH, RT, 65%; c) HCHO aq., NaBH3CN,
AcOH, MeOH, RT, 78%; d) Cs2CO3 (10 mol%), MeCN, RT, 82%.
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Angew. Chem. Int. Ed. 2012, 51, 2505 –2508
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addition of second additive, eventually lead to the formation
of a mixture of regioisomers.
[9] R. Josephson, L. J. Andrews, R. M. Keefer, J. Am. Chem. Soc.
1961, 83, 3562 – 3567.
[10] The structure of racemic amathaspiramide D (4) was unambig-
uously determined by an X-ray crystallographic analysis
(CCDC 858046 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.). This result was obtained in
our initial synthetic studies on the racemate and successfully
corroborated the relative stereochemistry. All attempts to grow
a single crystal from the enantiopure material for X-ray analysis
were unsuccessful. See the Supporting Information for the
ORTEP drawing and information on the crystal packing.
[11] a) M. A. Arnold, S. G. Durꢂn, D. Y. Gin, J. Am. Chem. Soc. 2005,
127, 6924 – 6925; b) M. A. Arnold, K. A. Day, S. G. Durꢂn, D. Y.
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[7] B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem. Soc.
2004, 126, 8352 – 8353.
[8] Attempted dibromination of other intermediates before the
construction of the bicyclic structure, with or without the
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