Practical Asymmetric Synthesis of Amathaspiramides B, D, and F

Article abstract of DOI:10.1021/acs.orglett.6b00588

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8R-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared.

Full text of DOI:10.1021/acs.orglett.6b00588

Letter
pubs.acs.org/OrgLett
Practical Asymmetric Synthesis of Amathaspiramides B, D, and F
Sen-Lin Cai,†,§ Ran Song,†,§ Han-Qing Dong,‡ Guo-Qiang Lin,†,‡ and Xing-Wen Sun*,†
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
‡Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The practical asymmetric synthesis of amathaspir-
amides B, D, and F has been accomplished by utilizing an aza-
Barbier allylation as the key step to construct the common
intermediate with two adjacent stereocenters. A kinetically
controlled cyclization to build the challenging thermodynamically
less stable 8R-hemiaminal moiety is also important in the
synthesis of amathaspiramide D. The route is readily scalable,
and gram quantity of the final product D has been prepared.
mathaspiramides A−F (Figure 1) were isolated by Prinsep
and Morris from a collection of the marine bryozoans
amathaspiramide family members contain an 8R-hemiaminal
A
unit, a highly efficient synthetic approach is desirable to access
them. In the meantime, we have reported several practical
approaches4 for Zn-mediated allylation of N-tert-butanesulfinyl
imines5 under mild conditions, with which a series of homoallylic
amines, especially β-substituted homoallylic amines, could be
constructed in high efficiency. Noticeably, ketimines are also
suitable substrates in these allylations and generated homoallylic
amines with quaternary stereocenters in high yields and
diastereoselectivities. Herein, we report an approach to prepare
amathaspiramides B, D, and F utilizing this allylation.
As shown in the retrosynthetic analysis (Scheme 1),
amathaspiramide D, a versatile precursor to the other
amathaspiramide family members in Fukuyama’s work, can be
prepared from aldehyde 7 through cyclization. Although the 8R-
isomer is thermodynamically less stable, the nucleophilic attack
of N7 to the aldehyde is likely to occur from the side of Si face as
the hydrogen bond N1−H−O fixed the comformation. Thus, it
is possible to access the 8R-isomer under kinetically controlled
reaction conditions. Aldehyde 7 can be prepared from alkene 8
through aminolysis and ozonolysis, while the corresponding β-
aryl-substituted homoallylic amine framework in 8 can be derived
by applying the tert-butanesulfinyl ketimine based aza-Barbier-
type allylation to construct C5 and C9 stereocenters.
Our synthesis began with the preparation of aza-Barbier
allylation partners allyl bromide 10 and ketimine 11. Compound
10 could be synthesized from known compound 126 (Scheme
2), and 11 was prepared from the condensation between diester
14 and chiral sulfinamine 15 (Scheme 3).7
With both allylation partners in hand, the aza-Barbier reaction
was evaluated (Table 1). The allylation between (Ss)-ketimine 11
and the in situ generated organozinc reagent from allyl bromide
10 and Zn dust in N,N-dimethylformamide (DMF) afforded two
Figure 1. Amathaspiramides A−F.
Amathia wilsoni.1 The family members share a densely
functionalized aza-spirobicyclic core possessing three contiguous
stereocenters, including a tert-alkylamino carbon center and a
hemiaminal center. Due to their attractive bioactivities and
chemical structure,1 significant efforts have been devoted to the
development of their total syntheses.2,3 Previous synthetic
studies suggest that the 8R-hemiaminal moiety, which was
found in amathaspiramides A−E (1−5), is thermodynamically
less stable than the corresponding 8S-isomer (e.g., amathaspir-
amide F).2 The first total synthesis of the 8R series was reported
by Fukuyama and co-workers.3a They were able to obtain
amathaspiramide D from a spiroimide by selective reduction,
from which amathaspiramides A−C, E, and F were synthesized.
Very recently, Lee reported a rapid access to amathaspiramides
utilizing a similar reduction.3b As five compounds out of six
Received: March 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00588
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Scheme 1. Retrosynthetic Analysis of Amathaspiramide D
Table 1. Optimization for the Aza-Barbier Allylation
a
b
c
entry
solvent
temp (°C)
time (h)
yield (%)
dr (9a/9b)
1
2
3
4
5
DMF
DEF
DEF
DEF
DEF
DEF
RT
RT
0.5
0.5
12
24
30
24
66
2:1
4:1
72
−20
−40
−60
−40
67
7:1
68
10:1
9:1
60
de
,
6
72 of 9a
6 of 9b
82
10:1
df
,
7
8
DEF
THF
−40
RT
24
2
10:1
2:3
60
a
Unless otherwise noted, the reaction was performed with 11 (1.0
b
equiv, 0.25 mmol), 10 (1.5 equiv), and Zn (2.0 equiv). Isolated yield
for the mixture of 9a and 9b. Determined by crude HNMR. With
10 (3.0 equiv) and Zn (4.0 equiv). The reaction was conducted with
1.0 mmol of 11. The reaction was conducted with 1.0 g (3.3 mmol) of
c
d
1
e
f
11.
reaction transition states (TSs) (Figure 2). In polar aprotic
solvent, the organozinc reagent was solvated and formed a bulky
Scheme 2. Synthesis of Allylbromide 10
Figure 2. Proposed transition states for the aza-Barbier allylation.
Scheme 3. Construction of C5 and C9 Stereocenters
R-ZnBrLx complex. The reaction mostly proceeded through
open-chain TS-1 and gave (5S,9R)-9a as the major product. The
coordinate capability of THF was weaker than that of the polar
aprotic solvent; therefore, the reaction mainly proceeded
through six-membered cyclic TS-2 and gave more (5R,9R)-9b
in THF. The yield of the reaction could be increased without
sacrificing the diastereoselectivity when more equivalents of 10
and Zn were used (Table 1, entry 6), and this result was
maintained even if the reaction was performed in gram scale
(Table 1, entry 7).
With a scalable route to highly functionalized sulfinamide 9a
established, we turned our attention to the construction of the
pyrrolidinone moiety (Scheme 4). Upon removal of the N-tert-
butanesulfinyl group in 9a under acidic condition, the resulting
hydrochloride salt was treated with Et3N to afford pyrrolidinone
8 in nearly quantitative yield. Interestingly, the two pyrrolidinone
isomers from compounds 9a and 9b showed quite different
physical properties. The desired isomer (5S,9R)-8 is a fine solid,
with poor solubility in EtOAc, while the (5R,9R)-isomer derived
from 9b is a semisolid, with excellent solubility in EtOAc. Such
significant solubility difference could be utilized to simplify the
purification process. For a multigram scale preparation, a mixture
of 9a and 9b from the aza-Barbier reaction could be subjected to
the above sequence to form pyrrolidinones, and the desired
isomer of 8 was conveniently obtained by recrystallization.
Next, we focused on the formation of the challenging C8
hemiaminal center. Alkene 8 was first subjected under ozonolysis
conditions to provide aldehyde 16, which was subsequently
treated with methylamine at room temperature (Scheme 4). Not
surprisingly, in accord with previous reports about direct
cyclization from aldehyde,2 the major product turned out to be
diastereoisomers (dr = 9a/9b = 2:1) in 66% yield (Table 1, entry
1). Compounds 9a and 9b could be separated by silica gel
chromatography. X-ray single-crystal diffraction unambiguously
assigned their absolute configurations as (5S,9R)-9a and
(5R,9R)-9b.8 When N,N-diethylformamide (DEF) was em-
ployed as solvent, the dr increased to 4:1 (Table 1, entry 2). The
diastereoselectivity could be further improved by lowering the
reaction temperature, and the best dr (10:1) was obtained at −40
°C (Table 1, entry 4). The selectivity did not improve further at
−60 °C (Table 1, entry 5) because the reaction mixture became
very viscous at −50 °C (the melting point of DEF is −61 °C).
Interestingly, when THF was employed as the solvent, the
percentage of 9b was increased to 60% (Table 1, entry 8). These
stereochemical outcomes could be explained by the proposed
B
DOI: 10.1021/acs.orglett.6b00588
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treatment of 20 with O3 in dichloromethane at −78 °C and
subsequent quenching with PPh3 successfully gave the kinetically
controlled 8R-amathaspiramide D in moderate 65% yield and
decreased the 8S-epimer 17 to 33% yield.
Scheme 4. Initial Approach to Amathaspiramide D
Amathaspiramide B could be synthesized in a manner similar
to that of amathaspiramide D. As shown in Scheme 5, selective
N-methylation was achieved for the lactam N−H by using 1
equiv of NaH in dry THF, resulting in compound 21 in 84%
yield. Following the established ozonolysis and cyclization
procedures, 46% yield of amathaspiramide B and 50% yield of
its 8S-epimer 22 were obtained, respectively.
Alternatively, the correctly established three stereocenters in
17 could allow for rapid preparation of amathaspiramide F
(Scheme 6). Upon the treatment with Schwartz’s reagent,3,9 the
Scheme 6. Synthesis of Amathaspiramide F
8S-hemiaminal 17, while the desired product D was isolated only
in 9% yield.
secondary amide was selectively reduced to an imine
intermediate, which was further reduced by NaBH3CN in one
pot to afford amathaspiramide F in 51% yield. The structure of F
was further comfirmed by X-ray single-crystal diffraction.8
In summary, the practical asymmetric synthesis of amathaspir-
amides B, D, and F was achieved. The key feature of this route is
the construction and regulation of two adjacent stereocenters,
including a tert-alkylamino carbon center, through an aza-
Barbier-type allylation. In addition, the thermodynamically less
stable 8R-hemiaminal unit was first achieved by a direct
kinetically controlled cyclization under nonbasic conditions at
low temperature. The choice of prefunctionalized allyl bromide
10 significantly streamlined the synthetic work. The longest
linear route, 10 steps from 3-hydroxybenzaldehyde to
amathaspiramide D, could be operated in gram scale and
achieved in 27% overall yield. Benefiting from the inexpensive
materials and the efficient transformations, our stereoselective
diversity-oriented synthesis strategy readily affords a library of
amathaspiramide derivatives for biological studies.
Although 17 can be transformed into amathaspiramide D by a
protocol of oxidation and subsequent selective reduction,3a
a
straightforword and efficient method to obtain a R-hemiaminal
moiety is highly desirable. Based on the analysis mentioned
before, we assumed that the reaction might favor the kinetically
controlled product if conducted at lower temperature and under
nonbasic conditions. Thus, we converted the ester 8 to N-methyl
amide 20 prior to the ozonolysis (Scheme 5). As expected,
Scheme 5. Final Approach to D and B
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00588.
X-ray data for amathaspiramide F (CIF)
X-ray data for 8 (CIF)
X-ray data for 9a (CIF)
X-ray data for 9b (CIF)
X-ray data for 20 (CIF)
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sunxingwen@fudan.edu.cn.
C
DOI: 10.1021/acs.orglett.6b00588
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Author Contributions
§S.-L.C. and R.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the National
Natural Science Foundation of China (21342009 and
21472019). We also thank Prof. Ran Hong (SIOC), Dr. Yiyang
Liu (Caltech), and Dr. Haoxuan Wang (MIT) for their valuable
advice.
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DOI: 10.1021/acs.orglett.6b00588
Org. Lett. XXXX, XXX, XXX−XXX