Improved synthesis of (-)-agelastatin A

Article abstract of DOI:10.1080/00397910802618885

Optimization of key steps in the synthesis of the architecturally unique tetracyclic antitumor alkaloid (-)-agelastatin A (1) improved the overall yield of the 11-step process (eight operations) from 9% to 23%. Changing the solvent and using a more effici

Full text of DOI:10.1080/00397910802618885

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Improved Synthesis of (–)-
Agelastatin A
Franklin A. Davis a , Junyi Zhang a , Yanfeng Zhang a
& Hui Qiu a
a Department of Chemistry , Temple University ,
Philadelphia, Pennsylvania, USA
Published online: 27 Apr 2009.
To cite this article: Franklin A. Davis , Junyi Zhang , Yanfeng Zhang & Hui Qiu (2009)
Improved Synthesis of (–)-Agelastatin A, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:11, 1914-1919,
DOI: 10.1080/00397910802618885
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Synthetic Communications1, 39: 1914–1919, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802618885
Improved Synthesis of (ꢀ)-Agelastatin A
Franklin A. Davis, Junyi Zhang, Yanfeng Zhang, and Hui Qiu
Department of Chemistry, Temple University, Philadelphia,
Pennsylvania, USA
Abstract: Optimization of key steps in the synthesis of the architecturally unique
tetracyclic antitumor alkaloid (ꢀ)-agelastatin A (1) improved the overall yield of
the 11-step process (eight operations) from 9% to 23%. Changing the solvent and
using a more efficient N-benzyl deprotecting-group procedure enhanced the
yields of the C-ring and D-ring intermediates, (ꢀ)-4 and (ꢀ)-7, respectively.
Bromination of (ꢀ)-7 with 1,3-dibromo-5,5-dimethylhydantoin, rather than
N-bromosuccinimide (NBS), increased the yield of (ꢀ)-1 from 69% to more than
94% yield.
Keywords: (ꢀ)-Agelastatin A, 1,3-dibromo-5,5-dimethylhydantoin, Michael
addition
Recently we described a concise asymmetric synthesis of (ꢀ)-agelastatin
A (1) from the key C-ring intermediate 4,5-diamino cyclopenten-2-enone
(ꢀ)-2 (Scheme 1).[1,2] Compound 2 was efficiently prepared from the
sulfinimine-derived (ꢀ)-2,3-diamino ester 3 using ring-closing metathesis.
(ꢀ)-Agelastatin A (1) is an architecturally unique cytotoxic tetracyclic
alkaloid isolated from the marine sponge Agelas dedromorpha.[3] It is
reported to be active against a number of tumor cell lines, and it inhibits
glycogen synthase kinase-3b.[4] Although our synthesis of (ꢀ)-1 is the
most efficient one to date, 11 steps under eight operations (9% overall
yield), there were several steps that proceeded in modest or low yields.
We describe here an improved synthesis of (ꢀ)-1, 11 steps under eight
operations (23% overall yield), with a 10-fold increase in scale.
Received August 22, 2008.
Address correspondence to Franklin A. Davis, Department of Chemistry,
Temple University, Philadelphia, PA 19122. E-mail: fdavis@temple.edu
1914

Improved Synthesis of (ꢀ)-Agelastatin A
1915
Scheme 1. Retro-synthetic analysis of (ꢀ)-agelastatin A.
Our improved synthesis begins with 4,5-diamino cyclopenten-
2-enone (1R,5S)-(ꢀ)-2, which was prepared in six steps (four operations)
from (ꢀ)-3 in 58% overall yield as previously described.[1] 2,3-Diamino
ester (ꢀ)-3 was prepared by addition of the lithium enolate of ethyl
(dibenzylamino)acetate to an acrolein-derived sulfinimine in 73% yield.
Experimental details for the synthesis of (ꢀ)-2 can be found in Ref. 1.
Weinreb and coworkers had earlier reported the synthesis of the C-ring
intermediate by an intramolecular Michael cyclization using Cs2CO3=
MeOH.[2a] By applying this procedure with 10 equivalents of Cs2CO3=
MeOH, we obtained (ꢀ)-4 in 68% yield, but control of the reaction time
was critical (Table 1, entry 1). It was found that reaction times longer
than 16 min resulted in formation of the retro-Michael product cyclo-
pentenone (R)-(ꢀ)-5 and decomposition products (Table 1, entry 2). By
switching the solvent to tetrahydrofuran (THF), the reaction was much
slower, and it was possible to avoid formation of (ꢀ)-5 (Scheme 2). How-
ever, it was only possible to push the reaction yield to 66% with recovery
of 26% of (ꢀ)-2. Increasing the reaction time failed to improve the yield
of (ꢀ)-4, and decomposition products were observed (Table 1, entry 4).
When recovered (ꢀ)-2 was subjected to the reaction conditions, an addi-
tional 15% of (ꢀ)-4 was isolated for a combined yield of 81%.
Formation of (ꢀ)-debromoagelastatin A (7) requires removal of the
N-benzyl protecting groups in (ꢀ)-4 to give the a-amino ketone 6, which
is reacted with methyl isocyanate to give the D-ring (Scheme 3).
Scheme 2. Synthesis of the C-ring intermediate.

1916
F. A. Davis et al.
Table 1. Conversion of (ꢀ)-2 to (ꢀ)-4 using 10 equiv of Cs2CO3
Entry
Solvent
Time (h)
Products (% isolated yield)
1
2
3
4
MeOH
0.27
(ꢀ)-4 (68); (ꢀ)-5 (trace)
(ꢀ)-4 (0); (ꢀ)-5 (46)a
(ꢀ)-4 (66); (ꢀ)-2 (26)
(ꢀ)-4 (66); (ꢀ)-2 (20)a
2
2
4
THF
aDecomposition products observed.
However, a-amino ketones are notoriously unstable and rapidly epimer-
ize and self-condense.[5] This was avoided by removal of the benzyl pro-
tecting groups (10% Pd-C, H2) in the presence of methyl isocyanate,
thereby trapping the amino ketone 6 (Scheme 3).[1] Unfortunately, in
addition to the desired (ꢀ)-debromoagelastatin A (7), N-benzyl debro-
moagelastatin A (8) was also produced in significant amounts. All
attempts to remove the N-benzyl group in 8 proved unsuccessful. Rea-
soning that the problem was incomplete debenzylation of (ꢀ)-4, we
switched to 30% Pd-C and increased the amount to 6.5 equivalents. This
resulted in an isolated yield of 70% (ꢀ)-7 and 8% 8 being formed
(Scheme 3).
Scheme 3. Synthesis of the D-ring intermediate and (ꢀ)-agelastatin A.

Improved Synthesis of (ꢀ)-Agelastatin A
1917
Bromination of (ꢀ)-7 using N-bromosuccinimide (NBS) according to
Feldman’s protocol originally afforded (ꢀ)-1 in 69% yield.[1,2c] However,
when the bromination was conducted with 1,3-dibromo-5,5-dimethylhy-
dantoin (9) in MeOH-THF, the yield rose to 94% (Scheme 3).
In summary, an improved synthesis of the novel marine alkaloid (ꢀ)-
agelastatin A (1) has been accomplished by employing THF to optimize
the Michael addition reaction, (ꢀ)-2 to (ꢀ)-4, increasing the efficiency of
the N-benzyl deprotection step, by using excess 30% Pd-C, (ꢀ)-4 to (ꢀ)-7,
and employing 9 to brominate (ꢀ)-7. The result was 11 steps (eight opera-
tions) with an overall yield of 23% from the sulfinimine.
EXPERIMENTAL
N-(ꢀ)-[(1R,5S)-5-(Dibenzylamino)-4-oxocyclopent-2-enyl)]-1H-pyrrole-
2-carboxamide (2) was prepared as previously described.[1]
(ꢀ)-Pyrrole (4)
In a 250-mL, single-necked, round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum, and argon balloon, (ꢀ)-2 (0.64 g,
1.68 mmol) and Cs2CO3 (5.48 g, 16.8 mmol) in THF (60 mL) were placed.
The solution was stirred at rt for 2 h before it was filtered and concen-
trated. Chromatography (hexanes–EtOAc, 1:1) gave 0.16 g of (ꢀ)-2 and
0.42 g (66%) of (ꢀ)-4. Cs2CO3 (1.37 g, 4.2 mmol) was added to the solu-
tion of recovered (ꢀ)-2 (0.16, 0.42 mmol) in THF (15 mL), and the reac-
tion mixture was stirred at rt for 2 h. At this time, the solution was filtered
and concentrated, and chromatography (hexanes–EtOAc, 1:1) gave
0.096 g (15%) of an off-white solid. Combined (ꢀ)-4, 0.52 g (81%) yield;
mp 195.5ꢁC (lit.[1] mp 195ꢁC); [a]20 ¼ ꢀ10.5 (c 0.3, CHCl3) [lit.[1]
¼
D
ꢀ10.2 (c 0.28, CHCl3)]; IR (neat): 3854, 1653, 1350 cmꢀ1
;
1H NMR
(CDCl3) d 2.64 (dd, J ¼ 6.0 Hz, J ¼ 19.2 Hz, 1 H), 3.0 (d, J ¼ 19.2 Hz,
1 H), 3.49 (d, J ¼ 10.5 Hz, 1 H), 3.88 (m, 1 H), 3.94 (s, 4 H), 4.68 (t,
J ¼ 6.0 Hz, 1 H), 6.27 (m, 1 H), 6.45 (d, J ¼ 3.0 Hz, 1 H), 6.71 (m, 1 H),
6.91 (m, 1 H), 7.24–7.4 (m, 10 H); 13C NMR d 43.0, 50.4, 54.6, 56.5, 70.0,
111.3, 115.4, 122.4, 123.8, 127.9, 128.9, 138.9, 158.9, 211.3. The spectral
data are consistent with literature values.[1]
(ꢀ)-Debromoagelastatin A (7)
In a 50-mL, two-necked, round-bottomed flask equipped with a magnetic
stirring bar, rubber septum, and hydrogen balloon, (ꢀ)-4 (0.266 g,

1918
F. A. Davis et al.
0.69 mmol) and 30% Pd=C (1.33 g, 3.75 mmol) in THF (25 mL) were
placed, and methyl isocyanate (0.407 mL, 6.9 mmol) was quickly added.
After 12 h, the catalyst was filtered, and the filtrate was concentrated.
Chromatography (10% MeOH in CH2Cl2) gave 0.019 g (8%) of (ꢀ)-8[1]
and 0.108 g (70%) of (ꢀ)-7 as an off-white solid, mp 244.0–244.5ꢁC (lit[1]
mp 244–245ꢁC); [a]20 ¼ ꢀ67.2 (c 0.4, MeOH) [lit.[1] [a]20 ¼ ꢀ66.2 (c
D
D
0.21, MeOH)]. IR (neat): 3281, 2849, 1653, 1559 cmꢀ1 1H NMR
;
(CD3OH) d 2.27 (dd, J ¼ 10.5 Hz, J ¼ 12.9 Hz, 1 H), 2.55–2.54 (m, 1 H),
2.78 (s, 3 H), 3.79 (s, 1 H), 3.98 (d, J ¼ 5.4 Hz, 1 H), 4.6–4.67 (m, 1 H),
6.21 (t, J ¼ 5.4, 1 H), 6.87 (d, J ¼ 3.9 Hz, 1 H), 7.01–7.2 (m, 1 H); 13C
NMR d 24.2, 41.6, 55.6, 62.8, 68.0, 95.8, 111.0, 115.4, 122.9, 125.6,
161.3, 162.0. The spectra data are consistent with literature values.[1]
(ꢀ)-Agelastatin A (1)
In a 25-mL, one-necked, round-bottomed flask equipped with a magnetic
stirring bar, rubber septum, and argon balloon, MeOH (5 mL), THF
(10 mL), (ꢀ)-7 (0.026 g, 0.1 mmol) were placed. The solution was cooled to
ꢀ 78ꢁC, and 1,3-dibromo-5,5-dimethylhydantoin (9) (0.014 g, 0.049 mmol)
was added. The reaction mixture was stirred at this temperature for 2 h,
warmed to rt, and stirred for 12 h. At this time, the solution was concen-
trated and purified by preparative thin-layer chromatography (TLC) (1:4
MeOH=EtOAC) to give 0.032 g (94%) of an off-white solid; [a]20 ¼ ꢀ
D
60.8 (c 0.35, MeOH) [lit.[1]ꢀ62.2 (c 0.18, MeOH)]; the compound decom-
posed at 180ꢁC; IR (neat): 3289, 2917, 1657, 1564 cmꢀ1 1H NMR
;
(CD3OD) d 2.08 (t, J ¼ 12.9 Hz, 1 H), 2.62 (dd, J ¼ 6.3 Hz, J ¼ 13.2 Hz,
1 H), 2.79 (s, 3H), 3.87 (s, 1 H), 4.06 (J ¼ 5.7 Hz, 1 H), 4.58 (m, 1 H),
6.30 (J ¼ 3.9 Hz, 1 H), 6.89 (J ¼ 3.9 Hz, 1 H); 13C NMR 24.6, 40.4,
54.8, 62.6, 67.8, 96.1, 107.6, 114.2, 116.4, 124.5, 161.5, 161.8. The spectral
data are consistent with literature values.[1]
ACKNOWLEDGMENT
This work was supported by the National Institute of General Medical
Sciences (GM 51982 and 57870).
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Improved Synthesis of (ꢀ)-Agelastatin A
1919
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S.; Pietra, F. Agelastatin A, a new skeleton cytotoxic alkaloid of the oroidin
family: Isolation from the axinellid sponge Agelas dendromorpha of the coral
sea. J. Chem. Soc., Chem. Commun. 1993, 1305–1306; (b) D’Ambrosio, M.;
Guerriero, A.; Chiasera, G.; Pietra, F. Conformational preferences and abso-
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NMR, and exciton splitting for diamide and hydroxyamide derivatives. Helv.
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4. For a review of the synthesis and mechanisms of action of (ꢀ)-1, see: Hale, K. J.;
Domostoj, M. M. Total synthesis and mechanism of action studies on the
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352–394.
5. For leading references, see (a) Davis, F. A.; Ramachandar, T.; Liu, H.
Asymmetric synthesis of a-amino 1,3-dithioketals from sulfinimines (N-
sulfinyl imines): Synthesis of (2S,3R)-(ꢀ)-3-hydroxy-3-methylproline. Org. Lett.
2004, 6, 3393–3395; (b) Davis, F. A.; Ramachandar, T.; Chai, J.; Skucas, E.
Asymmetric synthesis of h-amino aldehydes from sulfinimine (N-sulfinylimine)-
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dihydroxyproline. Tetrahedron Lett. 2006, 47, 2743–2746.