A Scalable Total Synthesis of (-)-Nakadomarin A

Article abstract of DOI:10.1021/acs.orglett.6b03137

The convergent total synthesis of the manzamine alkaloid (-)-nakadomarin A (1) is described. The retrosynthetic analysis recognized spirocycle 3, assembled via an organocatalyst-promoted Michael addition/cyclization between bicyclic lactam 4 and furan ald

Full text of DOI:10.1021/acs.orglett.6b03137

Letter
pubs.acs.org/OrgLett
A Scalable Total Synthesis of (−)-Nakadomarin A
Robert K. Boeckman, Jr.,* Hui Wang, Kyle W. Rugg, Nathan E. Genung, Ke Chen, and Todd R. Ryder
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
*
S Supporting Information
ABSTRACT: The convergent total synthesis of the manzamine alkaloid (−)-nakadomarin A (1) is described. The
retrosynthetic analysis recognized spirocycle 3, assembled via an organocatalyst-promoted Michael addition/cyclization between
bicyclic lactam 4 and furan aldehyde 5, both accessible from achiral starting materials and on a multigram scale. Lactam 4 is
assembled through an S 2′/reduction/Staudinger/retro-aza-Claisen sequence on scale. After spirocyclization, the synthesis of
N
nakadomarin is completed in only six steps.
solated from the marine sponge Amphimedon sp. in 1997 by
Kobayashi and co-workers, the manzamine alkaloid
1
I
(
−)-nakadomarin A (1) has demonstrated a wide range of
2
−4
biological properties. These include cytotoxic activity against
murine lymphoma L1210 cells (IC50 = 1.3 μg/mL), inhibition
of cyclin-dependent kinase 4 (IC50 = 9.9 μg/mL; associated
with tumorigenesis of a variety of cancers), and antimicrobial
activity against the Gram-positive bacterium Corynebacterium
xerosis (MIC = 11 μg/mL) and the fungus Trichophyton
1
,5
mentagrophytes (MIC = 23 μg/mL). In addition to biological
activity, an architecturally unique framework has garnered much
attention for nakadomarin A in the synthetic community,
We envisioned (−)-nakadomarin A (1) as arising retro-
synthetically from metathesis and partial hydrogenation of
diyne 2 (Scheme 1), from which we anticipated that ring B
could be readily accessed via Friedel−Crafts-type ring closure
of spirocycle 3 (owing to the electrophilic character of the
vinylogous sulfimidinium ion; vide infra). We believed that this
spirocycle could be assembled by an organocatalyst-promoted
Michael addition/spirocyclization cascade between bicyclic
lactam 4 (10 steps from achiral and racemic starting materials)
and unsaturated β-furyl aldehyde 5 (five steps).
6
−17
consequently resulting in a number of total syntheses
synthetic approaches.
and
18−30
A preponderant number of strat-
egies have entailed either creating a tricyclic core encompassing
rings A, B, and D or constructing a DE fragment and appending
A then C. One of the two most recent efforts by Evans and co-
1
2
workers features a novel strategy and is extraordinarily brief,
creating ring A by combining a macrocyclic CF fragment with a
chiral DE fragment. However, no synthesis to date has begun
with racemic/achiral starting materials to produce the
enantioenriched target, and thus, these methods require the
use of chiral pool building blocks or resolution, which can limit
the scalability and throughput of the synthetic route (versus, for
example, chiral organocatalysis). Herein we describe an original
and efficient approach toward (−)-nakadomarin A (1) utilizing
achiral or racemic starting materials while minimizing the use of
protecting groups.
Our synthesis of (−)-nakadomarin A (1) commenced with
the preparation of bicyclic lactam 4 (Scheme 2) via an initial
31
Roush-modified Horner−Wadsworth−Emmons (HWE) ole-
fination of aldehyde 6 with phosphonate 7 in 90% yield. (R)-
32
CBS-catalyzed reduction of the resultant enone 8 provided
the expected (S)-allylic alcohol, which was subsequently
subjected to acylation with chloroformate 9 to provide allylic
Received: October 21, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03137
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis for 1
Scheme 3. Transition States for S 2′ Cyclization
N
38
was then directly reduced to aldehyde 14 with LDBBA (50%
over two steps). Aldehyde 14 was immediately subjected to
Staudinger imine formation using preformed TMS phosphani-
mine to minimize the formation of the oxocine via retro-
Claisen rearrangement. The resulting imine underwent thermal
retro-aza-Claisen rearrangement, and azocine 15 was thus
obtained in 90% yield from 14 and from allylic carbonate 10
with excellent overall efficiency.
Scheme 2. Preparation of Bicyclic Lactam 4
With azocine 15 in hand, cleavage of the primary silyl ether
followed by oxidation of the resulting alcohol using TPAP/
39
NMO, subsequent ring closure, and further in situ oxidation
provided bicyclic lactam 16 in 77% overall yield. Carboxylation
followed by amidation with alkynyl amine 17 gave lactam 4 in
high yield. The foregoing sequence is one of two reported
routes that does not employ ring-closing metathesis to
construct the five/eight-membered D/E rings of (−)-nakado-
marin A and has been executed reproducibly on multigram
scale.
By means of procedures adapted from those reported by
14
16
Dixon and Funk, the synthesis of β-furyl aldehyde 5
commenced with propargylation of the dianion of phosphonate
18 with 1-bromo-2-butyne (19) (Scheme 4). Subsequent HWE
Scheme 4. Preparation of β-Furyl Aldehyde 5
carbonate 10 in high yield and enantiomeric excess (93%, >95%
ee) over two steps. Using methodology previously developed in
3
3−37
our laboratories,
azocine 15 was assembled from allylic
carbonate 10 via an S 2′/reduction/Staudinger/retro-aza-
N
Claisen sequence. Allylic carbonate 10 was deprotonated to
give the more stable Z sodium enolate, which can exist as two
rotamers about the adjacent single bond in the counterion-
olefination with 1,3-diacetoxyacetone (20) provided enone 21
(55% over two steps). Acid-catalyzed cyclization in ethanol
followed by Swern oxidation provided furyl aldehyde 22 (68%
over two steps). HWE reaction with iminophosphonate 23
followed by biphasic hydrolysis (HCl/petroleum ether)
provided β-furyl aldehyde 5 in high yield (86%).
35
templated transition states 11 and 12 (Scheme 3). It has been
postulated that the phenylsulfonyl group should prefer the syn
transition state 11, as it leads to a reduction in steric
interactions with the adjacent olefinic side chain compared
3
5
with 12. This is consistent with observed 3:1 diastereose-
lectivity favoring the desired major diastereomer, syn-13.
During the formation of cyclobutane syn-13 and its
diastereomer, the diisopropylphenoxycarbonyloxy group is
With the coupling partners 4 and 5 in hand, we sought to
investigate the organocatalyst-promoted Michael/spirocycliza-
tion cascade with malonamide as a nucleophile to construct
ring A (Scheme 5). It was found that under the optimized
conditions, the Jørgensen−Hayashi catalyst 24 was the most
effective among those examined (pyrrolidine as an achiral
catalyst did not afford acceptable diastereoselectivity in an
displaced, ultimately degrading to CO and diisopropylpheno-
2
late. The use of phenyl choroformate, however, results in
diminished yields because of regeneration of the (S)-allylic
alcohol via deacylation of 10. The purified cyclobutane syn-13
40−42
analogous system).
Catalytic benzoic acid was required to
B
DOI: 10.1021/acs.orglett.6b03137
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Spirocycle Formation and Completion of the Synthesis of (−)-Nakadomarin A
facilitate iminium formation, and the presence of 3 Å molecular
desulfonylation of this material was initially attempted with
t
sieves was required to sequester the H O generated in order to
Li/NH / BuOH, (−)-nakadomarin A (1) was produced in low
2
3
prevent retro-Paal−Knorr-type cleavage of furan 5. The
resulting adduct was obtained in good yield (73% yield, 85%
conversion) with very good selectivity (92:8 dr) on at least a
yield along with a major byproduct resulting from β-elimination
(ring opening) of eight-membered azocine ring E. Fortunately,
4
4
inclusion of (NH
)
SO
promoted protonation of the
4
2
4
0.5 g scale of amide 4. The resulting cycloadduct with a chiral
intermediate carbanion, resulting in clean desulfonylation
auxiliary incorporated (as confirmed by X-ray crystallographic
analysis; see the Supporting Information) was treated with
BF −OEt and triethylsilane to cleave the auxiliary to provide 3.
without fragmentation to give 1 in 75% yield. Spectral data
1
13
25
(
=
IR, H and C NMR) of synthetic (−)-nakadomarin A ([α]
D
−72.6 (c = 0.26, CH OH)) were compared to those of
3
3
2
synthetic (−)-nakadomarin A and found to be identical.
Efforts to conduct the reaction employing catalytic 24 (in the
absence of molecular sieves in order to release the catalyst via
hydrolysis) resulted in hydrolytic decomposition (retro-Paal−
Knorr) of furan 5. Further investigation of the feasibility of a
catalytic process is currently underway in our laboratories.
The pentacyclic core of (−)-nakadomarin A (ABCDE ring
system) was then completed by a Friedel−Crafts-type closure
to afford ring B, promoted by the formation of the tricyclic
iminium ion via regioselective reduction of the more reactive
vinylogous sulfimide carbonyl to the aminol borate with
In conclusion, we report herein an efficient synthesis of
(
−)-nakadomarin A (1) from achiral and racemic starting
materials. The synthesis is completed in 17 steps (longest
linear) in 3% overall yield. This route has to date provided
>
100 mg of 1. Current efforts in our laboratories toward a
second-generation synthesis aimed at improving the overall
selectivity, scalability, and efficiency of the synthetic route are
well underway.
ASSOCIATED CONTENT
LiEt BH and subsequent triflation. Under the optimized
3
■
conditions, addition of acetone was required to quench any
*
S
Supporting Information
remaining hydride. Cyclization then occurred efficiently under
6
−30
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03137.
milder conditions than for related transformations,
affording pentacyclic system 2 in a good yield (76%) due to
the increased electrophilicity of the more electron-deficient
vinylogous sulfimidinium ion.
Experimental procedures and spectroscopic and crystallo-
graphic data (PDF)
In the presence of the alkyne metathesis catalyst 25,
43
̈
developed by Furstner, diyne 2 was readily converted to
the 15-membered-ring macrocycle 26 in 78% overall yield after
hydrogenation of the resulting macrocyclic alkyne in the
presence of Lindlar’s catalyst. Interestingly, when the RCAM
was performed on the azocine derivative of 2 bearing no vinyl
sulfone group (a free tertiary amine), the major product
obtained was the saturated acyclic dimer of the substrate.
AUTHOR INFORMATION
■
*
Corresponding Author
rkb@rkbmac.chem.rochester.edu
ORCID
Treatment of hexacyclic amine 26 with TFA/Et SiH
3
Robert K. Boeckman, Jr.: 0000-0001-7230-4642
Notes
followed by in situ treatment with DIBAL-H resulted in
reduction of both the lactam and the vinylogous sulfonamide to
afford sulfone 27 in 60% yield (unoptimized). When
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b03137
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Organic Letters
Letter
(
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DOI: 10.1021/acs.orglett.6b03137
Org. Lett. XXXX, XXX, XXX−XXX