Direct coupling of indoles with carbonyl compounds: Short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families

Article abstract of DOI:10.1021/ja047874w

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapali

Full text of DOI:10.1021/ja047874w

Published on Web 05/29/2004
Direct Coupling of Indoles with Carbonyl Compounds: Short,
Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and
Fischerindole Alkaloid Families
Phil S. Baran* and Jeremy M. Richter
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received April 13, 2004; E-mail: pbaran@scripps.edu
Embedded in countless natural products and medicinally relevant
compounds, the indole heterocycle has served to inspire synthetic
chemists for well over a century.1 The hapalindole and fischerindole
classes of natural products piqued our interest by virtue of their
structural beauty and bioactivity.2 Our retrosynthetic analysis of
hapalindole Q (1, Figure 1)2 led to hypothetical indole- and carvone-
derived synthons 2+ and 3- (Figure 1). By analogy to Barton’s
classic synthesis of usnic acid, which utilized a phenolate radical
coupling,3 we reasoned that bond formation between 2 and 3 could
conceivably be accomplished through a coupling of radicals 2• and
3• which should be accessible via oxidation of the corresponding
anions 2- and 3-. While oxidative dimerization of enolates is
known,4 the analogous process with indoles (or metallo-enamines)
is not. In fact, the heterocoupling of enolates has seen little use in
synthesis since the process is plagued by low yields, the use of equi-
molar quantities of metal salts relative to those of all enolate species
present, and the requirement of a large excess (3-10 equiv) of one
of the partners to avoid homocoupling. Described herein are short,
Figure 1. Retrosynthetic analysis of (+)-1 leads to the invention of a direct
coupling of indoles with carbonyl compounds.
enantioselective, protecting group-free total syntheses of (+)-1 and
12-epi-fischerindole U isothiocyanate (-)-108 based on the analysis
outlined above. Further, these syntheses overcome the limitations
of enolate coupling and set a precedent that is extended to the
coupling of indoles with a diverse set of ketones, esters, and amides.
Empirical validation of our design (Figure 1) was obtained by
employing “standard” conditions for ketone enolate couplings.4
Thus, as shown in Table 1 (entry 1), addition of LDA (4.0 equiv)
to a 3-fold excess of 3 relative to 2 followed by FeCl3 (4.0 equiv)
resulted in ca. 15% yield of adduct 4 as a single diastereomer
(colorless cubes, mp 129-130 °C, see Scheme 1 for X-ray
crystallographic analysis). After evaluating numerous oxidants we
found that copper(II)2-ethylhexanoate5 consistently provided higher
yields and eliminated the need to use DMF as cosolvent (entry 2).
Similar results were obtained by using equimolar amounts of both
2 and 3 (entry 3). Another increase in yield occurred using a 3-fold
excess of 2 (entry 4). The optimum protocol emerged upon addition
of LHMDS (3.0 equiv) to a solution of 2 (2.0 equiv) and 3 (1.0
equiv) in THF at -78 °C followed by addition of 1.5 equiv of
copper(II)2-ethylhexanoate to furnish 4 in 53% isolated yield (70%
based on recovered starting material (sm), entry 5). The remainder
of the material consists of recovered 2 and 3 and a small amount
of carvone dimer (indole dimer was not observed). The yield is
not diminished even on >100 mmol scale. The use of substoichio-
metric quantities of oxidant (relative to moles of all anionic species)
in an enolate coupling is without precedent,4 and the mechanistic
implications of this finding will be discussed elsewhere.6
Table 1. Selected Optimization Results of 2 + 3 f 4
a Isolated yield after chromatography. b Yield based on recovered sm.
resulting enolate with acetaldehyde (L-Selectride, THF, -78 °C, 1
h; then CH3CHO, -78 f 23 °C, 2 h); (2) dehydration of the crude
alcohol 5 (Martin sulfurane, CHCl3, 23 °C, 10 min) to give indole
67a in 75% overall yield, intersecting with the Albizati synthesis;7a
(3) microwave-enhanced11,12 reductive amination (NaBH3CN (10
equiv), NH4OAc (40 equiv), MeOH, THF, 150 °C, 2 min) to furnish
the amine 7 as a 6:1 mixture of diastereomers; and (4) conversion
to (+)-1 by isothiocyante formation7a (CS(imid)2 (1.1 equiv, CH2-
Cl2, 23 °C).13
The total synthesis of (-)-108 was completed from indole 6 by
the following short sequence: (1) biomimetic8,14 acid-catalyzed ring
closure (TMSOTf, 25 °C, 1 h) of 6 to afford ketone 8 in 75% yield
based on recovered sm; (2) standard reductive amination of 8 to
furnish the amine 9 as a 10:1 mixture of diastereomers in 60%
yield; and (3) conversion of 9 to (-)-10 by isothiocyanate formation.
Based on the optical rotation of synthetic (-)-10 {[R]D -200 (CH2-
Cl2, c 0.020), lit. [R]D +231 (CH2Cl2, c 0.035)}, the absolute
configuration of natural (+)-10 is opposite that depicted in Scheme
1 (9S,10R,11R,12R). The synthetic pathway to (+)-hapalindole Q
With a simple route to obtain multigram quantities of 4 from
(R)-carvone, completion of the total synthesis of (+)-17 was
accomplished by executing the following operations (Scheme 1):
(1) deprotonation of the indole N-H of 4 (LHMDS, THF, -78
°C),9 conjugate reduction10 and stereoselective quenching of the
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10.1021/ja047874w CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preparation of R-Indole Carbonyl Compounds
Scheme 1. Enantioselective Total Syntheses of (+)-1 and (-)-10a
a Isolated yield after chromatography. b Yield based on recovered sm.
c LDA used.
generous donation of process vials used in this study (6 f 7).
Financial support for this work was provided by The Scripps
Research Institute, Eli Lilly & Co, and the National Science
Foundation (predoctoral fellowship to J.M.R.).
Supporting Information Available: Detailed experimental pro-
cedures, copies of all spectral data, and full characterization. X-ray
crystallographic file in CIF format. This material is available via the
Internet at http://pubs.acs.org.
References
(1) One-third of the following book is dedicated to indole-containing natural
products: Nicolaou, K. C.; Snyder S. A. Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003; Chapters 5, 8, 12, 18, 19, 20, and 22, p
639. For an excellent overview of indole synthesis and reactivity, see:
Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; p 175.
(2) Hapalindole isolation: Moore, R. E.; Cheuk, C.; Yang, X.-Q. G.; Patterson,
G. M. L.; Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.;
Jones, N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987,
52, 1036-1043; Fischerindole isolation: Park, A.; Moore, R. E.; Patterson,
G. M. L. Tetrahedron Lett. 1992, 33, 3257-3260.
a Reagents and conditions: (a) LHMDS (1.5 equiv), THF, -78 °C, 20
min then L-Selectride (1.05 equiv), 1 h, then CH3CHO (6.0 equiv), -78f23
°C, 2 h; (b) Martin sulfurane (1.1 equiv), CHCl3, 10 min, 75% overall; (c)
TMSOTf (3.0 equiv), MeOH (1.1 equiv), CH2Cl2, 0 °C, 1 h, 75% bsm; (d)
NaBH3CN (10 equiv), NH4OAc (40 equiv), MeOH, THF, 150 °C, 2 min,
61% (7); for 9: same reagents, 23 °C, 48 h, 55%; (e) CS(imid)2 (1.1 equiv),
CH2Cl2, 0f23 °C, 3 h, 63% (1), 60% (10).
(3) Barton, D. H. R.; Deflorin, A. M.; Edwards, O. E. J. Chem. Soc. 1956,
530-534.
(1) and (-)-12-epi-fischerindole U isothiocyanate (10) proceeds
in 22% and 15% overall yield from (R)-carvone, respectively.
The scope of the direct indole coupling was briefly evaluated
by the study of the examples summarized in Table 2 using
conditions established for the synthesis of 4. Free alcohols are
tolerated (12, additional LHMDS added), hindered indoles such as
13 are accessible, and amides also participate in this reaction (14-
18) as illustrated with Evans and Oppolzer auxiliaries. The latter
substrates (15-18) proceed with high diastereoselectivity. The
method also works with functionalized indole substrates (16-18)
and tert-butyl esters (19).
In conclusion, we have developed a new and practical method
for the direct coupling of indoles with carbonyl compounds that
has been applied to the most concise and efficient synthesis of (+)-1
yet reported and to the first total synthesis and absolute configu-
ration assignment of a fischerindole [(-)-10]. This protocol can
be used to construct quaternary carbon centers, is amenable to
asymmetric synthesis, and can be performed on a multigram scale.
Indoles that would be otherwise unobtainable in a single step from
readily available materials are now easily accessed, thus filling a
gap in indole synthesis methodology.1
(4) (a) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 4605-4606.
(b) Dessau, R. M.; Heiba, E. I. J. Org. Chem. 1974, 39, 3457-3459. (c)
Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912-
2914. (d) Ito, Y.; Konoike, T.; Harada, T.; Saegusa T. J. Am. Chem. Soc.
1977, 99, 1487-1493. (e) Frazier, R. H.; Harlow, R. L. J. Org. Chem.
1980, 45, 5408-5411. (f) Paquette, L. A.; Bzowej, E. I.; Branan, B. M.;
Stanton, K. J. J. Org. Chem. 1995, 60, 7277-7283.
(5) Commercially available from several sources, including Aldrich.
(6) We initially imagined the mechanism shown in Figure 1, but other
mechanistic pathways may be operative such as addition of 3• to 2- to
give 4•- followed by oxidation to 4.
(7) Total syntheses of (+)-1: (a) Vaillancourt, V.; Albizati, K. F. J. Am. Chem.
Soc. 1993, 115, 3499-3502 (ca. 4% yield). (b) Kinsman, A. C.; Kerr, M.
A. J. Am. Chem. Soc. 2003, 125, 14120-14125 (ca. 1.0% yield). Total syn-
thesis of racemic 1: Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3, 3189-
3191 (ca. 9% yield). Yields are from commercially available material.
(8) Isolation (+)-10: Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter,
J. B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935-9942.
(9) Addition of L-Selectride (1-3 equiv) to 4 followed by addition of
acetaldehyde led only to the corresponding saturated ketone due to internal
quenching of the resulting enolate onto the indole N-H.
(10) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194-2200.
(11) The conditions used by Albizati (ref 7a) for reductive amination were
NaBH3CN (10 equiv), NH4OAc (40 equiv), 7 days, dr ) 3:1.
(12) For recent uses of microwave irradiation in complex natural product
synthesis, see: Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 706-707; Baran, P. S.; O’Malley, D. P.; Zografos,
A. L. Angew. Chem., Int. Ed. 2004, 43, 2674-2677.
(13) The minor amine diastereomer was identical to 12-epi-hapalindole D
isothiocyanate (ref 8), see Supporting Information for details.
(14) Fukuyama observed this ring closure as an undesired byproduct during
the course of a beautiful total synthesis of (-)-hapalindole G: Fukuyama,
T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125-3126.
Acknowledgment. We thank Dr. D. H. Huang and Dr. L.
Pasternak for NMR spectroscopic assistance and Dr. G. Suizdak
and Dr. R. Chadha for mass spectrometric and X-ray crystal-
lographic assistance, respectively. We are grateful to Biotage for a
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