Towards the total synthesis of marineosin A: Construction of the macrocyclic pyrrole and an advanced, functionalized spiroaminal model

Article abstract of DOI:10.1002/ejoc.201300643

Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core of marineosin A in 5.1 % overall yield from (S)-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is subjected to Paal-Knorr pyrrole synthesis and ring-closing metathesis to afford the macrocycle. A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system through an acid-mediated hydroxy oxo amide cyclization strategy. Copyright

Full text of DOI:10.1002/ejoc.201300643

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300643
Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic
Pyrrole and an Advanced, Functionalized Spiroaminal Model
[
a]
[a]
[a]
[a]
Leslie N. Aldrich, Cynthia B. Berry, Brittney S. Bates, Leah C. Konkol,
[a]
[b]
Miranda So, and Craig W. Lindsley*
Keywords: Natural products / Nitrogen heterocycles / Alkaloids / Metathesis / Chiral pool
Herein, we describe the enantioselective construction of the
metathesis to afford the macrocycle. A divergence point in
the synthetic scheme also enabled access to a highly func-
12-membered macrocyclic pyrrole core of marineosin A in
5
.1% overall yield from (S)-propylene oxide. The route fea- tionalized spiroaminal model system through an acid-medi-
tures a key Stetter reaction to install a 1,4-diketone, which
is subjected to Paal–Knorr pyrrole synthesis and ring-closing
ated hydroxy oxo amide cyclization strategy.
Introduction
synthesis of an unfunctionalized spiroaminal model system
of 1 that enabled late-stage introduction of the C1–C4 pyr-
Marineosin A (1) is a novel macrocyclic spiroaminal alk-
aloid isolated in 2008 from a marine-derived Streptomyces-
related actinomycete, and it is structurally related to the
[6]
role moiety. This was a significant development, as syn-
thetic efforts with early-stage pyrrole incorporation uni-
formly led to compound instability and poor results that
forced routes to be abandoned. Herein, we describe the
enantioselective construction of macrocyclic pyrrole core 4
and highly functionalized spiroaminal 8 en route to the to-
tal synthesis of 1.
[1]
[
2]
prodigiosin family. Marineosin A displays potent inhibi-
tion against human colon carcinoma cell growth, with an
IC50 of 0.5 μm in HCT-116 cells.[ In the isolation paper,
Fenical proposed a biosynthesis of 1 by employing an in-
verse-electron-demand hetero-Diels–Alder reaction; how-
ever, we were unable to demonstrate this proposal syntheti-
1]
[
1,3]
cally.
Shortly thereafter, Snider proposed an alternative,
Results and Discussion
prodigiosin-inspired biosynthesis requiring only a two-elec-
tron oxidation, which he then validated in a model system
Our retrosynthetic analysis for marineosin A (1) is shown
of the spiroiminal moiety of 1.[4] Thus, despite significant in Scheme 1 and relies on late-stage introduction of the C1–
interest from the synthetic community, limited synthetic ef- C4 pyrrole. Spiroaminal 2 can be formed by acid-mediated
forts have been reported en route to a total synthesis of 1.
cyclization of advanced intermediate 3. A Paal–Knorr pyr-
role synthesis and ring-closing metathesis (RCM) allow for
the formation of macrocycle 4 from 1,4-diketone 5. The
Stetter reaction will be employed as a key carbon–carbon
bond-forming reaction en route to 5 from 6. Polyfunction-
alized 6 is a critical intermediate derived ultimately from
Evans’ auxiliary phosphonate 7, vinylmagnesium bromide,
and (S)-propylene oxide, which defines the stereochemistry.
Intermediate 6 also serves as a divergence point to validate
the acid-mediated cyclization strategy for 2 and provides
access to model system 8.
In light of our longstanding interest in the synthesis of
[
5]
[2,6]
alkaloids, and 1 in particular,
we recently reported the
[
[
a] Department of Chemistry
Vanderbilt University
The synthesis of 2 started from commercial (S)-propyl-
ene oxide (9, Scheme 2). Opening of the epoxide with a cop-
per-catalyzed Grignard addition and in situ silylation of the
resulting secondary alcohol provided olefin 10 in 81% yield
over the two steps. Ozonolysis afforded aldehyde 11 in 84%
yield. Required Evans’ auxiliary phosphonate 7 was pre-
pared in two steps from (R)-oxazolidinone 12 in 73% yield
over the two steps. Aldehyde 11 then underwent Horner–
Wadsworth–Emmons olefination with Evans’ auxiliary
Nashville, TN 37232-6600, USA
b] Departments of Pharmacology & Chemistry
Vanderbilt Center for Neuroscience Drug Discovery
1
2415D MRBIV, Vanderbilt University Medical Center
Nashville, TN 37232-6600, USA
Fax: +1-615-345-6532
E-mail: craig.lindsley@vanderbilt.edu
Homepage: www.lindsleylab.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300643.
Eur. J. Org. Chem. 2013, 4215–4218
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. W. Lindsley et al.
SHORT COMMUNICATION
phosphonate 7 to provide acyloxazolidinone 14 in 75%
yield. A copper-catalyzed conjugate addition with allylmag-
nesium bromide delivered 15 in 81% yield with Ͼ20:1dr.
With intermediate 15 in hand, we then prepared aldehyde
18 to access key intermediate 6 (Scheme 3). Commercial cis-
butene-1,4-diol (16) was mono-PMB protected to provide
alcohol 17 and subsequently oxidized with MnO to afford
2
aldehyde 18 in 25% yield over the two steps. Intermediate
1
5 was treated with TiCl , followed by introduction of alde-
4
hyde 18 to facilitate an aldol reaction under Crimmins’ con-
ditions to deliver Evans’ syn product 19 in 65% yield with
[
7,8]
10:1dr.
Hydrolysis of the auxiliary with LiBH in MeOH
4
liberated the primary alcohol in low yield (44%, a survey
of multiple reactions conditions failed to improve the yield),
which was immediately protected as TIPS silyl ether 20 in
8
2% yield. A hydroxy-directed VO(acac) -mediated epoxid-
2
ation produced oxirane 21 as a single stereoisomer in 95%
[
9]
yield. Protection of the secondary hydroxy group as a
Scheme 1. Retrosynthesis of marineosin A (1) and functionalized
spiroaminal lactam 8. TBDPS = tert-butyldiphenylsilyl, TIPS = tri-
isopropylsilyl, Piv = pivalate, Bn = benzyl.
Scheme 3. Synthesis of key intermediate 6. Reagents and condi-
tions: (a) NaH, TBAI, PMBCl, THF, 0 °C, r.t., 12 h, 68%.
(
b) MnO
CH Cl , 0 °C; 2. 18, CH
MeOH, THF, 0 °C, 6 h, 44%; 2. TIPSCl, ImH, CH
2%. (e) VO(acac) , TBHP, CH Cl , 0 °C, 3 h, 95%. (f) 1. BnBr,
NaH, TBAI, THF, 0 °C, 4 h, 85%; 2. DDQ, CH Cl , pH 7 buffer,
0 °C, 14 h, 73%. (g) Red-Al, THF, 0 °C to r.t., 4 h, 79% (Ͼ20:1,
Cl , r.t., 3 h; 2. Me OBF , CH Cl
2
, CH
2
Cl
2
, r.t., 36 h, 36%. (c) 1. TiCl
Cl , 0 °C, 65% (10:1dr). (d) 1. LiBH
Cl , r.t., 4 h,
4
, DIPEA, NMP,
2
2
2
2
4
,
2
2
8
2
2
2
Scheme 2. Synthesis of advanced intermediate 15. Reagents and
2
2
conditions: (a) 1. CuI (20 mol-%), vinylmagnesium bromide, THF,
–
20 °C, 20 h; 2. TBDPSCl, ImH, CH
steps. (b) 1. O , CH Cl , 1 h, –78 °C; 2. PPh
Bromoacetyl bromide, THF, –78 °C to r.t., 89%. (d) P(OEt)
2
Cl
2
, r.t., 4 h, 81% over two 1.3:1.2). (h) 1. PivCl, pyr, CH
2
2
3
4
2
2
,
3
2
2
3
, r.t., 1 h, 84%. (c) α-
r.t., 1.5 h, 75% over two steps. PMB = p-methoxybenzyl, TBAI,
tetrabutylammonium iodide, DIPEA = N,N-diisopropylethylamine,
3
,
1
00 °C, 2 h, 82%. (e) 7 + 11, NaH, THF, –78 to 0 °C, 2 h, 75%. NMP = N-methylpyrrolidone, TIPS = triisopropylsilyl, ImH =
(
f) CuBr·DMS (20 mol-%), allylmagnesium bromide, THF/SMe
2
imidazole, acac = acetylacetonate, TBHP = tert-butyl hydrogen
peroxide, Bn = benzyl, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone, Piv = pivalate, pyr = pyridine.
(2:1), –78 °C, 81% (Ͼ20:1dr). TBDPS = tert-butyldiphenylsilyl,
ImH = imidazole, Bn = benzyl, DMS = dimethyl sulfide.
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Towards the Total Synthesis of Marineosin A
benzyl ether and subsequent DDQ-mediated removal of the the advanced macrocyclic pyrrole moiety of marineosin A
PMB group led to primary alcohol 22 in 62% yield for the (1) in 5.1% overall yield from (S)-propylene oxide.
two steps. Directed opening of the epoxide with Red-Al af-
To complete the total synthesis of marineosin A, we
forded desired 1,3-diol 23 in 79% yield with Ͼ20:1 ratio wanted to ensure that our strategy to form spiroaminal lact-
over the 1,2-diol congener.[ Finally, protection of the pri- am 2 from 3 through an acid-mediated cyclization strategy
mary hydroxy group as a pivalate and conversion of the was viable. With intermediate 6 in hand, we thought it pru-
secondary alcohol into a methyl ether afforded key interme- dent to explore this chemistry on a properly functionalized,
diate 6 in 75% yield over the two steps. With 6 in hand, we yet minimized model system, before committing advanced
were poised to evaluate our synthetic approach to access material. Reductive removal of pivalate 6 with DIBAL-H
macrocyclic pyrrole core 4 as well as functionalized spi- proceeded smoothly to give primary alcohol 29 in 93%
10]
roaminal model system 8.
yield, which was then oxidized under Parikh–Doering con-
Our next goal was to prepare 4 from 6. Towards this end, ditions to provide aldehyde 30 in 75% yield (Scheme 5).[
11]
we deprotected the TIPS ether by using BF ·OEt , the only Pinnick oxidation rapidly afforded the corresponding car-
3
2
conditions identified for chemoselective removal, to provide boxylic acid, which was coupled to ammonium chloride un-
primary alcohol 24 in 94% yield (Scheme 4). The primary der standard coupling conditions to deliver primary amide
[
15,16]
hydroxy group was oxidized by using Parikh–Doering con- 31 in 78% yield over the two steps.
Hydrogenolysis of
ditions to give aldehyde 25 in 75% yield.[ Then a two-step the benzyl ether and concomitant hydrogenation of the ole-
sequence involving the addition of vinyl Grignard reagent fin provided a secondary alcohol that was immediately oxi-
followed by Dess–Martin periodinane oxidation generated dized under Ley conditions to ketone 32 in 84% yield over
α,β-unsaturated ketone 26 in 68% yield over the two steps. the two steps. After surveying a number of conditions, we
Application of a Stetter reaction by employing 6-heptenal found that 0.01 m HCl in MeOH effected the acid-mediated
afforded RCM substrate 27 in 80% yield.[ We surveyed a cyclization strategy to provide 8 in 82% yield as a single
number of RCM catalysts and conditions to form the 13- diastereomer. Interestingly, the TIPS ether was hydrolyzed
membered macrocycle and found that the Grubbs II cata- under these conditions and was intercepted by MeOH to
lyst provided primarily cross-metathesis; however, the afford the methyl ether, which was confirmed by 1D and
Grubbs I catalyst (30 mol-%) under dilute conditions in re- 2D NMR studies. Efforts are under way to study this trans-
fluxing CH Cl provided desired RCM product 28 in 84% formation more thoroughly. Extensive analysis of HMBC,
11]
12]
2
2
yield. Similarly, a diverse array of Paal–Knorr conditions HSQC, and COSY and NOESY NMR experiments con-
were explored to facilitate pyrrole construction from 1,4- firmed the absolute structure of 8 as the marineosin A iso-
diketone 28, but all classical conditions provided low yields mer on the basis of the stereochemistry relative to the axial
[
13,14]
or decomposition.
Ultimately, we developed micro- methyl group within the pyran ring, which was set by the
wave-assisted conditions (NH OAc, MeOH, 120 °C, (S)-methyloxirane at the outset of the synthesis. From 6,
4
20 min) that delivered desired macrocyclic pyrrole 4 in 78% overall yield to 8 was 37.4%. Thus, advanced intermediate
yield. Thus, our retrosynthetic strategy granted access to 6 provided access to both macrocyclic pyran core 4 and
Scheme 4. Synthesis of macrocyclic pyrrole 4 moiety of marineosin A (1). Reagents and conditions: (a) BF
4%. (b) SO –pyr, Et N, DMSO, CH Cl , 6 h, r.t., 75%. (c) 1. Vinylmagnesium bromide, THF, –78 °C, 1 h; 2. Dess–Martin periodinane,
CH Cl , 0.75 h, r.t., 68% over two steps. (d) 6-Heptenal, Et N, thiazolium hydrochloride, 1,4-dioxane, 70 °C, 12 h, 80%. (e) Grubbs I
(0.0005 m), 9 h, 40 °C, 84%. (f) NH OAc, MeOH, 120 °C, microwave irradiation, 20 min, 78%. pyr = pyr-
3 2 2 2
·OEt , CH Cl , 0.5 h, r.t.,
9
3
3
2
2
2
2
3
catalyst (30 mol-%), CH
idine.
2
Cl
2
4
Eur. J. Org. Chem. 2013, 4215–4218
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4217

C. W. Lindsley et al.
SHORT COMMUNICATION
rineosin A, and efforts are underway to complete the total
synthesis by employing these tactics and strategies with the
final pyrrole incorporation step. Further refinements, appli-
cations to related alkaloids, and biological investigations
are in progress and will be reported in due course.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and spectral data.
Acknowledgments
The authors acknowledge the Vanderbilt Department of Pharma-
cology, Vanderbilt University Medical Center, and the National In-
stitutes of Health (NIH) for funding our research, and in particular
the Molecular Library Probe Center Network (MLPCN)
(
U54MH084659) for the Vanderbilt Specialized Chemistry Center.
Financial support from the Warren Foundation in the form of the
William K. Warren Jr. Endowed Chair is gratefully acknowledged.
[
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[
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2
Cl
, 0 °C, 1 h,
, 2-methyl-2-butene, 0 °C, 0.5 h;
Cl, DMF, r.t., 78% over two steps.
, EtOAc, r.t., 8 h; 2. TPAP, NMO, CH Cl , 0 °C to
2
,
–
7
2
78 °C, 1 h, 75%. (b) SO
5%. (c) 1. NaO Cl, NaH
. EDC, HOBt, DIPEA, NH
3
–pyr, Et
3 2 2
N, DMSO, CH Cl
2
2
PO
4
4
(d) 1. Pd/C, H
2
2
2
2
012, 18, 5826–5831; d) K. N. Hahn, O. O. Fadeyi, H. P. Cho,
r.t., 2 h, 84% over two steps. (e) 0.01 m HCl, MeOH, r.t., 10 h, 82%.
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2012, 3, 658–664.
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propylammonium perruthenate, NMO = N-methylmorpholine ox-
ide.
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2
091–2096.
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retrosynthetic approach for the total synthesis of ma-
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Received: May 2, 2013
Published Online: June 4, 2013
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Eur. J. Org. Chem. 2013, 4215–4218