Total synthesis of enantiopure phalarine via a stereospecific pictet-spengler reaction: Traceless transfer of chirality from L -tryptophan

Article abstract of DOI:10.1021/ja1030968

An appropriately constructed 2-substituted derivative of l-tryptophan undergoes conversion to a prephalarine structure in a single step. The reaction occurs in a diastereoselective fashion, leading shortly thereafter to the naturally occurring version of the alkaloid phalarine.

Full text of DOI:10.1021/ja1030968

Published on Web 05/28/2010
Total Synthesis of Enantiopure Phalarine via a Stereospecific
Pictet-Spengler Reaction: Traceless Transfer of Chirality
from L-Tryptophan
John D. Trzupek,† Dongjoo Lee,† Brendan M. Crowley,† Vasilios M. Marathias,‡ and
Samuel J. Danishefsky*,†,§
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York
AVenue, New York, New York 10065, Pfizer Global Research and DeVelopment, 200
Cambridgepark DriVe, Cambridge, Massachusetts 02140, and Department of Chemistry,
Columbia UniVersity, HaVemeyer Hall, 3000 Broadway, New York, New York 10027
Received April 19, 2010; E-mail: s-danishefsky@ski.mskcc.org
Abstract: An appropriately constructed 2-substituted derivative of L-tryptophan undergoes conversion to a
prephalarine structure in a single step. The reaction occurs in a diastereoselective fashion, leading shortly
thereafter to the naturally occurring version of the alkaloid phalarine.
Introduction
mechanistic nuance that in turn have stimulated new departures
in synthesis. Particularly insightful in this regard have been
For those who take delight in the imagination of nature as
well as in its efficiency, the alkaloid phalarine (1) would hold
a special fascination. Although, at least for the moment, no
promising biological activity has been asserted on behalf of
phalarine,1 it was clear from the time that we learned of its
structure that our laboratory would inevitably find itself engaged
in its total synthesis. We have been participants in a long-term
tutorial centered on indole-related alkaloids dating back to the
mitomycins.2-11 The novelty of the propeller-like interlocking
of the gramine-related moiety (EF) with the carboline-related
subunit (ABC) via ring C served well to invite a variety of
speculative retrosynthetic designs of a biomimetic flavor target-
ing phalarine. Aside from the heuristic challenges posed by the
phalarine structure per se, it seemed likely that the struggle to
accomplish its total synthesis in a concise way would offer
opportunities to teach us more about the chemistry of indole-
based natural products. Over the years, indoles have provided
diverse contexts for posing and answering subtle questions of
alkaloids, which share with phalarine the features of dearoma-
tized “indolic” sectors.12 It seemed likely that a total synthesis
excursion directed to phalarine would oblige us to revisit core
issues that have provoked stimulating discussion and fruitful
research since the 1950s.13-17
Results and Discussion
Our earliest synthetic intuitions for addressing phalarine
contemplated setting up circumstances designed to achieve the
oxidative union of a suitably protected tetrahydro-ꢀ-carboline
with 3,4-dimethoxyphenol (Scheme 1).18 The systems were to
be presented to allow for the possibility of a rather concise route
to reach phalarine. While some interesting instances in this
regard were demonstrated in practice, the unfettered reacting
systems did not spontaneously converge to give rise to
prephalarine substructures (e.g., see 2 + 3 f 4 and 6 + 3 f
7). Following these reverses, we next attempted to join the
† Sloan-Kettering Institute for Cancer Research.
‡ Pfizer Global Research and Development.
§ Columbia University.
(1) Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower,
K.; Gardner, D.; Willing, R. I. Phytochemistry 1999, 51, 153–157.
(2) Danishefsky, S.; Doehner, R. Tetrahedron Lett. 1977, 3031–3034.
(3) Danishefsky, S.; Regan, J.; Doehner, R. J. Org. Chem. 1981, 46, 5255–
5261.
(4) Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475–490.
(5) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann,
W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953–11963.
(6) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 512–
515.
(12) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Publishing: Malden, MA, 2000; pp 324-379.
(7) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 1967–
1970.
(13) Jackson, A. H.; Smith, P. Chem. Commun. (London) 1967, 264–266.
(14) Jackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403–413.
(15) Iyer, R.; Jackson, A. H.; Shannon, P. V. R.; Naidoo, B. J. Chem. Soc.,
Perkin Trans. 2 1973, 872–878.
(8) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51.
(9) Depew, K. M.; Danishefsky, S. J.; Rosen, N.; Sepp-Lorenzino, L.
J. Am. Chem. Soc. 1996, 118, 12463–12464.
(16) Jackson, A. H.; Naidoo, B.; Smith, P. Tetrahedron 1968, 24, 6119–
6129.
(10) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N.
J. Am. Chem. Soc. 1999, 121, 2147–2155.
(17) Ganesan, A.; Heathcock, C. H. Tetrahedron Lett. 1993, 34, 439–440.
(18) Chan, C.; Li, C.; Zhang, F.; Danishefsky, S. J. Tetrahedron Lett. 2006,
47, 4839–4841.
(11) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964–11975.
9
8506 J. AM. CHEM. SOC. 2010, 132, 8506–8512
10.1021/ja1030968  2010 American Chemical Society

Total Synthesis of Enantiopure Phalarine
A R T I C L E S
Scheme 1
Scheme 2. Route to Racemic Phalarine
Scheme 3
subunits with an orienting connectivity that is more predisposed
to progress toward a phalarine-type architecture.
Wagner-Meerwein genre,21,22 thereby progressing to 13 and
thence to 14.
Having accomplished the total synthesis of the phalarine
racemate, we projected that a clear route for producing
substantially enantiopure phalarine was also at hand. The
thought, na¨ıve in hindsight, was that one had only to start with
enantiopure 8 to reach enantiomerically pure 1. In fact, as was
disclosed, we were able to reach enantiopure (S)-8 via L-
tryptophan (Scheme 3).20 This compound was coupled to the
model aryllithium reagent species derived from 15 to provide
(S)-16. After deprotection of the MOM group, the resultant
phenol (S)-17 was treated with camphorsulfonic acid (CSA) in
the usual way to provide key intermediate 18, which was formed
as the racemate.20 Even when the reaction was interrupted at a
very early stage, 18 still emerged as the racemate. Furthermore,
in a control experiment, substantially enantiopure 18 was
As previously reported, recourse to orchestrated mergers of
the required subunits eventually found success and in time
resulted in a total synthesis of phalarine, albeit as its racemate
(see below; Scheme 2).19 For instance, the required subunits
could be joined via reaction of an N-tosyl-3,3-spiro-substituted
oxindole with a suitably nucleophilic aryllithium reagent (see
8 + 9 f 10). Deprotection of the methoxymethyl ether (MOM)
group of 10 followed by acid-mediated treatment, as shown in
Scheme 2, afforded 14,20 which lent itself to conversion to
racemic phalarine (rac-1).19 At the mechanistic level, we
envisioned that under acidic mediation, 11 had cyclized to afford
12, which suffered suprafacial 1,2-rearrangement of the
(19) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2007, 46, 1448–1450. The absolute configuration of nature’s
phalarine remained unknown until the present study.
(21) Starling, S. M.; Vonwiller, S. C.; Reek, J. N. H. J. Org. Chem. 1998,
63, 2262–2272.
(20) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2007, 46, 1444–1447.
(22) Olah, G. A. Acc. Chem. Res. 1976, 9, 41–52.
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A R T I C L E S
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Scheme 4
obtained by “enantiodiscriminating HPLC” (so-called “chiral
HPLC”)23 and resubjected to the conditions for cyclization of
(S)-17 as provided above. While there was erosion in the optical
purity of 18, the rate of racemization was far too low to account
for the conversion of enantiopure (S)-17 to racemic 18. Hence,
the formation of racemic 18 did not arise from racemization of
the substantially enantiopure product.20
Mechanistic questions aside, the retro-Mannich cleavage
sequence had undermined our hopes of synthesizing optically
pure phalarine from pure (S)-8, thereby frustrating our goal of
determining the absolute configuration of the natural product.20
Before describing how this problem was overcome, we will relay
results of some additional preliminary studies that helped fashion
the ultimately successful strategy. While the routes that we had
described to systems such as 18 were reasonably convergent,
we decided to explore a significant variation in the chemistry
described above: the thought was that we should build an indole
system that already contained a suitable aromatic structure at
the R-carbon. At the ꢀ-carbon, there would already reside a
ꢀ-ethylamino group modeled after tryptamine. Such systems
were ultimately helpful in sharpening our mechanistic thinking
in regard to the Pictet-Spengler reaction as well as in preparing
for the ultimately successful sequence (see below).
We reasoned that upon acid treatment, (S)-17 undergoes
cyclization by joining the tosylamino group and the ketone
function, formally giving rise to (S)-19. The latter would
presumably undergo retro-Mannich cleavage, leading to achiral
20. Two pathways could be envisioned for the conversion of
achiral 20 to racemic 18. In one instance, a Pictet-Spengler
reaction24 would occur at the R-indolic carbon of 20 (see 21).
This step would be followed by attack of the phenolic hydroxy
group at the cationic ꢀ-center of the “indolenine” moiety, leading
to 18. Alternatively, Mannich capture to reproduce 19 could be
followed by a suprafacial spiro-fused Wagner-Meerwein rear-
rangement (WMR)21 to give 21 (of course as the racemate) and
thence 18. While achiral 20 appeared to be a necessary player
in the reaction coordinate from (S)-17 to racemic 18, these two
subvariations for generating 21 were not readily distinguish-
able.25 They differ only in regard to whether the penultimate
prephalarine cyclization product 21 arises from the achiral
iminium ion 20 by direct Pictet-Spengler reaction at C2 or by
only a Wagner-Meerwein-like rearrangement of 19. In the
strictest form of the latter view, a direct Pictet-Spengler reaction
at C2 does not occur with the aryl group already in place.25,26
We then explored the reversibility of the cyclization-“rear-
rangement” pathway. By interruption of the CSA-induced reaction
to fashion 18, it was found that the starting material (S)-17 was
obtained with no detectable loss in optical integrity.20 This “optical
stability” could be interpreted to mean that the recovered (S)-17
had never entered into the path toward 18. Alternatively and more
likely, the early steps might well be reversible, with the initial
achiral structure 20 already being committed to advance to product
18. Therefore, the optical purity of recovered (S)-17 would not be
“contaminated” by racemate arising from the “return” of achiral
20 to the feedstock of starting material.
As related elsewhere,27 the indole-type system was con-
structed from a sequence that started with a Castro-type
coupling28 of a suitable acetylide (in this case, an unprotected
butynol) and an appropriate aromatic ring that would become
the precursor of the final gramine subunit of 1 (Scheme 4). After
this merger, the resulting internal acetylene linkage was
combined with 2-iodobenzenesulfonamide in a Larock indole
synthesis.29,30 In this way, compound 23 was fashioned, albeit
accompanied by significant amounts of the alternate indole
arising from interchange of the functionalities at the R and ꢀ
(23) Even modest reflection is sufficient to reveal the noncoherence of the
term chiral HPLC. With considerable misgivings, we employ it here
for purposes of communicating our results. We urge that in the future,
the nonfathomable term “chiral HPLC” be discontinued in favor of
“enantiodiscriminating HPLC”.
(24) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036.
(25) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842.
(26) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schenker, K. Tetrahedron 1963, 19, 247–288.
(27) Trzupek, J. D.; Li, C.; Chan, C.; Crowley, B. M.; Heimann, A. C.;
Danishefsky, S. J. Pure Appl. Chem. 2010, in press.
(28) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315.
(29) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–6690.
(30) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652–7662.
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Total Synthesis of Enantiopure Phalarine
A R T I C L E S
Scheme 5
Scheme 6
above, it did not seem very likely that we could defeat the
potentiality for retro-Mannich-induced loss of enantiointegrity
at the quaternary ꢀ-carbon in the spiroindolenine en route to
phalarine (see Scheme 3). Happily, an interesting alternative
solution presented itself.25,31-33 A structure such as 31 would
be generated in the tryptophan ester series, and this would
subsequently be converted to a prephalarine product (32; Scheme
6). Key intermediate 32 contains an apparently extraneous
stereogenic center with known configuration (indicated by the
solid red circle) in addition to the cis-related junction centers
(indicated by the asterisks) that are central to the structure of
phalarine. Conversion of 32 to phalarine itself, presumably by
radical-mediated decarboxylation,34,35 would lead to the target
in substantial optical purity. It would be desirable if compound
31 could be produced in a stereospecific fashion. Otherwise, it
would be necessary to separate the diastereoisomers produced
by whatever reaction is used to give 32 from 31. In any case,
it would be critical to know the relative configuration of the
ester and cis-related junction centers in 32. Without a doubt,
clarity on the matter of relative configuration was needed, since
this relationship defines the absolute stereochemical assignment
of synthetic phalarine after decarboxylation, indolization, and
installation of the gramine side chain.
It was at this point that we decided to exploit the chemistry
demonstrated above with the pre-existing aromatic substitution
at C2 of the indole. In view of the need for an enantiomerically
defined amino acid corresponding to tryptophan and the lack
of chemospecificity in the synthesis of 23, the program for
construction of the required substrate was revamped, and we
started with L-tryptophan methyl ester (33; Scheme 7).36
Fortunately, it was possible to incorporate some known chem-
istry for the conversion of 33 to iodo compound 34.37 We then
synthesized compound 36 to serve as a coupling partner with
35, which was derived from 34 using standard methods. The
synthesis of 36 involved creation of the borate ester linkage
with a view toward a Suzuki coupling. In this fashion, the aryl
group could hopefully be installed with regiocontrol. Indeed,
this plan was accomplished in practice, placing compound 37
in hand.38 Deprotection of the MOM ether afforded 38.
Following early studies resulting in low-yielding Pictet-Spengler
reactions with the free primary amine, it was decided to carry
carbons. With 23 in hand, the tryptamine side chain was installed
by conventional chemistry, giving rise to 24. Happily, conden-
sation of 24 with formalin under Pictet-Spengler conditions
gave rise to 25. This sequence provided corroboration of the
feasibility of 20 as an intermediate, although it did not
definitively answer the mechanistic uncertainty discussed above
concerning whether the cyclization (Pictet-Spengler) step in
fact occurs at C2 or first takes place at C3 and then is followed
by a Wagner-Meerwein-like rearrangement (see the question
posed in Scheme 3).
With this more convergent (albeit less chemospecific) strategy
in place, we were able to address the question of the minimum
criteria necessary to realize an indolenine-to-phalarine type of
rearrangement. It should be recalled that at the outset of our
synthesis studies, probe substrate 26 did not in fact rearrange
to give 27 under a variety of conditions;20 thus, it was of
considerable interest to ascertain the substitutions that enable
such a rearrangement (Scheme 5). Accordingly, compound 28
lacking the N-tosyl function and containing an Nb-methyl group
rather than a carbamate was synthesized. Remarkably, after
treatment with formaldehyde under Pictet-Spengler conditions,
28 gave rise to 29.27 Thus, at least in this setting, it was
demonstrated that with an aryl group at C2 of the indole and
no tosyl group at nitrogen Na, cyclization occurs more rapidly
at C3, and the indolenine is actually quite stable. Once again,
as in the case of 28, there was no indication that a spiroindo-
lenine lacking the Na-tosyl group or an equiValent could
subsequently be induced to undergo rearrangement to the
phalarine series.
(31) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086–1087.
However, we did observe another reaction that demonstrates
the interconnectivity of the various pathways: treatment of 29
with CSA in the absence of formaldehyde led smoothly to 28.
It seems very likely that this regression arose from a retro-
Mannich reaction (about which we had speculated earlier) to
give iminium salt 30, which affords 28 after hydrolysis. Thus,
it had been shown that the mechanistically relevant structures
reside on a connectable energy surface.
(32) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558–
10559.
(33) Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2402–2403.
(34) Yoshimi, Y.; Itou, T.; Hatanaka, M. Chem. Commun. 2007, 5244–
5246.
(35) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1988,
44, 5479–5486.
(36) An alternative method utilizing the Schollkopf auxilliary is described
in the Supporting Information.
We return now to the problem of the total synthesis of
optically defined phalarine. Given the information provided
(37) Vicente, J.; Saura-Llamas, I.; Bautista, D. Organometallics 2005, 24,
6001–6004.
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Scheme 7
Scheme 8
out the critical cyclization with Nb being a secondary amine.39,40
Toward this end, 38 was converted to 39 by reductive amination
with benzaldehyde. Gratifyingly, treatment of 39 with formal-
dehyde led to the formation of the prephalarine molecule 41 as
a single diastereoisomer in excellent yield.41
At this point, it was of course critical to establish the relative
configuration of the tryptophan-like methyl ester in 41 with
respect to the cis-related carbon bridge of phalarine. Two lines
of evidence were marshaled to deal with this problem. Initially,
the relative stereochemical assignment of 41 was determined
from a series of 2D NMR experiments (see the Supporting
Information). By establishing the positions of the indoline and
the methoxy-bearing aryl ring with respect to the position of
the N-benzylpiperidine ring relative to the known chiral
center, the relationship of the two unknown tetrasubstituted
stereocenters (positions 2 and 3, assigned as R and S, respec-
tively; see Schemes 7 and 8) was deduced.
While the NMR-based deduction certainly seemed to be
convincing, full confidence in the correctness of the assignment
of the relative stereochemistry within 41 was so central to our
final assignment of the absolute stereochemistry that additional
corroboration was sought. As it turned out, it was possible to
obtain compound 41 in crystalline form (mp 199-200°) suitable
for crystallographic study. Indeed, this determination confirmed
that the assignment of relative configurations initially determined
by NMR analysis was correct (Figure 1). On the basis of the
fact that we had started with L-tryptophan, the absolute
configurations of the three stereogenic centers in compound 41
could then be assigned as shown in Scheme 8.
(38) The modest reaction yield was a result of competitive formation of
the reduced product and detosylation of 37 under the reaction
conditions. Although we could not verify the level of optical purity
here, it was observed that reactions using either a stronger base or
higher temperatures tended to erode the optical purity of isolated
37.
(39) Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.;
Yamanaka, E.; Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem.
1979, 44, 535–545.
(40) Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org. Chem.
1981, 46, 164–168.
(41) As was the case with compound 29, the formation of 41 was
completely reversible. Upon resubjection to the reaction conditions
for formation of 41 without dessicant, 39 was cleanly recovered
without any loss in optical purity (data not shown).
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Total Synthesis of Enantiopure Phalarine
A R T I C L E S
Thus, the synthesis in the optically defined series led from
14 to optically pure intermediates 44 through 47, which were
characterized in a fashion that also included their optical
rotations. In the last step of the linkage exercise, compound 47
was converted to (-)-phalarine, which was now substantially
enantiomerically pure. The optical rotation of the fully synthetic
phalarine obtained was -84° (c 0.24, MeOH), whereas the
optical rotation of natural phalarine has been reported to be -92°
(c 0.0075, MeOH).1 Thus, it was clear that by chance we had
synthesized nature’s phalarine. The small discrepancy in the
value of the levorotary direction caused us no concern for several
reasons. As early as the stage of compound 14, it was possible
to resolve the two enantiomers from the racemate synthetic
program by HPLC.20 Correspondingly, the fully synthetic
version of 14 obtained in this work showed only one of the
two peaks associated with the previously synthesized racemate.19
Therefore, we concluded that the synthetic material was
substantially enantiopure at the stage of 14.45 Moreover, under
suitable HPLC conditions, it was possible to distinguish the
antipodes of the previously synthesized rac-phalarine. Therefore,
the substantially single peak46 exhibited by the totally synthetic
(-)-phalarine prepared in the manner described above confirmed
its very high optical purity.47 In short, we now know that the
total synthesis of substantially optically pure (-)-phalarine has
been accomplished and are confident about the rotations quoted
above.
Figure 1. ORTEP diagram for compound 41.
Of course, the highly diastereoselective nature of the trans-
formation of 39 to 41 was extremely gratifying and provided
the basis for the synthesis of enantiomerically defined phalarine
(see below). It is of interest to conjecture about the origin of
the powerful diastereoselectivity in the cyclization step. This is
not a simple matter, in view of the fact that the mechanistic
ambiguity regarding the nature of the cyclization remains (see
Scheme 3). In one view, the stereochemistry of 41 is determined
by a cyclization event at C3 (the ꢀ-carbon of the indole). The
configurational information at C3 is transferred to C2 by
suprafacial WMR, which then ultimately relays its stereochem-
ical information to C3 by cyclization of the resident phenol
group (40a). However, if Pictet-Spengler reaction occurs at
C2, the stereochemistry at that center (i.e., the R-carbon of the
indole) is defined initially through the iminium-C2 cyclization
event and only subsequently at C3 through the attack by the
phenolic linkage (see 40b). Until this issue is fully explicated,
a satisfying rationalization of the basis of the face selectivity
of the Pictet-Spengler reaction cannot be offered. A further
complication at the level of interpretation arises from the
possibilities of kinetic or thermodynamic control in each of the
two cyclization modes (see 40a and 40b).
Conclusion
In summary, it would seem that as predicted above, the total
synthesis of (-)-phalarine and the assignment of its absolute
configuration has provided significant learning opportunities.
While not all of the subtle mechanistic issues have been fully
clarified, the work as it stands provides some significant insights
into the chemistry of spiroindolenines and, more broadly, their
intermediacy in apparent Pictet-Spengler reactions of 2-sub-
stituted indoles. This question has not previously been addressed
in detail. In the case at hand, the 2-substituted indole contained
an aromatic structure wherein the pendant phenolic hydroxyl
group could capture the transient cationic species at C3, thereby
establishing the propeller-like display of phalarine.
Globally, the chirality inherent in L-tryptophan was transferred
to phalarine in a traceless fashion, since the asymmetry initially
present within the tryptophan could be discerned in the ultimate
phalarine product only in a legacy sense. It is important to
emphasize that our mission was accomplished by gathering
insights from the toils of the true pioneers of indole alkaloid
chemistry and fashioning productive experiments from that
corpus of hard-won knowledge.12-18,26
With the stereochemical assignment of 41 secure,42 we
directed our attention to completing the total synthesis of
enantiopure phalarine, parenthetically allowing for the deter-
mination of its absolute configuration. Indeed, we were able to
connect with an established intermediate in our earlier total
synthesis of racemic phalarine19 by excision of the carboxyl
group and its replacement by a hydrogen atom. Thus, ester
saponification provided 42, which was induced to decarboxylate
as shown, providing N-benzyl derivative 43 (Scheme 8).43 The
method used here was achieved only after significant optimiza-
tion efforts for what proved to be a challenging decarboxylation
step.44 Debenzylation followed by reductive methylation pro-
vided the junction compound 14 in good yield. Since in the
racemic series this compound had been converted to racemic
1,19 a clear route to enantiopure phalarine was now in hand. It
was only necessary to conduct the same steps as had been used
in the substantially enantiopure series. This was in fact ac-
complished as shown.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant HL25848 to S.J.D.). We acknowledge
Dr. Lori Gavrin, Dr. John McKew, Dr. John Ellingboe, Dr. Walt
Massefski, and Dr. Oliver McConnell at PGRD for supporting the
NMR-based efforts to assign the relative stereochemistry of 41.
(42) Enantiodiscriminating HPLC data supporting the enantiospecific
formation of 41 and ent-41 from 39 and ent-39, respectively, are
included in the Supporting Information. These data also eliminated
any concern about a loss of optical purity during the Suzuki coupling
to forge compound 37.
(45) It should be noted that we also verified complete optical purity at the
stage of compound 39.
(46) We would conservatively estimate the optical purity of our synthetic
phalarine as 98%.
(47) Attempts to evaluate the reversibility of the late steps in the synthesis
were undertaken. The thought was to subject the final optically pure
phalarine to treatment with CSA in order to determine whether it would
undergo racemization. However, in the event, this type of treatment
resulted in major decomposition of phalarine, no doubt resulting from
the instability of gramine side chains toward acidic agents.
(43) Boto, A.; Herna´ndez, R.; Sua´rez, E. J. Org. Chem. 2000, 65, 4930–
4937.
(44) Several variants of free-radical-based decarboxylations were attempted.
The more successful varieties are described in the Supporting
Information.
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A R T I C L E S
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We also thank Kevin Yurkerwich and Professor Gerard Parkin for
solving the X-ray structure of 41. The National Science Foundation
(CHE-0619638) is thanked for funding to acquire an X-ray
diffractometer. S.J.D. also thanks Rebecca Wilson for stimulating
discussions on the work described herein as well as on the rendering
of the manuscript.
methods for 42, analytical enantiodiscriminating HPLC data for
41 and ent-41, diagnostic 2D NMR data for 41, and crystal-
lographic data for 41 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Full experimental details,
the first-generation approach to 37, alternative decarboxylation
JA1030968
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8512 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010