On the rearrangement of an azaspiroindolenine to a precursor to phalarine: Mechanistic insights

Article abstract of DOI:10.1002/anie.200604071

(Chemical Equation Presented) An interesting rearrangement: Management of functional groups in derivatives of indoles enables a rearrangement to take place which provides the pentacyclic ring system found in phalarine (see scheme, CSA = camphorsulfonic ac

Full text of DOI:10.1002/anie.200604071

Communications
DOI: 10.1002/anie.200604071
Mechanistic Studies
On the Rearrangement of an Azaspiroindolenine to a Precursor to
Phalarine: Mechanistic Insights**
Chaomin Li, Collin Chan, Annekatrin C. Heimann, and Samuel J. Danishefsky*
In an agronomy-centered investigation directed at the
suitability of Phalaris coerulescens (blue canary grass) for
introduction into Australia, Colegate and co-workers isolated
a furanobisindole alkaloid which they termed phalarine.[1] On
the basis of spectroscopic analysis, in particular NMR and MS,
the structure of phalarine was assigned as 1 (Scheme 1). This
representation was not supported by systematic degradation,
let alone corroboratory crystallographic studies. Given our
long term involvement in novel indole alkaloids,[2] we took an
interest in the structure 1 proposed for phalarine, and began
to formulate possible routes for its total synthesis.
In the early stages, our thinking was influenced by the
isolation of N-methyl-b-carboline (2) together with phalar-
ine,[3] which led to proposals to account for its biosynthesis,
and, by extension, ideas for its chemical synthesis (Scheme 1).
It was conjectured, both for the biogenesis and chemical
synthesis, that oxidative heterocoupling of 2 with a suitable
derivative of 5-hydroxygramine (3) could lead to a phalarine-
like structure. To reach phalarine would require the sites of 2
and 3 marked by asterisks to be connected (red to red, blue to
blue) in some manner (Eq. (1) in Scheme 1). Our first thought
was to simulate such a biogenesis. In fact we never explored
this invitingly simple notion for the synthesis in the context of
the mature structures 2 and 3. Rather, the central idea was
first evaluated with the seemingly relevant models (4 and 5).
While we did indeed realize the oxidative heterocoupling of 4
and 5, we were unable to do so in the manner required for
phalarine. Thus, as previously reported,[4] oxidative coupling
of these two compounds produced compound 6 (see alter-
native positions of asterisks, Eq. (2), Scheme 1). As a further
complication, an affinity between the benzyl C1atom of the
carboline and the C6 atom of the phenol served to overwhelm
a
potential alternative solution (see 7+5!8, Eq. (3),
Scheme 1).[5,6]
On the basis of these and numerous other setbacks, we
decided that prospects for success could well require a
ꢀ
substrate in which the C C bond between the a-carbon
atom of the indole (C9a, phalarine numbering) and the
O-hydroxyaryl moiety (C4’) would be securely in place prior
to the reactions which would set up the linkage of the
phenolic oxygen atom to the b-carbon atom of the carboline
(C4a). Of course, this prospectus would mean forgoing the
option of passing through a readily synthesizable b-carboline
derivative, such as 2, in the oxidative coupling itself. Rather,
in our new route, the carboline moiety would be constructed
on-site by ring expansion of an azaspiroindolenine structure
such as 10 (Scheme 2). Indeed, we envisioned that the
rearrangement step that would fashion the hexahydrocarbo-
line framework would itself create a positive charge at the b-
carbon atom of the indoline, thereby setting the stage for the
Scheme 1. Original strategy toward phalarine.
[*] Dr. A. C. Heimann, Prof. S. J. Danishefsky
The Laboratory for Bioorganic Chemistry
Sloan-Kettering Institute for Cancer Research
1275 York Avenue, New York, NY 10021 (USA)
Fax: (+1)212-772-8691
E-mail: s-danishefsky@ski.mskcc.org
Dr. C. Li, C. Chan, Prof. S. J. Danishefsky
The Department of Chemistry
Columbia University
ꢀ
critical O C4a bond formation which had eluded us. We
further conjectured that an azaspirooxindole system such as 9,
albeit with as yet unspecified protecting groups on the two
nitrogen atoms, would serve as a matrix from which to reach
azaspiroindolenine 10. Herein we report on the development
of this new strategy, which led to the desired rearrangement of
an azaspiroindolenine to give the precursor of phalarine, and
thus subsequently enabled the inaugural total synthesis of
phalarine.[7]
Havemeyer Hall, New York, NY 10027 (USA)
[**] This work was supported by the National Institutes of Health (Grant
HL25848) and by a postdoctoral fellowship from the German
Academic Exchange Service (DAAD) to A.C.H. We thank D. Buccella
for X-ray crystallographic analysis. We also thank Dr. G. Sukenick
(NMR Core Facility, Sloan-Kettering Institute) and Dr. Y. Itagaki
(Columbia University) for NMR and mass spectrometric analysis,
respectively.
We began our study with the hope of examining the
proposed rearrangement in the context of the azaspiro-
Supporting information for this article is available on the WWW
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individual factors contributing to the failed conversion of 18
into 19. However, for purposes of the synthesis, we focused
instead on the identification of an optimal system which might
undergo the critical rearrangement step, thus validating the
central idea and enabling convergence on phalarine itself.
To meet this goal, we concentrated on gaining access to 25,
or a functional equivalent thereof (Scheme 4). This structure
would contain an activating tosyl function at the N1-position,
Scheme 2. Modified strategy toward phalarine. PG=protecting group.
indolenine structure 18, which we expected would rearrange
to 19 (Scheme 3). This reasoning led us back to the simple b-
carboline 13, which was converted into 14 and then, by a well-
precedented NBS-induced oxidative rearrangement, to
Scheme 3. Reagents and conditions: a) methyl chloroformate, CH2Cl2/
sat. aq NaHCO3 (1:1), RT, 99%; b) NBS, THF/H2O then AcOH, 08C,
84%; c) Boc2O, Et3N, DMAP, CH2Cl2, 84%; d) 17, tBuLi, THF, ꢀ788C;
e) TFA, CH2Cl2, 54% (2 steps). NBS=N-bromosuccinimide, Boc=tert-
butoxycarbonyl, DMAP=4-dimethylaminopyridine, MOM=methoxy-
methyl, TFA=trifluroacetic acid.
Scheme 4. Reagents and conditions: a) LiAlH4, THF, 99%; b) NBS,
THF/H2O/AcOH (1:1:1.5), RT, 79%; c) LiHMDS, TsCl, THF, 08C,
89%; d) 17, nBuLi, THF, ꢀ788C, 94%; e) TFA, CH2Cl2, 08Cto RT,
95%; f) CSA, PhCH3, 1508C, 52%; g) MeI, benzene, 60% conv.
HMDS=1,1,1,3,3,3-hexamethyldisilazane, Ts=para-toluenesulfonyl,
CSA=(ꢁ)-camphorsulfonic acid.
spirooxindole 15.[8] Following a further carbamoylation, we
had the bisurethane 16 in hand. Coupling 16 with the aryl
lithium 17 gave a 1:1 adduct, which, on treatment with
trifluoroacetic acid, afforded imine 18. Surprisingly, all
attempts to achieve the rearrangement of 18 to the desired
model product system 19 were unsuccessful. Remarkably
such attempts, under a range of conditions, led primarily to
the recovery of 18.
Several possibilities could account for the failure of this
seemingly straightforward rearrangement (18!19) to prog-
ress. First, the migratory aptitude of the urethane-bound
methylene carbon atom (see asterisk, 18, Scheme 3) of the
spiroazaoxindole could be rather low, when attached to a
ureido-type nitrogen atom.[9] Moreover, hydrogen bonding
between the phenolic function and the nitrogen atom of
and an N-methyl function at the N2-position of the azaspiro-
indolenine. Fortunately, the carbomethoxy group of 14 could
be converted into the N-methyl tertiary amine 20 (Scheme 4).
An oxidative rearrangement of 20 mediated by NBS afforded
21,[8] which, on tosylation of the N1-position, gave rise to 22.
Arylation of 22 with 17 led to the 1:1 adduct 23. Removal of
the MOM ether afforded ketone 24, whose structure was
confirmed by X-ray analysis.[10] While at the planning stage we
had been thinking in terms of 25 (or its hydrate precursor) as
the substrate that would undergo rearrangement, we antici-
pated that the tosyliminium linkage, which would provoke
rearrangement, would still be accessible by progression from
24.
ꢀ
indolenine could restrict the free rotation around the C9a C2’
bond.[10] Such a rotation is likely to be vital to the establish-
ment of the phenyl ether–C4a bond (phalarine numbering),
which is needed to drive the ring-expanding rearrangement
step in the direction of the precursor to phalarine. In future
studies, it will be interesting to further investigate the
In the event, treatment of 24 with camphorsulfonic acid at
1508C afforded 26 in 52% yield, presumably via an inter-
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Communications
mediate such as 25. The structure assignment of 26 was
confirmed by X-ray analysis of its methiodide derivative 27.[10]
Thus, with proper substitution, the hypothesized rearrange-
ment of azaspiroindolenine 25 to the precursor to phalarine
26 was indeed realizable.
In the following Communication,[7] we will show how this
core chemistry, appropriately modified, enabled realization of
our goal, namely, the total synthesis of phalarine. Herein, we
concentrate on some subtle issues which we found to be
fascinating in their own right, especially in regard to their
impact on broad issues in the chemistry of extended indoles.
From the presumed intermediate 25, one could, in
principle, formulate two separate mechanistic interpretations
to account for progression to 26. The first (path a, Scheme 5)
would entail a Wagner–Meerwein-like 1,2-shift, which is
expected to proceed in a suprafacial fashion.[11] Following
Scheme 6. Reagents and conditions: a) MeOH, 2n aq HCl; b) 37%
aq formaldehyde, MeOH, reflux; c) TMSCl, MeOH, reflux; d) 37% aq
formaldehyde, NaBH3CN, MeOH, AcOH, 69% after recrystallization
(4 steps); e) NBS, AcOH, THF, 08C, quant.; f) 7m NH3/MeOH, RT,
quant.; g) TFA, Et3N, CH2Cl2, quant.; h) NaBH4, EtOH, reflux, 73%;
i) LiHMDS, TsCl, THF, 98%; j) 1. tBuLi, THF, ꢀ788C , 2.32, 83%;
k) TFA, CH2Cl2, 85%. TMS=trimethylsilyl.
ꢀ
O C4a bond formation, structure 26 would emerge. In an
alternative pathway (path b), 25 would first undergo a retro-
Mannich reaction.[12] The ensuing achiral intermediate 28
would be susceptible to the Pictet–Spengler reaction,[13] thus
providing the carbocation 29. The latter would be well-
disposed to undergo attack by the resident phenolic function-
ality, ultimately providing the observed rearrangement
adduct 26.
preparative scales.[15] Similarly, separation of the enantiomers
of 26 could be accomplished on an analytical scale.[16] With
these capabilities, it was possible to analyze the rearrange-
ment step in considerable detail.
Inspection of these two mechanistic pathways reveals a
distinction which can, in principle, be tested. In the Wagner–
Meerwein-like pathway (path a), there is a chirality transfer
between C4a and C9a in going from 25 to 26. By contrast,
path b proceeds via the achiral intermediate 28. Thus, the
configurational information inherent at the sp3 center at C4a
in 25 is forfeited at the stage of retro-Mannich intermediate
28, en route to racemate 26. Of course, exploitation of this
mechanistic distinction requires that the reaction be con-
ducted in the context of enantioenriched or ideally enantio-
pure starting material. In this way, one might hope to
determine the degree of chirality transfer in the rearrange-
ment step. With this goal in mind, l-tryptophan was used as
the starting material to reach substrate (+)-24 (Scheme 6) via
the P. coerulescens co-metabolite coerulescine ((S)-21).[14] It
was also possible to work out chromatographic procedures to
separate the enantiomers of 24 on both analytical and
Substantially enantiopure (+)-24 (> 95% ee) was sub-
jected to the now-standard rearrangement conditions. We
initially planned to monitor the optical enrichment of 26 as a
function of time. In the event, as soon as 26 was produced (as
judged by HPLC) it emerged as the racemate.[16] On the basis
of these findings, it is clear that the rearrangement of (+)-24
to 26 occurs with loss of configurational information, pre-
sumably via 28.
We also examined the optical purity of unconsumed 24 as
the reaction proceeded. In the event, 24 was re-isolated and
found to have fully retained its optical activity.[16] This
observation can be readily explained through inspection of
the proposed reaction pathway. Thus, the first step entails the
cyclization of ketone 24 to indolenine 25 (Scheme 5). From
there, the retro-Mannich reaction to give 28 abrogates the
incident chirality and product 26 emerges as a racemate.
These data do not tell us intrinsically whether achiral 28, on its
Scheme 5. Possible mechanistic pathways of the rearrangement sequence.
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J. A. Edgar, K. Flower, I. Vit, R. I. Willing, Phytochemistry 1998,
48, 437.
[4] C. Chan, C. Li, F. Zhang, S. J. Danishefsky, Tetrahedron Lett.
2006, 47, 4839 – 4841.
formation, must progress on to 26 or whether it can revert to
25. In principle, 28 and 25 could well be in equilibrium. All
that can be said with confidence is that 28 does not revert all
the way back to 24, for it is 24 which was detected.[17] Given
our inability to resolve this issue (that is, whether achiral 28
reverts to racemic 25), there would remain an uncertainty as
to whether the Pictet–Spengler pathway actually occurs. In
principle, if 28 reverted to racemic 25, a pathway to racemic
26 would be enabled even in the absence of a direct
cyclization of 28 to rac-26.[18]
To further understand the pathway, it was also necessary
to determine whether 26 itself racemizes spontaneously under
the conditions of its formation. Since we were able to resolve
26 by HPLC,[16] we subjected optically pure compound to the
reaction conditions. It was found that 26 did indeed racemize,
but at a rate that would not have immediately generated
racemate from the initial cyclization of 24 (Scheme 7).[19]
[5] a) B. Witkop, J. B. Patrick, J. Am. Chem. Soc. 1953, 75, 2572;
b) A. W. Burgett, Q. Li, Q. Wei, P. G. Harran, Angew. Chem.
2003, 115, 5111; Angew. Chem. Int. Ed. 2003, 42, 4961.
[6] a) G. Buchi, R. E. Manning, S. A. Monti, J. Am. Chem. Soc. 1964,
86, 4631; b) G. Buchi, R. E. Manning, J. Am. Chem. Soc. 1966,
88, 2532.
[7] See the following Communication: C. Li, C. Chan, A. C.
Heimann, S. J. Danishefsky, Angew. Chem. 2006, DOI:
10.1002/ange.200604072; Angew. Chem. Int. Ed. 2006, DOI:
10.1002/anie.200604072.
[8] a) E. E. van Tamelen, J. P. Yardley, M. Miyano, W. B. Hinshaw, J.
Am. Chem. Soc. 1969, 91, 7333; b) S. D. Edmondson, S. J.
Danishefsky, L. Sepp-Lorenzino, N. Rosen, J. Am. Chem. Soc.
1999, 121, 2147.
[9] On migratory aptitudes, see: J. March, Advanced Organic
Chemistry, Wiley, New York, 1992, pp. 1058 – 1061.
[10] CCDC-620358 and 620502 contain the supplementary crystallo-
graphic data for compounds 24 and 27, respectively. In addition
we also provide a crystal structure of the 6-bromo derivative of
compound 18 (CCDC-620357), which strongly suggests the
rotameric state shown. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre:
www.ccdc.cam.ac.uk/data request/cif.
[11] For an example, see: S. M. Starling, S. C. Vonwiller, J. N. H.
Reek, J. Org. Chem. 1998, 63, 2262.
[12] For a proposed retro-Mannich reaction which led to epimeriza-
tion of reserpine to isoreserpine, see: a) A. J. Gaskell, J. A. Joule,
Tetrahedron 1967, 23, 4053; for an alternative mechanism for the
reserpine epimerization, see: b) L. H. Zhang, A. K. Gupta, J. M.
Cook, J. Org. Chem. 1989, 54, 4708.
Scheme 7. Racemization of 26.
[13] E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797.
[14] a) For the preparation of 31, see: G. Palmisano, R. Annunziata,
G. Papeo, M. Sisti, Tetrahedron: Asymmetry 1996, 7,
1 ;
In retrospect, the accessibility of substantially enantio-
merically pure 24, either through synthesis or through
chromatographic resolution turned out to be quite valuable.
In particular, it served to show the intervention of a
mechanistically dominant intermediate and the reversibility
of the key steps.
In the following Communication, we show how the
chemistry elucidated above served us well in the context of
the total synthesis of phalarine.[7]
b) coerulescine: N. Anderton, P. A. Cockrum, S. M. Colegate,
J. A. Edgar, K. Flower, I. Vit, R. I. Willing, Phytochemistry 1998,
48, 437.
[15] Preparative HPLC was performed on a Chiralcel OD-H column
(250 ” 20 mm), l = 280 nm, hexane/2-propanol = 9/1, flow rate =
12.0 mLminꢀ1. Rt = 11.3 min (enantiomer 24A), Rt = 17.3 min
(24B).
[16] Analytical chiral HPLC was performed on a Chiralcel OD-H
column (250 ” 4.6 mm), l = 280 nm, hexane/2-propanol = 19/1,
flow rate = 1.2 mLminꢀ1. Under these conditions, a mixture of
racemic 24 and 26 gave the following peaks which were assigned
by MS: Rt = 5.9 (enantiomer 26A), Rt = 10.5 min (26B), Rt =
12.7 min (24A), Rt 16.3 min (24B).
Received: October 3, 2006
Published online: January 19, 2007
[17] The recovery of 24 without loss of configurational integrity while
26 is immediately produced in racemic form serves to rule out
another unlikely but potential sequence which would avoid the
steps 24!25. This route would have involved ring expansion of
24 to produce a tertiary alcohol. Cyclization of the phenolic
hydroxy group to the migration origin followed by cyclization of
the NH group to the tertiary alcohol would afford 26, but
without loss of configurational integrity.
[18] a) A. H. Jackson, A. E. Smith, Tetrahedron 1965, 21, 989;
b) A. H. Jackson, A. E. Smith, Tetrahedron 1968, 24, 403;
c) A. H. Jackson, P. Smith, Tetrahedron 1968, 24, 2227.
[19] The optically pure product racemized under the rearrangement
conditions (4.5 mm in toluene, CSA (2 equiv), 1308C) with a half
life of 136 min. In contrast, the rearrangement reaction imme-
diately produces racemate under these conditions. The half life
in going from 24!26 was 40–55 min.
Keywords: alkaloids · indoles · natural products ·
rearrangement · retro-Mannich reaction
.
[1] N. Anderton, P. A. Cockrum, S. M. Colegate, J. A. Edgar, K.
Flower, D. Gardner, R. I. Willing, Phytochemistry 1999, 51, 153.
[2] a) S. P. Marsden, K. M. Depew, S. J. Danishefsky, J. Am. Chem.
Soc. 1994, 116, 11143; b) J. Schkeryantz, J. Woo, S. J. Danishef-
sky, J. Am. Chem. Soc. 1995, 117, 7025; c) K. M. Depew, S. J.
Danishefsky, N. Rosen, L. Sepp-Lorenzino, J. Am. Chem. Soc.
1996, 118, 12463; d) S. D. Edmondson, S. J. Danishefsky, Angew.
Chem. 1998, 110, 1190; Angew. Chem. Int. Ed. 1998, 37, 1138.
[3] a) C. A. Bourke, S. M. Colegate, S. Slattery, N. Oram, Aust. Vet.
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