Nine-step enantioselective total synthesis of (+)-minfiensine

Article abstract of DOI:10.1021/ja906472m

(Chemical Equation Presented) An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic Diels-Alder/amine cyclization sequen

Full text of DOI:10.1021/ja906472m

Published on Web 09/02/2009
Nine-Step Enantioselective Total Synthesis of (+)-Minfiensine
Spencer B. Jones, Bryon Simmons, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received July 31, 2009; E-mail: dmacmill@princeton.edu
Scheme 1. Retrosynthetic Approach to Minfiensine Pentacycle
Over the last 50 years, the Strychnos alkaloids have become
recognized as a family of molecular benchmarks, used to calibrate
the utility of new complexity-generating reactions or novel synthetic
strategies.1 In this context, minfiensine (1),2 a structurally unique
isolation product from Strychnos minfiensis, has received considerable
attention from the chemical synthesis community,3 culminating recently
in the highly elegant (and first) enantioselective total synthesis by
Overman and co-workers.3a Minfiensine is characterized by an
embedded 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole moi-
ety, a tetracyclic core that is also found among related akuammiline
alkaloids vincorine (2) and echitamine (3).4 In this communication,
we document a new organocatalytic Diels-Alder/amine cyclization
sequence that allows rapid and enantioselective access to this tetracyclic
carbazole framework using only an amine catalyst, propynal, and a
simple tryptamine derivative. Moreover, we elaborate upon this new
asymmetric protocol to achieve a nine-step total synthesis of min-
fiensine beginning from commercial materials.
cycloaddition while providing a latent handle for radical formation,8
as required in the final ring-forming step.
Synthesis of the minfiensine core began with production of the
requisite [4 + 2] cycloaddition substrate 8 in three steps from
commercial materials using the standard procedures outlined in
Scheme 3. With this material in hand, we were able to examine
the pivotal Diels-Alder-cyclization cascade in detail. As shown
in Table 1, we were delighted to find that subjection of 2-vinylindole
8 to propynal in the presence of imidazolidinone catalyst 7 produced
the desired tetracycle 15, albeit with moderate selectivity (entry 1,
Scheme 2. Enantioselective Catalytic Cascade Sequence to Core
Design Plan
As outlined in Scheme 1, we envisioned two key steps that would
allow rapid access to the complete pentacyclic topography of
minfiensine. From a disconnection approach, we assumed the fifth
and final ring of the natural product might be forged via a 6-exo-
dig cyclization between an allylic radical and a pendent alkyne 4,
a carbon-carbon bond union that would also create the requisite
stereogenicity at C(15) and the exocyclic olefin at C(20).5 As for
our second key step, we hypothesized that the structurally complex
pyrroloindoline tetracycle 5 might arise directly from vinyl indole
6 via a cascade reaction that would incorporate an organocatalytic
Diels-Alder cycloaddition, enamine to iminium isomerization, and
an amine cyclization sequence.6 More specifically, we proposed
that condensation of secondary amine catalyst 7 with propynal
should generate an activated iminium ion with the acetylenic group
being partitioned away from the bulky t-butyl substituent of the
catalyst framework (Scheme 2, TS-A). In this conformation, the
aryl ring would shield the top face of the reactive alkyne, facilitating
an endo-selective7 Diels-Alder cycloaddition with 2-vinylindole
8 in a regioselective manner to produce the tricyclic diene 9.
Protonation of the enamine moiety would then give rise to an
iminium ion 10, facilitating a 5-exo amine heterocyclization to
deliver the tetracyclic pyrroloindoline 11. As a key design element,
the dienyl substructure of indole 8 incorporates a 1-methyl sulfide
substituent, a moiety that we hoped would accelerate the Diels-Alder
9
13606 J. AM. CHEM. SOC. 2009, 131, 13606–13607
10.1021/ja906472m CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Nine-Step Total Synthesis of Minfiensine (1)a
a Reagents and Conditions: (a) NaH, PMBCl, DMF, 0 °C. (b) n-BuLi, THF, -78 °C; then DMF, -78 °C to rt. (c) (EtO)2P(O)CH2SMe, NaH, THF, 0 °C
to rt. (d) Table 1, entry 3. (e) TESOTf, MeCN, 0 °C. (f) 4-(tert-Butylthio)but-2-ynal (17), NaBH(OAc)3, CH2Cl2, rt. (g) 3 equiv of t-Bu3SnH, 0.3 equiv
AIBN, toluene, 110 °C. (h) Pd/C, H2, THF, -15 °C; >20:1 E/Z selectivity. (i) PhSH, TFA, rt.
would provide the trans-ethylidene subunit that is commonly found
Table 1. Organocatalytic Diels-Alder-Cascade Cyclization Studies
throughout the Strychnos alkaloid family. In the event, we were pleased
to find that the proposed reduction could be realized via subjection of
allene 19 to 10% Pd/C and H2 in THF at -15 °C to give the desired
trans-ethylidene with greater than 20:1 E/Z selectivity.13 Finally, a
global deprotection using neat TFA at room temperature delivered (+)-
minfiensine (1) in 90% yield, a substance that was identical in all
respects to the natural isolate.
In summary, the total synthesis of (+)-minfiensine (1) was
completed in nine steps and 21% overall yield from commercial
materials. Prominent features of this synthesis include (i) a new
cascade organocatalysis sequence to build the central tetracyclic
pyrroloindoline framework and (ii) a 6-exo-dig radical cyclization
to forge the final piperidinyl ring system.
Acknowledgment. Financial support was provided by the
NIGMS (R01 GM078201-01-01) and kind gifts from Merck and
Amgen. B.S. and S.B.J. thank Merck and Bristol-Myers Squibb,
respectively, for graduate fellowships.
entry
catalyst·HA
mol %
time (h)
% yielda
% eeb
1
7·TFA
20
20
15
10
5
12
12
24
48
72
84
81
87d
83
80
75
88
96
94
94
2
7·TBA
14·TBA
14·TBA
14·TBA
3c
4
Supporting Information Available: Experimental procedures and
spectral data for all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
5
a Yield determined by 1H NMR with internal standard. b Enantiomeric
excess determined by chiral SFC analysis. c At -50 °C. d Isolated yield.
References
(1) Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100, 3455.
75% ee). A catalyst structure evaluation revealed that the 1-naphthyl
substituted catalyst 14 in conjunction with tribromoacetic acid
(TBA) cocatalyst provided superior levels of yield and enantiose-
lectivity, presumably due to the extended shielding effect of the
naphthyl ring in the [4 + 2] transition state (entry 3, 87% yield,
96% ee). It is important to note that catalyst loadings as low as 5
mol % were sufficient to effect the cascade while maintaining high
levels of reaction efficiency (entries 4 and 5, 80% yield, 94% ee).
Subsequent conversion of the pyrroloindoline tetracycle 15 to
minfiensine (1) was achieved in a five-step sequence as shown in
Scheme 3. Simultaneous N-Boc deprotection and primary alcohol
protection were performed by exposure of carbamate 15 to TESOTf
in acetonitrile at 0 °C to afford silyl ether 16 in 84% yield. Reductive
amination of secondary amine 16 with butynal t-butyl sulfide 17 was
readily accomplished with NaBH(OAc)3 in CH2Cl2 to render the
requisite radical cyclization substrate 18 in 96% yield. At this stage,
we were surprised to find that all attempts to forge the final piperidine
ring of minfiensine via alkyne radical cyclization were unsuccessful
using prototypical conditions (AIBN, Bu3SnH).9 However, replacement
of Bu3SnH with the more bulky t-Bu3SnH10 (with AIBN in refluxing
toluene) cleanly afforded the allene 19 in 61% yield.11,12 Next, we
envisioned that regio- and diastereoselective allene hydrogenation
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(7) Acetylenic [4 + 2] cycloadditions are typically exo-selective: (a) Corey,
E. J.; Lee, T. W. Tetrahedron Lett. 1997, 38, 5755. (b) Ishihara, K.; Kondo,
S.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 3026.
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(11) Bachi, M. D.; Bar-Ner, N.; Melman, A. J. Org. Chem. 1996, 61, 7116.
(12) Cyclization onto the analogous methyl alkyne gives a 1:1 E/Z ratio.
(13) A related allene hydrogenation has been achieved in modest yield: Bonjoch,
J.; Sole´, D.; Garc´ıa-Rubio, S.; Bosch, J. J. Am. Chem. Soc. 1997, 119, 7230.
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