Synthetic and theoretical investigations of myrmicarin biosynthesis

Article abstract of DOI:10.1002/anie.201005825

Off to a good start: Use of a carefully designed building block coupled with several highly selective reactions has enabled the syntheses of the monomeric myrmicarins (see scheme) and the investigation of higher-order oligomer synthesis by enabling access

Full text of DOI:10.1002/anie.201005825

Angewandte
Chemie
DOI: 10.1002/anie.201005825
Oligomeric Natural Products
Synthetic and Theoretical Investigations of Myrmicarin Biosynthesis**
Scott A. Snyder,* Adel M. ElSohly, and Ferenc Kontes
Isolated as the active components of the poison gland
secretion from various Myrmicaria ant species found in
Africa and characterized by the Francke group over a decade
ago, the myrmicarin alkaloids[1] (1–6, Figure 1) provide a truly
unique array of synthetic challenges. Indeed, myrmicarins
215A and B (1 and 2) as well as myrmicarin 217 (3) are
the first examples of naturally occurring pyrrolo-
[2,1,5cd]indolizidines, while the higher-order structures (4–
6) constitute some of the most complex alkaloids isolated
from any insect to date with formidable stereochemical
complexity displayed across up to ten ring systems. Enhancing
this synthetic challenge is their marked fragility. For example,
myrmicarin 430A (4) proved sensitive not only to air but also
to silica gel and alumina, requiring that its structure be
deduced from a series of two-dimensional NMR experiments
performed on the crude isolation mixture.[1c]
To date, a number of total syntheses of the simplest
members (i.e. 1–3) have been achieved,[2] some of which are
enantioselective;[2d–f] however, none of the higher-order
members has been synthesized in the laboratory despite the
existence of several reasonable biosynthetic hypotheses for
how structures 4–6 might be formed in nature.[1b,3b] In all
cases, efforts to reduce these ideas to practice have led to
materials that are stereo- and regioisomeric to the natural
isolates. For instance, extensive efforts by the Movassaghi
group[3] to effect acid-promoted dimerizations of myrmicarin
215B (2) have afforded isomers 8a and 8b through a synthetic
pathway that sets the incorrect C-3 stereochemistry (the
ꢀ
highlighted center; Figure 1) in the opening C C bond-
forming operation. As such, access to 4 is prevented; unclear
is whether this stereochemistry also induces the final cycliza-
tion to proceed from the incorrect carbon of the pyrrole
[*] Prof. Dr. S. A. Snyder, A. M. ElSohly,[+] F. Kontes[+]
Department of Chemistry, Columbia University
Havemeyer Hall, 3000 Broadway, New York, NY 10027 (USA)
Fax: (+1)212-932-1289
E-mail: sas2197@columbia.edu
Homepage: http://www.columbia.edu/cu/chemistry/groups/
snyder/
[+] These authors contributed equally to this work.
Figure 1. Structures of the myrmicarin alkaloids, previous work
towards the dimeric structures, and a proposed building block to
accomplish the selective synthesis of the entire family of natural
products.
[**] We thank the Friesner Group (Columbia University) for generous
CPU time and Michelle Lynn Hall for assistance in using the
computational resources. Financial support was provided by
Columbia University, Eli Lilly (New Faculty and Grantee Awards to
S.A.S.), the Research Corporation for Science Advancement (Cottrell
Scholar Award to S.A.S.), the National Science Foundation (Pre-
doctoral Fellowship to A.M.E.), the Paul and Daisy Soros Founda-
tion (Predoctoral Fellowship to A.M.E.), and Bristol-Myers Squibb
(Predoctoral Fellowship to F.K.). S.A.S. is a Fellow of the Alfred P.
Sloan Foundation.
within 7. Here we present our biomimetic synthetic studies
towards these targets, efforts that have led to the most
efficient syntheses of the monomeric members to date as well
as provided the means to access the correct ethyl group
stereochemistry at the critical C-3 position. These studies, in
combination with a series of quantum chemical calculations,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005825.
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Communications
question whether the higher-order structures can be obtained
ex vivo through acid-promoted biomimetic synthesis.
tion), into key intermediates 12 and 13. This process required
five operations, and their critical relative configurations were
established with greater than 20:1 selectivity by either basic
(12) or acidic (13) work-up following formylation.[7] With this
key stereodivergence secured, we then directed our attention
towards stereoselectively adding the linear crotyl chains
needed to obtain the target alkene isomers. Among available
methods, Lewis acid promoted variants appeared the most
appealing since a simple switch in the Lewis acid used could
potentially enable selective access to the respective E- and
Z-isomers.
Given the consistently reported failure of structures of
general architecture 1–3 to afford the dimeric members of the
family, our synthetic approach was predicated on the idea that
an alternate starting material was required if a biomimetic
synthesis was to prove successful. In our past efforts seeking
to achieve the controlled synthesis of members of other
oligomeric natural product families,[4] we have often identi-
fied such unique building blocks by searching for anomalous
structural features within the higher-order members; here, we
wondered if the structure of myrmicarin 663 (6) might provide
the needed design clues since one-third of its architecture is
inconsistent with direct oligomerization of myrmicarin 215-
type monomers. Indeed, retrosynthetic cleavage of its C-7/C-8
and C-20/C-21 bonds suggested a structure of type 9 as a
possible alternate building block.[5] Its cyclodehydration was
anticipated to afford monomers 1–3, while the influence of
both its olefin geometry and C-5 ketone stereochemistry was
hoped capable of setting the critical C-3 ethyl stereocenter
and ultimately leading to 4. Despite the appeal of this idea,
literature precedent regarding the stability of compounds
with structures similar to 9 was discouraging,[2a] and even if
they could be prepared, it was not obvious which combination
of isomers would give rise to the desired product stereo-
chemistry. We thus set out to answer these questions, hoping
to selectively synthesize all four possible diastereomers of
generalized starting material 9.
As shown in Scheme 2, this approach proved successful, as
the exposure of 12 and 13 to the crotylcerium reagent
[8]
prepared from CeCl3 and 2-butenylmagnesium chloride
afforded selective access to the linear E-isomers (6:1 a:g, 8:1
[9]
E/Z), while use of the crotylaluminum reagent from AlCl3
furnished the linear Z-isomers (4:1 a:g, > 15:1 Z/E). Sub-
sequent Dess–Martin oxidation of the resultant diastereo-
meric mixture of diols and separation of the minor branched
isomer through silica gel chromatography afforded rapid and
highly selective access to 14–17 in 26–36% overall yield from
commercial materials. Finally, N-Boc deprotection of each of
these four isomers with TFA in the presence of H2O,[10]
followed by a cold aqueous NaOH quench,[11] afforded
dienamines 18–21 as stable and fully characterizable com-
pounds.[12] This outcome is in stark contrast to previous
studies on myrmicarin 217 (3, Figure 1). Indeed, unlike their
monoenamine counterparts that have been shown to both
spontaneously epimerize at the C-5 position (as noted within
9) and cyclize to myrmicarin 217 (albeit in low yields),[2a] these
compounds are both configurationally stable[13] and do not
undergo spontaneous cyclization in aprotic solvents. When
exposed to protic solvents, however, 18–21 were readily
converted into the monomeric myrmicarin alkaloids 215A (1)
and 215B (2) through Knorr pyrrole condensation. For 18 and
19, simple dissolution in argon-purged MeOH at 238C proved
sufficient, while 20 and 21 required stirring in NaOMe/MeOH
at 508C for 1 h (through presumed epimerization at C-5 prior
to cyclodehydration). Overall, these natural products were
synthesized in ten linear steps from commercial materials in
29% and 31% overall yield, respectively. A similar sequence
also enabled access to myrmicarin 217 (3) as well as myrmi-
carin 237B (see Supporting Information for full details). More
significantly, with 18–21 in hand and the means to arrest or
effect their cyclodehydration through solvent control, explo-
rations into unique biomimetic dimerizations could begin.
Initial efforts commenced by exposing 18–21 to a series of
acidic and aqueous buffers, hoping for a direct, biomimetic
synthesis of myrmicarin 430A (4, Figure 1). Unfortunately,
despite the ease with which 1 and 2 were formed under some
of these conditions, we never observed the formation of
characterizable dimeric materials.[14] Thus, we shifted to
stepwise approaches, hoping to identify a method to stoichio-
metrically protonate dienamines 18–21 and generate their
corresponding extended iminium ions as a prelude to adding
more 18–21 (to serve as nucleophile).[15] As indicated in
Scheme 3, previous work by Movassaghi and Ondrus dem-
onstrated that myrmicarin 215 (2) does not undergo stoichio-
metric protonation to give a stable Z-azafulvenium (22),[3ab]
We began by elaborating compound 10 (Scheme 1),
prepared in one step in 84% yield and 86% ee using a
method developed by Ma et al.[6] (see Supporting Informa-
Scheme 1. Synthesis of key intermediates 12 and 13: a) H2 (1 atm),
Pd/C (10%, 0.05 equiv), Boc2O (1.3 equiv), EtOAc, 238C, 16 h, 84%;
concentrate; DIBAL-H (1.1 equiv), THF, ꢀ788C, 45 min; 08C, 15 min,
98%; b) TBSCl (1.3 equiv), imidazole (2.0 equiv), CH2Cl2, 238C, 12 h,
98%; c) sBuLi (1.8 equiv), TMEDA (2.2 equiv), Et2O, ꢀ78!ꢀ408C,
1 h; DMF (10 equiv), ꢀ78!ꢀ408C, 1.5 h; K2CO3/MeOH or NH4Cl,
90% for 12, 97% for 13; d) CeCl3 (1.5 equiv), EtMgBr (1.5 equiv),
THF, ꢀ40!08C; HCl (2.0 equiv), 3 h, 70% for 12, 89% for 13;
e) TEMPO (0.05 equiv), NCS (1.0 equiv), nBu4NCl (0.1 equiv), NaBr
(1.0 equiv), CH2Cl2, pH 8.6 aqueous buffer, 08C, 1.5 h, 93% for 12,
96% for 13. Boc2O=di-tert-butyldicarbonate, DIBAL-H=diisobutylalu-
minum hydride, TBS=tert-butyldimethylsilyl, DMF=N,N-dimethylfor-
mamide, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free radical,
NCS=N-chlorosuccinimide, TMEDA=N,N,N’,N’-tetramethylethylene-
diamine.
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Scheme 2. Synthesis of dimerization precursors 18–21 and the total syntheses of myrmicarins 215A (1) and 215B (2): a) CeCl3 (3.0 equiv), 2-
butenylmagnesium chloride (3.0 equiv), THF, ꢀ78!ꢀ408C, 3 h; b) Dess–Martin periodinane (3.0 equiv), CH2Cl2, ꢀ108C, 1.5 h, 71% over 2
steps, E/Z = 8:1 for 14, 66% over two steps, E/Z=8:1 for 16; c) TFA/CH2Cl2/H2O (4:4:1), 08C, 1 h, 99%; d) MeOH, 238C, 1 h, 99%; e) AlCl3
(6.0 equiv), 2-butenylmagnesium chloride (3.0 equiv), THF, ꢀ78!08C, 1 h, 62% [two steps, (e) and (b)], E/Z > 15:1 for 15, 72% [two steps, (e)
and (b)], E/Z > 15:1 for 17; f) NaOMe (10 equiv), MeOH, 508C, 1 h, 85%. TFA=trifluoroacetic acid.
only to olefin isomerization while stronger acids led exclu-
sively to protonation at nitrogen to afford 24. Furthermore, if
less polar solvents (such as benzene or CH2Cl2) were used
during the protonation step, various degrees of decomposi-
tion were observed.
With the means to prepare extended iminium ions
secured, we then began probing dimerizations. Scheme 4
presents the optimized sequence following dozens of exper-
imental variations. In the event, dienamine 18 was added to a
solution of iminium ion 23 that had been formed in MeCN at
238C as described above. After stirring for 30 min, the
reaction contents were quenched with cold aqueous NaOH,
affording 25 as a complex diastereomeric mixture that was
immediately treated with degassed MeOH to effect bis-
cyclization. This operation afforded, after purification on
neutral alumina, hexacycle 26 as a 2:1 mixture of diastereo-
mers (54% combined yield) which could be separated by
semi-preparative reverse-phase HPLC.[16] Extensive NMR
analysis, particularly 2D nOe experiments, firmly established
that these compounds were diastereomers about the C-3
position, with the minor component assigned as the undesired
C-3 b-ethyl stereoisomer upon comparison with data pre-
viously reported by the Movassaghi group.[3d] In accordance
with direct dimerizations of myrmicarin 215[3a,d] (1 or 2), the
stereochemical outcome of this reaction can be rationalized as
resulting from the preferred approach of the nucleophile onto
the convex face of the electrophile wherein the difference in
the solution conformation of electrophile 23 compared to the
presumed protonated form of myrmicarin 215 (22) leads to
Scheme 3. Regiospecific protonation to form iminium ion 23: a) TFA
(1.0 equiv), MeCN, 238C, 99%.
though it is a presumed intermediate en route to dimerization
with residual 2 in the synthesis of 8a and 8b shown within
Figure 1. After much experimentation, we found that dien-
amines 18–21 could be stoichiometrically protonated regio-
selectively at the g-position with TFA in MeCN to give stable
iminium ions such as 23 (Scheme 3). Key nOe correlations
(see Supporting Information) revealed that this protonated
species exists exclusively as the E-isomer in an s-trans
conformation in solution, which is the conformational equiv-
alent to a prohibitively strained E-azafulvenium ion. We note
that TFA was unique among the more than ten acid sources
screened in effecting this transformation; weaker acids led
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attack onto the presumed azafulvenium, similar to 7!8 (cf.
Figure 1).[18] Given that the generally preferred alkylation of
pyrroles at either the C-2 or C-5 position is usually a kinetic
outcome,[19] attempts were then made to isomerize 27 into
myrmicarin 430A (4) under strongly acidic conditions, both
with and without heating. However, all such experiments led
to either complete decomposition or recovered starting
material. In addition, efforts were made to cyclize hexacycle
26 with HCl at both elevated temperatures and at ꢀ208C, but
these experiments led to decomposition and variable mixtures
of starting material and 27, respectively. Though the observed
decomposition cannot rule out the possibility of initial
isomerization to myrmicarin 430A (4) followed by decom-
position, these results, coupled with the extensive studies by
Movassaghi and co-workers, led us to wonder if these
collective observations were the result of both a thermody-
namic and kinetic preference for C-3b attack. To probe this
hypothesis, a series of ab initio quantum chemical calculations
were performed.[20]
Figure 2 depicts an energy plot of equilibrium geometries
from B3LYP[21]/6-31G(d) optimizations of the hexacyclic
iminium ion 29 (its two rotameric isomers about the C-3/
C-3a bond, 29a and 29b), the two competing C-3b and C-8b
alkylation transition states 30 and 32, and the cyclized
iminium products 31 and 33. The results of these calculations
indicate that the two transition states are essentially isoener-
getic, though isomer 30 is consistently lower at all levels of
theory examined. In addition, these results predict that
though rotamer 29b is more stable than its counterpart, 31
should be the thermodynamic product by 2.9 kcalmolꢀ1 from
this reaction. It is worth noting that the geometric distortion
associated with rotamers 29a and 29b is very small, with the
Scheme 4. Dimerization of monomer and acid mediated cyclization:
a) 23 (1.0 equiv), CH3CN, 238C, 1 h; 1m NaOH, 08C; b) MeOH, 238C,
3 h, 54% over 2 steps; c) HCl (1.0m in Et2O, 20 equiv), CH2Cl2, 238C,
1 h, 60%; d) H2, Pd/C (10%, 0.8 equiv), C6D6, 0.5 h, 40%.
the reversed stereochemical outcome. Efforts to optimize the
diastereomeric ratio of this dimerization through the change
of solvent, temperature, and electrophile/nucleophile combi-
nations led either to no improvement or a reversal of
selectivity. Indeed, the d.r. for this reaction ranges from 2:1
to 1:1.5.[17] Furthermore, attempts to dimerize compounds 18–
21 with myrmicarin 215A or B (1 or 2) were unproductive.
Thus, the overall success of this sequence in delivering the
correct C-3 stereochemistry within 26 was wholly dependent
on our ability to access all building blocks of type 9, form
stable iminium species from them, effect regioselective
dimerization, and use solvent changes to control the timing
of the Knorr cyclodehydration.
The question now was what effect would the previously
unattainable C-3 stereochemistry have on the regiochemistry
of the final ring closure. When hexacycle 26 was treated with
an ethereal solution of HCl in CH2Cl2 at 238C for 1 h and then
worked up with base, 1H NMR analysis of the crude reaction
mixture showed the exclusive formation of compound 27, the
regio- and stereochemistry of which was determined from
nOe correlations in 27 and reduced product 28 (see Support-
ing Information). Thus, the central cyclopentane in 27
displays the correct trans-trans C-1/C-2, C-2/C-3 disposition
of myrmicarin 430A (4), but reflects regioisomeric pyrrole
Figure 2. Potential energy surface of the acid catalyzed cyclization of
26. All values are DG in kcalmolꢀ1
.
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Lett. 2005, 7, 4423 – 4426; f) M. Santarem, C. Vanucci-Bacquꢁ, G.
Lhommet, Heterocycles 2010, 81, 2523 – 2537.
major difference due to the dihedral angle defined by C-2/
C-3/C-3a/C-8b (848 vs 698, respectively). Furthermore, the
effects of solvation do not affect the qualitative description of
the potential energy surface.
[3] a) A. E. Ondrus, M. Movassaghi, Tetrahedron 2006, 62, 5287 –
5297; b) M. Movassaghi, A. E. Ondrus, B. Chen, J. Org. Chem.
2007, 72, 10065 – 10074; c) A. E. Ondrus, M. Movassaghi, Chem.
Commun. 2009, 4151 – 4165; d) A. E. Ondrus, M. Movassaghi,
Org. Lett. 2009, 11, 2960 – 2963; e) A. E. Ondrus, H. U. Kanis-
kan, M. Movassaghi, Tetrahedron 2010, 66, 4784 – 4795.
[4] a) S. A. Snyder, A. L. Zografos, Y. Lin, Angew. Chem. 2007, 119,
8334 – 8339; Angew. Chem. Int. Ed. 2007, 46, 8186 – 8191; b) S. A.
Snyder, F. Kontes, J. Am. Chem. Soc. 2009, 131, 1745 – 1752;
c) S. A. Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L.
Zografos, J. Am. Chem. Soc. 2009, 131, 1753 – 1765. For the
subsequent use of one of these building blocks to prepare a
member of a distinct natural product family, see: d) S. A. Snyder,
T. C. Sherwood, A. G. Ross, Angew. Chem. 2010, 122, 5272 –
5276; Angew. Chem. Int. Ed. 2010, 49, 5146 – 5150.
[5] A related biosynthetic hypothesis has been advanced by Francke
and Schrꢀder, though it invokes cross-conjugated endocyclic
dienamines that differ from 9: see Ref. [1b].
[6] Z. Sun, S. Yu, Z. Ding, D. Ma, J. Am. Chem. Soc. 2007, 129,
9300 – 9301.
[7] P. Beak, W. K. Lee, J. Org. Chem. 1993, 58, 1109 – 1117.
[8] S. Matsukawa, Y. Funabashi, T. Imamoto, Tetrahedron Lett.
2003, 44, 1007 – 1010.
[9] Y. Yamamoto, K. Maruyama, J. Org. Chem. 1983, 48, 1564 –
1565. This literature report characterized the major product as
the E-isomer; however, no justification was given for the
stereochemical assignment. In our hands, this procedure
almost exclusively leads to the Z-isomer, even on substrates
included in the initial report. A similar Z-selectivity has been
observed in other Lewis acid mediated linear crotylations and an
open transition state has been proposed to account for this
outcome: V. Fargeas, F. Zammattio, J.-M. Chrꢁtien, M.-J.
Bertrand, M. Paris, J.-P. Quintard, Eur. J. Org. Chem. 2008,
1681 – 1688.
[10] A. S. Ripka, R. S. Bohacek, D. H. Rich, Bioorg. Med. Chem.
Lett. 1998, 8, 357 – 360. H2O was required to prevent isomer-
ization to the a,b-unsaturated ketone, a molecule which proved
recalcitrant to cyclization.
[11] Cold NaOH was critical to obtaining high yields in this reaction.
[12] Although we use the term “stable”, these compounds cannot be
purified on deactivated silica gel, neutral alumina, or basic
alumina and must be used directly following extraction without
further purification.
Overall, these results indicate that the cyclization to form
compound 27 is not only thermodynamically favored, but
there is also no kinetic or thermodynamic preference for the
formation of the desired heptacycle 4. In other words, it does
not appear to be possible to access 4 from intermediate 26
under protic conditions. Thus, the combination of our
experimental results and theoretical calculations strongly
suggest either that intermediates such as 26 are not biomim-
etic, that enzyme participation plays an important role in
preventing rotation about the C-3/C-3a bond, and/or that the
alkylation event is coupled to an irreversible deprotonation
leading to myrmicarin 430B,[22] a compound that is known to
spontaneously isomerize to myrmicarin 430A (4). The latter
explanation is particularly appealing given that our calcula-
tions indicate that 27 and myrmicarin 430A (4) are isoener-
getic and once formed, myrmicarin 430A (4) would require
isomerization to the thermodynamically less stable myrmi-
carin 430B prior to protonation at C-8. Thus, once formed, 4 is
not likely to equilibrate to 27 under acidic conditions.
In conclusion, we have completed the shortest and most
efficient total syntheses of four of the members of the
myrmicarin family, including myrmicarins 215A (1), 215B (2),
and 217 (3). Using the key dienamine intermediates 18–21, we
were able to achieve dimerizations that selectively accessed
the required C-3 ethyl stereochemistry and the all-trans
cyclopentane backbone of myrmicarin 430A (4) for the first
time. Experimental results also imply that the tricyclic
members of this class are formed spontaneously under
biological conditions from oxidized myrmicarin 237 conge-
ners 18 and 19, though efforts to form the desired dimeric
materials have thus far been thwarted. As such, if 26 is indeed
a biosynthetic intermediate, reactivity modes other than
direct acid catalysis would appear necessary if the higher-
order myrmicarins are to be forged from it in a reaction flask.
Received: September 16, 2010
Published online: November 10, 2010
[13] The natural product myrmicarin 237 (the fully saturated form of
9) also lacks configurational stability at the a-position. Calcu-
lations suggest that the level of pyramidalization about nitrogen
in 18–21 is less than in either their monoenamine counterparts or
myrmicarin 237, which may account for their observed config-
urational stability.
Keywords: dienamines · iminium ion · Knorr pyrrole synthesis ·
.
myrmicarins · total synthesis
[14] We found that dissolving 18 and 19 in either pH 7.4 or 8.6
aqueous buffers also led to the clean formation of myrmicar-
in 215A and B (1 and 2), suggesting that 1–3 are spontaneously
formed upon oxidation of the n-butyl sidechain in myrmi-
carin 237-like structures. Although these experiments cannot
rule out the possibility of other biosynthetic precursors, the
above hypothesis is strengthened by the structural features
found in the natural isolates myrmicarin 237 and 663 (6).
[15] For a review on dienamines, see: P. W. Hickmott, Tetrahedron
1984, 40, 2989 – 3051.
[16] A number of experiments demonstrated that the desired ethyl
epimer cyclizes to 26 faster than the undesired epimer. Perform-
ing the reaction in isopropyl alcohol allowed for a sufficiently
low overall rate of cyclization to achieve a kinetic resolution
leading to up to a 5:1 d.r., albeit in reduced yield (12%).
[1] a) W. Francke, F. Schrꢀder, F. Walter, V. Sinnwell, H. Baumann,
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Tetrahedron 1996, 52, 13539 – 13546; c) F. Schrꢀder, V. Sinnwell,
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Schrꢀder, V. Sinnwell, H. Baumann, M. Kaib, W. Francke,
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Angew. Chem. Int. Ed. 2010, 49, 9693 –9698
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Communications
[17] The reduced d.r. observed in these reactions compared to
myrmicarin 215 dimerizations may be reflection of the
[21] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785 – 789;
b) A. D. Becke, J. Chem. Phys. 1993, 98, 5648 – 5652.
[22] The proposed structure of myrmicarin 430B is shown below; it
was found to convert spontaneously to myrmicarin 430A upon
standing: F. Schrꢀder, Ph.D. Thesis, University of Hamburg
(Germany), 1996.
a
conformational flexibility in the dienamine sidechain as well as
the less sterically demanding environment of the electrophilic
site, thereby allowing for some approach from the concave face
of the electrophile to occur. The Supporting Information section
contains a listing of various combinations and the resultant
product ratios.
[18] Extended reaction times for this final cyclization result in the
exclusive formation of compound 8b, in accordance with the
reversibility reported by Movassaghi (Ref. [3d]). In addition,
theoretical calculations indicate that 8b is more stable than 27 by
2.9 kcalmolꢀ1
.
[19] a) M. H. Palmer, D. S. Leitch, C. W. Greenhalgh, Tetrahedron
1978, 34, 1015 – 1021; b) J. R. Carson, N. M. Davis, J. Org. Chem.
1981, 46, 839 – 843; c) C. Schmuck, D. Rupprecht, Synthesis 2007,
3095 – 3110.
[20] Calculations were performed with Jaguar, version 7.6, Schrꢀ-
dinger, LLC, New York, NY, 2009. See the Supporting Informa-
tion section for full details of the ab initio calculations. Cartesian
coordinates and raw energies are also provided therein.
9698 www.angewandte.org
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Angew. Chem. Int. Ed. 2010, 49, 9693 –9698