Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels-Alder Reactions of Double Diene Precursors

Article abstract of DOI:10.1021/jacs.5b07710

The enantioselective total syntheses of himandravine and GB17 were completed through a common biomimetic strategy involving Diels-Alder reactions of unusual double diene containing linear precursors. The double diene precursors, containing or lacking a C12 substituent as required to produce GB17 or himandravine, respectively, were found to undergo Diels-Alder reactions to afford mixtures of regioisomeric cycloadducts that map onto the alternative carbocyclic frameworks of both himandravine and GB17. Computational investigations revealed that these Diels-Alder reactions proceed via transition state structures of similar energy that have a high degree of bispericyclic character and that the low levels of regioselectivity observed in the reactions are a consequence of competing orbital interaction and distortion energies. The combined experimental and computational results provide valuable insights into the biosynthesis of the Galbulimima alkaloids. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b07710

Article
pubs.acs.org/JACS
Total Synthesis of the Galbulimima Alkaloids Himandravine and
GB17 Using Biomimetic Diels−Alder Reactions of Double Diene
Precursors
†
‡
†
,‡
,†
Reed T. Larson, Ryan P. Pemberton, Jenna M. Franke, Dean J. Tantillo,* and Regan J. Thomson*
†
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
‡
Department of Chemistry, University of CaliforniaDavis, 1 Shields Avenue, Davis, California 95616, United States
*
S Supporting Information
ABSTRACT: The enantioselective total syntheses of himan-
dravine and GB17 were completed through a common
biomimetic strategy involving Diels−Alder reactions of
unusual double diene containing linear precursors. The double
diene precursors, containing or lacking a C12 substituent as
required to produce GB17 or himandravine, respectively, were
found to undergo Diels−Alder reactions to afford mixtures of
regioisomeric cycloadducts that map onto the alternative
carbocyclic frameworks of both himandravine and GB17. Computational investigations revealed that these Diels−Alder reactions
proceed via transition state structures of similar energy that have a high degree of bispericyclic character and that the low levels of
regioselectivity observed in the reactions are a consequence of competing orbital interaction and distortion energies. The
combined experimental and computational results provide valuable insights into the biosynthesis of the Galbulimima alkaloids.
INTRODUCTION
arise due to the extent of oxygenation about the carbocyclic
skeleton. The Class IV alkaloids have little resemblance to other
classes or to each other, and for this reason are sometimes
known as “Miscellaneous” alkaloids.
■
The Diels−Alder reaction occupies a special position among
organic reactions due to its ability to convert relatively simple
starting materials into highly complex molecular frameworks in
1
Due to their fascinating structural features, the alkaloids have
a single step. Recognizing the reaction’s potential, synthetic
9
,10
been popular targets for total synthesis.
Early work focused
organic chemists have invested significant effort developing and
on the synthesis of himbacine (1), the simplest member of the
family, with the first synthesis of 1 reported by Hart and
applying a seemingly endless array of useful variations of the
2
Diels−Alder reaction, while simultaneously seeking to under-
11
3
Kozikowski in 1995. Subsequent completed efforts were
stand its fundamental theoretical basis. The Diels−Alder
1
2
reported by the groups of both Chackalamannil and
reaction also occurs in Nature, with many natural products
biosynthesized through pathways thought to involve the
1
3,14
15
16
Baldwin,
while the Terashima, De Clercq, and
1
7
4
,5
Sherburn laboratories reported formal syntheses. Much of
the excitement surrounding himbacine (1) was due to its
reported activity as a potent and selective muscarinic receptor
agonist (M2 receptor subtype K = 5−10 nM vs M3 subtype K
reaction. Taking inspiration from these biosynthetic hypoth-
eses, synthetic chemists have sought to replicate the proposed
Diels−Alder reactions in the laboratory through so-called
4
i
i
biomimetic syntheses. Within this context, we were partic-
1
8,19
=
150 nM).
Indeed, interest in himbacine as a potential
ularly drawn to the Galbulimima family of alkaloids (Figure 1).
Isolated from Galbulimima belgraveana and G. baccatta, trees
endemic to the rainforests of Northern Australia and Papua
New Guinea, the Galbulimima alkaloids possess a range of
unique polycyclic structures with decalin and piperidine rings
serving to unify the family. During a period from 1956 to 1965,
Taylor and co-workers reported the isolation of 28 alkaloids
from G. belgraveana and G. baccatta, for which the structures of
therapeutic fueled a significant medicinal chemistry effort at
20
Schering-Plough. In the early 2000s, interest in the more
complex members of the Galbulimima alkaloids was renewed
following Mander and MacLachlan’s inaugural synthesis of the
21
Class III alkaloid GB13 (5) in 2003, with ensuing total
2
2
syntheses of GB13 (5) from the laboratories of Movassaghi,
23
24
25
26
Chackalamannil, Evans, Sarpong, and Ma. The chemical
conversion of GB13 (5) into himgaline (6) was reported by
2
2 were determined through a combination of spectroscopic
23
24
both Chackalamannil and Evans. Movassaghi and co-
analysis, structural degradation and interconversion, and
6
7
8
workers reported an elegant synthesis of himandrine (3) in
semisynthesis. In two papers published in 2009 and 2011,
2
009 that remains the only Class II alkaloid to succumb to
Mander and co-workers reported the structures for five of the
remaining six alkaloids, as well as two new family members.
Based on structural similarities, the family has been divided into
four classes (I−IV). Differences within a given class typically
Received: July 23, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
pyruvate unit, and a molecule of ammonia to afford a linear
29
precursor akin to 9. They subsequently expanded their
proposal to include the formation of the Class II and III
alkaloids from the same biogenetic precursor but were never
30
specific regarding possible reaction details. In 2005, Baldwin
and co-workers refined the Taylor proposal by speculating that
double diene 10 might undergo an intramolecular Diels−Alder
reaction via iminium ion 12 to afford decalin 13, which after
reduction clearly maps onto the Class I alkaloids, such as
13
himbacine (1) and himandravine (2). Additional ideas about
how species similar to decalin 13 might be transformed into the
3
1
Class II and III alkaloids have been put forward by Baldwin,
22
8
Movassaghi, and Mander. Thus, the Diels−Alder reaction
where the iminium ion conjugated diene (green) serves as the
dienophile and the butenolide component (red) as the diene
provides a unified route for the biogenesis of all Class I−III
7
alkaloids, as well as GB16 (7)a Class IV alkaloid, but which
could well be considered a member of Class II. The structure of
GB17 (8), on the other hand, cannot be reconciled with this
same Diels−Alder reaction. In their 2009 paper describing the
7
structural elucidation of GB17 (8), Mander and co-workers
deduced that GB17 (8) must be derived from the alternative
combination of dienes within a similar linear precursor (i.e.,
1
1). Thus, the Diels−Alder reaction of intermediate 14 where
the iminium ion conjugated diene (green) serves as the diene
and the butenolide component (red) as the dienophile leads to
decalin 15, which has the correct connectivity to produce GB17
(
8).
The presence of two distinct dienes within a common linear
precursor that can each potentially react as either the diene or
the dienophile in an intramolecular Diels−Alder reaction to
generate vastly different carbocyclic products is unusual. The
placement of the single hydroxyl group within GB17 (8) drew
our attention and led us to consider the nature of the possible
regioisomeric Diels−Alder reaction transition state structures
leading to the divergent product outcomes (i.e., 13 vs 15).
When X = OH, the proposed chairlike transition state of 12
would necessarily place the C12 hydroxyl group in an
unfavorable axial orientation, while the alternative transition
state leading to adduct 15 allows the hydroxyl group to occupy
a more favorable equatorial orientation. Similar conformational
differences were utilized in Johnson’s elegant synthesis of 11α-
hydroxyprogesterone, wherein a single hydroxyl stereocenter
Figure 1. Representative Galbulimima alkaloids.
2
7
synthesis. Of the Class IV alkaloids, GB16 (7) was
26
synthesized by Ma and co-workers in 2010, while our own
group completed the synthesis of GB17 (8) in 2011.
There has also been a great deal of speculation and interest
regarding the biogenesis of the Galbulimima alkaloids (Figure
28
2
). In 1961, Taylor and co-workers proposed that the Class I
Galbulimima alkaloids were derived from nine acetate units, one
Figure 2. Proposed regiodivergent [4 + 2] cycloadditions in Galbulimima alkaloid biosynthesis.
B
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 1
a
Reagents and conditions: a. Twenty mol % (S)-BINOL, 10 mol % Ti(OiPr) , 4 Å molecular sieves, allyltributylstannane, 78%; b. BnBr, NaH,
4
Bu NI, 99% ee, 99%; c. Two mol % OsO , 2,6-lutidine, NaIO , 1,4-dioxanes:water, 96%; d. methyl (triphenylphosphoranylidene)acetate, THF,
4
4
4
reflux, 96%; e. DIBAL, −78 °C → 0 °C, 99%; f. 40−45% aq. HF, 0 °C, 99%; g. MnO , 76%; h. 1.0 M TiCl , MeOH, Et N, 94%; i. Dess−Martin
2
4
3
periodinane, pyridine, 86%; j. A, Et N, LiCl, 3:1 Z:E, 95%; k. O , MeOH:TsOH; Me S; l. methyl (triphenylphosphoranylidene)acetate, 72% (over 2
3
3
2
steps from 22); m. DIBAL, −78 °C → 0 °C; 1.0 M HCl, acetone; n. A, Et N, LiCl, 47% (over 3 steps from 23); o. MnO , 83%; p. 1.0 M TiCl ,
3
2
4
MeOH, Et N, 93%; q. LDA; then B; r. TsOH·H O MeOH; s. Et N, MsCl, 52% (26 over 3 steps from 21) or 54% (27 over 3 steps from 25); t. I ,
3
2
3
2
acetone; u. C, NaH, 0 °C → rt, 28 (81% over 2 steps from 26) or 29 (76% over 2 steps from 27).
dictated the stereochemical course of a biomimetic polyene
the GB17 series (A), the requisite hydroxyl stereocenter was
introduced with the necessary absolute configuration through
3
2
cyclization. We wondered whether this difference in
conformational arrangement would be enough to favor the
GB17 cycloadduct 15 over the corresponding Class I adduct
34
35
an enantioselective Keck allylation of aldehyde 16, thus
providing ether 18 in 77% yield and 99% ee after benzylation.
Allylic alcohol 19 was then generated over three standard steps
in 91% yield. Removal of the silyl protecting group within 19
allowed for selective oxidation of the allylic alcohol using MnO2
to afford an aldehyde, which was converted to the dimethyl
acetal 20 (60% yield over three steps). Oxidation of the free
primary alcohol within 20 followed by a Still−Gennari
1
3. We noted that no Class I alkaloids had been isolated that
possess a C12 hydroxyl group, which led us to speculate that
this pathway might be favored for the parent double diene
lacking the hydroxyl group (i.e., 10). Furthermore, Baldwin and
co-workers reported only observing Class I adducts in their
13,14
biomimetic synthesis;
they made no mention of the
36
alternative Diels−Alder cycloadducts being formed, although
at that time the structure of GB17 (8) had not been reported.
Consideration of the above information, coupled to our
olefination using phosphonate A generated cis-enoate 21 in
2% yield as a 3:1 mixture of Z:E isomers. Formation of the cis-
enoate was crucial in order to obtain high trans-selectivity in
8
33
37
previous interest in both iminium ion Diels−Alder reactions
the subsequent aldol reaction with aldehyde B. Minimization
of allylic strain within 21 during deprotonation with LDA
enforces generation of the trans-configured double bond during
28
and the Galbulimima alkaloids, led us to initiate research with
the goal to provide insight into these processes and investigate
the nature of these proposed regiodivergent Diels−Alder
reactions. Herein we report the synthesis of linear precursors
both with and without hydroxyl groups, examine their capacity
to participate in the proposed biomimetic Diels−Alder
reactions, provide computational insights into these reactions,
and report concise biomimetic syntheses of both himandravine
38
formation of the extended enolate. Diene 26 was thus
produced with excellent trans-selectivity after lactonization and
elimination, which avoided a problematic isomerization of the
cis-diene that was formed in significant quantities if the trans-
11
isomer of 21 was used in the aldol reaction with B.
Construction of the desired Diels−Alder reaction precursor
(2) and GB17 (8).
(
i.e., 28) was then completed in 81% yield by cleavage of the
dimethyl acetal within 26 and a subsequent Horner−Wads-
RESULTS AND DISCUSSION
13
■
worth−Emmons olefination using phosphonate C. Synthesis
A common strategy to access both the hydroxylated and
nonhydroxylated linear precursors required for the proposed
biomimetic Diels−Alder reactions is outlined in Scheme 1. For
of the corresponding precursor for the himandravine series (B)
combines elements of our synthesis of the GB17 analogue (i.e,
28) with the previously reported syntheses of himbacine
C
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 2
a
Reagents and conditions: a. TFA, DCM 0 °C → rt; b. MsOH, CDCl , 55 °C, 5−7 days; c. NaCNBH , EtOH, 0 °C → rt, 1:1:2 ratio of 38a:40:42
3
3
(
(
from 28) or 1:1:1 ratio of 39a:41:43 (from 29) as determined by 1H NMR spectroscopy of unpurified reaction mixture; d. (Boc) O, Et N, 38b
15%) + 40 and 42 (39% of mixture) from 28 or 39b (22%), 41 (18%) + 43 (12%) from 29.
2 3
1
1,13
(
1).
Ultimately, the requisite linear precursor 29 could be
hoped to replicate the Baldwin group’s experiments but more
thoroughly analyze the product outcomes in search of possible
GB17-type isomers. Unfortunately, exposure of double diene
29 to the identical set of conditions reported by Baldwin and
co-workers for this substrate gave rise only to iminium ion 31
and no cycloadducts. Like the OBn derivative 30, iminium
ion 31 was also stable enough at room temperature to allow full
characterization.
obtained in good overall yield after 11 steps from cycloheptene
22).
In 2005, Baldwin and co-workers reported that exposure of
double diene 29 to TFA (first at 0 °C, then at room
temperature for 60 min) followed by the addition of sodium
cyanoborohydride led to the formation of cycloadduct 39,
along with an equal quantity of the corresponding epimeric
trans-piperidine isomer (from a nonselective reduction of the
(
14
Frustrated by these outcomes, we were, however, inspired by
a report from the Evans lab that demonstrated significant
differences in reactivity based on counterion identity for a series
13,14
corresponding cyclic iminium ion).
They reported the
conversion of these two cycloadducts to the corresponding
natural products, himbacine (1) and himandravine (2 via 39).
Given this report, we were highly surprised to find that
exposure of OBn derivative 28 to TFA provided quantitative
cleavage of the Boc group and formation of iminium ion 30, but
no sign of any products from cycloaddition (Scheme 2). In fact,
iminium ion 30 proved quite stable at room temperature,
39
of related iminium ion Diels−Alder reactions. We found that
exposure of the TFA salts 30 or 31 to 1 equiv of
methanesulfonic acid at 55 °C induced counterion metathesis
and efficient intramolecular cycloaddition. Monitoring the
reactions by 1H NMR spectroscopy over 5 days allowed us
to observe the formation of himandravine-type cycloadducts 32
or 33, along with GB17-type cycloadducts 34 or 35 that
underwent complete isomerization to the conjugated iminium
ions 36 or 37 in situ. The reaction mixtures were subsequently
treated with sodium cyanoborohydride to yield the correspond-
ing piperidine products. Reduction of the intermediate iminium
ions gave rise to only a single cis-piperidine isomer for each case
(i.e., where X = OBn or H), the result of selective axial delivery
of hydride. The high selectivity of these reductions was
1
13
allowing for its full structural characterization ( H and
C
NMR, MS, and IR; see Supporting Information). Unfortu-
nately, heating of 30 in refluxing chloroform failed to induce
any reaction, while higher temperatures (benzene at reflux) led
to decomposition. We therefore turned our attention to the
corresponding investigation of the himandravine series using
double diene 29, assuming that the OBn group within
compound 28 was perturbing the system somehow. We
D
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
somewhat surprising given that Baldwin and co-workers had
reported obtaining a 1:1 mixture of piperidine epimers (see
Scheme 3
1
4
above). Our experimental results are, however, consistent
with reports of related reductions where high selectivity for
40
axial delivery is also found. Purification of the immediate
mixtures following reduction proved challenging but was aided
by selective Boc-protection of the himandravine-type adducts
(38a or 39a) allowing for their easy isolation from the
corresponding GB17-type adducts. The GB17-type adducts 41
and 43 derived from linear precursor 29 could be separated
using silica gel flash chromatography, while the corresponding
GB17-type products derived from 28 could not be separated
under a variety of conditions, including preparative HPLC.
Pure samples of each compound were, however, readily
obtained through an alternative route involving the thermal
Diels−Alder reaction of ketone 28 (80 °C, 5 days), which led
to separable cycloadducts that could be individually processed
to 40 or 42 (see Supporting Information).
Stereochemical confirmation for 38a, 40, 41, and 43 was
established through single crystal X-ray crystallography (CCDC
no. 1061572, 1061573, 1061574, and 1061575) as depicted in
Scheme 2. The structure of cycloadduct 39a was established by
conversion to himandravine (2) by conjugate reduction of 39b
with Stryker’s reagent and Boc-group cleavage thereby also
1
13
completing the biomimetic synthesis of 2. H and C NMR
spectral data of himandravine (2) prepared in this manner
matched those of an authentic sample, as well as published
4
1
data. Cycloadduct 42 could be transformed into GB17 (8) in
two steps (Scheme 3). The first of these steps involved
treatment of 42 with sodium methoxide, which induced a
lactamization and redox isomerization event to form the
diastereomeric ketones 44 and 45 in 85% yield. The major
isomer 45 was converted to GB17 (8) following removal of the
benzyl ether, thereby completing the biomimetic synthesis of
GB17 (8) and simultaneously confirming the stereochemistry
a
Reagents and conditions: a. PhSiH , [(PPh )CuH] , 99%; b. TFA,
3
3
6
DCM 0 °C → rt, 87%; c. NaOMe, MeOH, 2 days, 44 (15%) + 45
(70%); d. 10% Pd/C, H , EtOH, 73%.
2
1
13
of cycloadduct 42. H and C NMR spectral data of GB17 (8)
43,44
45
prepared in this manner matched those of an authentic sample,
set
and the SMD continuum solvation model, all with the
7
,28
as well as literature reports.
Gaussian09 software package (see Supporting Information for
additional details). The lack of selectivity observed exper-
imentally for 30 and 31 is recapitulated in the computational
results, which suggest that all three productswhether X = H
or X = ORform via transition state structures of similar free
energy (Figure 3A).
Having established the identities of all cycloadducts, we
could analyze the regiochemical and stereochemical outcome of
the iminium ion Diels−Alder reactions of both linear
precursors (i.e., 28 and 29). For the GB17 series, the three
cycloadducts 38a, 40, and 42 were formed in a 1:1:2 ratio,
respectively, based upon analysis of the reaction mixture
directly following reduction. Cycloadduct 42, which possesses
the correct connectivity and stereochemistry required for GB17
Consistent with experimental observations, one type of
transition state arrangement was preferred for himandravine
formation (TSA1 and TSB1), while both sets of possible endo
GB17 arrangements were found to be competitive (TSA2/B2
and TSA3/B3). For the himandravine case, facial selectivity is
controlled by the methyl stereogenic center on the lactone
leading to products 38a and 39a via TSA1 and TSB1,
respectively. For this scenario, the OR substituent has no
influence on the reaction outcome. For the GB17 arrangement,
the methyl substituent on the lactone is located far from the
newly forming bonds and therefore exerts no influence on the
facial selectivity (TSB2 vs TSB3). Addition of the C12
hydroxyl substituent leads to a small preference for TSA2
over TSA3 (−0.6 kcal/mol), a result consistent with the 2:1
ratio of 40 and 42 observed experimentally. These computa-
tional and experimental values also align closely with reported
(
8), was the slightly favored product. Formation of both 38a
and 40 forces the OBn substituent into an axial orientation.
Apparently, the steric influence of the OBn group in
determining the product distribution for this reaction is
minimal and not the dominant control element we had
hypothesized. This conclusion was reinforced by the Diels−
Alder reaction outcomes of the himandravine series using
double diene 29, where an equal ratio of the three cycloadducts,
3
9a, 41, and 43, was formed.
In order to gain insight into the nature of the regiodivergent
Diels−Alder reactions involved in the synthesis of himan-
dravine (2) and GB17 (8), we modeled the possible reactions
of 31 (X = H) and its analogue with X = OH (a crude model of
the OBn group in 30 and a model of a potential biosynthetic
precursor to GB17). All structures (minima and transition state
structures; counterions were not modeled) were optimized
46
A-values for the hydroxyl group and ether substituents.
It is interesting that essentially no regioselectivity is observed
in these cycloadditions, despite significant differences in the
structures of the dienes. Given that both dienes bear π-
42
using the M06-2X functional with the 6-311++G(2d,p) basis
E
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 3. (A) Diels−Alder reaction transition state structures. Free energy barriers (ΔG‡; kcal/mol) are relative to reactant structures. A complete
conformational search was performed on the X = OH reactant, and the best conformer used to calculate both the X = OH and X = H barrier heights.
C−C distances are shown in Å. (B) Highest occupied and lowest unoccupied molecular orbitals of C and D. Orbital energies are shown in kcal/mol
(
plain text) and eV (parentheses). (C) Distortion/interaction energy analysis for Diels−Alder reactions of C + D. All energies shown (kcal/mol) are
electronic (zero-point energy uncorrected). Individual distortion energies for C and D are shown to the left of the blue and green arrows,
respectively, and the sum of those is also given above the top black line. Calculated barriers (ΔE‡) are shown to the right of the black arrow, and
interaction energies (Int. E) are shown to the right of the red arrow; the latter are calculated as the difference between the total distortion energy and
ΔE‡.
accepting groups, an inverse-electron demand mode is expected
to predominate and the “matched” iminium-conjugated diene +
lactone-conjugated dienophile pair might reasonably be
expected to have a lower barrier than the “mismatched” ester-
conjugated diene + α,β-unsaturated iminium-conjugated
dienophile pair.
than for the latter (7.8 eV). Why, then, do both reaction
manifolds have very similar barriers? The answer is revealed by
47−51
a distortion/interaction analysis (Figure 3C).
For the
FMO-matched pair, which leads to the GB17 skeleton, the
more reactive iminium-conjugated diene pays a higher
distortion penalty in achieving its transition state geometry
(∼25 kcal/mol), due primarily to disruption of internal
conjugation, than it does in the FMO-mismatched pair.
Concomitantly, the lactone-conjugated dienophile pays a
This expectation is consistent with frontier molecular orbital
(
FMO) energies for models C and D in Figures 3B and 3C
the HOMO−LUMO gap for the former pair (5.8 eV) is smaller
F
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
smaller distortion penalty. Overall, the total distortion penalties
for the FMO-matched and FMO-mismatched pairs are
approximately the same, but the distribution of distortion
energies are different, with the greatest distortion penalty
counteracting the inherent electrophilicity of the iminium-
conjugated diene.
Notice also that the distances colored in red and green in
each transition state structure are similar; bond formation along
the red path would lead to the GB17 skeleton, whereas bond
formation along the green path would lead to the himandravine
skeleton (bond formation along the black path occurs during
formation of both products). Related transition state geo-
metries have been observed previously for other diene + diene
Diels−Alder reactions that were bispericyclicreactions where
a single symmetrical (or pseudosymmetrical) transition state
structure is connected to products of both possible diene−
dienophile combinations via a post-transition state bifurcation
52
on the potential energy surface. Recently, Hoye and co-
workers even described such a scenario for a biomimetic Diels−
Alder reaction in the synthesis of the dimeric natural product,
5
3
paracaseolide A. Although we have not found solid evidence
for a post-transition state bifurcation in our systems, perhaps
due to their low symmetry, the associated secondary
interactions between the dienes do appear to reduce the
differences in geometries and energies of our competing
transition state structures.
Our results corroborate the biosynthetic hypothesis advanced
13
Figure 4. Further speculation for the biosynthesis of the Galbulimima
alkaloids. Double diene 46 serves as a common intermediate leading to
all known family members by way of the bispericyclic-type transition
state structures, TS-47 and TS-50. Additional tailoring of the initial
cycloadducts 48, 49, and 51 by way of bond-forming reactions,
rearrangements, and/or oxidations/reductions would give rise to all of
the currently known Galbulimima alkaloids.
by Baldwin and co-workers that lactone-containing linear
precursors participate in iminium ion Diels−Alder reactions to
afford himandravine-type adducts, but we demonstrated that
the alternative GB17-type adducts are also formed with poor
selectivity between the two regioisomeric Diels−Alder reaction
pathways. In the cases investigated, three out of the four
possible endo Diels−Alder adducts were observed: both GB17-
type diastereomers and one of the two possible himandravine-
type stereoisomers. While our original hypothesis was that the
presence of a C12 substituent in the linear Diels−Alder
reaction precursor might allow the GB17-type adduct to be
favored over the himandarive-type adduct, experimental results
show that the C12 substituent exerts very little influence over
the product distribution. It therefore seems most likely that the
C12 hydroxyl group within GB17 (8) is introduced biosyntheti-
cally after a nonselective Diels−Alder reaction has occurred
single starting material such as 46. In this unified scenario, TS-
47 would provide access to the Class II−IV alkaloids and GB17
via decalins 48 and 49, respectively. The Class I alkaloids would
then derive from decalin 51, which forms via TS-50. If formed,
the isomeric GB17-type adduct 52 would lead to currently
unknown alkaloids.
CONCLUSIONS
■
(
see below). Late-stage hydroxylation is also consistent with the
Our combined experimental and computational studies have
provided new insights into the factors governing the complex
Diels−Alder reactions postulated to be involved in the
biosynthesis of the Galbulimima alkaloids. Intermediate
iminium ions underwent regiodivergent Diels−Alder reactions
via transition state structures of similar energy to generate the
carbocyclic skeletons of structurally distinct natural products,
allowing for the biomimetic total synthesis of both himan-
dravine (2) and GB17 (8). The orbital interactions associated
with bispericyclic character appear to promote these Diels−
Alder reactions and may play an important role in the
formation of a variety of polycyclic natural products. It is
intriguing to speculate that the structural diversity obtained
from the putative double diene biosynthetic precursor for the
Galbulimima alkaloids is Nature’s version of “diversity oriented
synthesis”, where the production of multiple chemotypes from
a single precursor might provide an evolutionary advantage to
the producing organism. Further investigations into the
biosynthetic machinery responsible for the formation of the
putative double diene precursor, its regiodivergent Diels−Alder
extensive degree of oxygenation that is observed in other
members of the Galbulimima family, such as himandrine (3)
and GB1 (4), for example.
Formation of the diastereomeric decalin ring system for the
GB17 arrangement (i.e., 40/41) is intriguing, and it is tempting
to speculate that there may exist as yet identified alkaloids
possessing this configuration. On the other hand, both decalin
isomers derived from the himandravine arrangement are known
in nature, yet only one isomer (i.e., 38/39) was observed in our
experiments. Our results indicate that access to the
diastereomeric decalin ring system required to generate the
Class II, III and IV alkaloids (except GB17) would require a
precursor with an epimeric methyl substituent on the lactone
moiety. Alternative possibilities have been posited where the
putative linear double diene precursor lacks this methyl
stereocenter entirely, but these speculations have not yet
8
,22,31
been verified experimentally.
In such a situation, as
depicted in Figure 4, it is reasonable to assume that both pairs
of diastereomeric decalin systems would be produced from a
G
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
reactions, and subsequent transformations should further
illuminate this remarkable family of natural products.
(19) Miller, J. H.; Aagaard, P. J.; Gibson, V. A.; McKinney, M. J.
Pharmacol. Exp. Ther. 1992, 263, 663.
(20) Chackalamannil, S.; Wang, Y.; Greenlee, W. J.; Hu, Z.; Xia, Y.;
Ahn, H.-S.; Boykow, G.; Hsieh, Y.; Palamanda, J.; Agans-Fantuzzi, J.;
Kurowski, S.; Graziano, M.; Chintala, M. J. Med. Chem. 2008, 51, 3061.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b07710.
■
*
S
(
21) Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125,
400.
22) Movassaghi, M.; Hunt, D. K.; Tjandra, M. J. Am. Chem. Soc.
006, 128, 8126.
23) Shah, U.; Chackalamannil, S.; Ganguly, A. K.; Chelliah, M.;
Kolotuchin, S.; Buevich, A.; McPhail, A. J. Am. Chem. Soc. 2006, 128,
2654.
.
2
(
2
(
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
All experimental procedures, computational data, and
complete characterization (NMR, MS, IR, optical
rotation) for all new compounds (PDF)
1
(
(
(
24) Evans, D. A.; Adams, D. J. J. Am. Chem. Soc. 2007, 129, 1048.
25) Larson, K. K.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 13244.
26) Zi, W. W.; Yu, S. Y.; Ma, D. W. Angew. Chem., Int. Ed. 2010, 49,
5887.
(27) Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem. Soc. 2009, 131,
9
(
2
(
648.
AUTHOR INFORMATION
Corresponding Authors
djtantillo@ucdavis.edu
r-thomson@northwestern.edu
■
28) Larson, R. T.; Clift, M. D.; Thomson, R. J. Angew. Chem., Int. Ed.
012, 51, 2481.
29) Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961, 14,
06.
(30) Mander, L. N.; Prager, R. H.; Rasmussen, M.; Ritchie, E.;
Taylor, W. C. Aust. J. Chem. 1967, 20, 1705.
31) Tchabanenko, K.; Chesworth, R.; Parker, J. S.; Anand, N. K.;
Russell, A. T.; Adlington, R. M.; Baldwin, J. E. Tetrahedron 2005, 61,
1649.
32) Johnson, W. S.; Brinkmeyer, R. S.; Kapoor, V. M.; Yarnell, T. M.
*
*
1
Notes
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
Support from the National Institutes of Health
R01GM085322) and U.S. National Science Foundation
CHE-030089 via XSEDE) is gratefully acknowledged. We
■
(
(
1
(
J. Am. Chem. Soc. 1977, 99, 8341.
(33) Kim, J.; Thomson, R. J. Angew. Chem., Int. Ed. 2007, 46, 3104.
(34) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
thank Professor Lewis N. Mander (The Australian National
University) for helpful discussions and authentic samples of
GB17 and himandravine.
(
35) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube,
́
J. J. Am.
Chem. Soc. 2008, 130, 6018.
(
(
36) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
37) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S.
REFERENCES
1) Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98.
2) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668.
3) Houk, K. N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81.
4) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
078.
5) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321.
6) Binns, S.; Dunstan, P.; Guise, G.; Holder, G.; Hollis, A.;
McCredie, R.; Pinhey, J.; Prager, R.; Rasmussen, M.; Ritchie, E.;
Taylor, W. Aust. J. Chem. 1965, 18, 569.
7) Mander, L. N.; Willis, A. C.; Herlt, A. J.; Taylor, W. C.
Tetrahedron Lett. 2009, 50, 7089.
8) Bradford, T. A.; Willis, A. C.; White, J. M.; Herlt, A. J.; Taylor, W.
C.; Mander, L. N. Tetrahedron Lett. 2011, 52, 188.
9) Rinner, U.; Lentsch, C.; Aichinger, C. Synthesis 2010, 2010, 3763.
10) Bhattacharyya, D. Tetrahedron 2011, 67, 5525.
11) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
■
(
(
Tetrahedron 1989, 45, 5767.
(
(
J. E.; Borg, G. A.; Evans, D. A. Org. Lett. 2011, 13, 3758.
(
(
38) Kende, A. S.; Toder, B. H. J. Org. Chem. 1982, 47, 163.
39) Marcoux, D.; Bindschadler, P.; Speed, A. W. H.; Chiu, A.; Pero,
̈
(
(
3
(
40) Ryckman, D. M.; Stevens, R. V. J. Org. Chem. 1987, 52, 4274.
41) Chackalamannil, S.; Davies, R.; McPhail, A. T. Org. Lett. 2001, 3,
1
427.
(
(
(
(
42) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
43) McLean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639.
44) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys.
(
1
980, 72, 650.
45) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
009, 113, 6378.
46) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994.
(
2
(
(
(
(
(
1
(
(47) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646.
(48) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187.
(49) Hayden, A. E.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 4084.
(50) Lopez, S. A.; Houk, K. N. J. Org. Chem. 2013, 78, 1778.
(51) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8,
17, 9369.
12) Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.;
Leone, D. J. Am. Chem. Soc. 1996, 118, 9812.
13) Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J.
E. Org. Lett. 2005, 7, 585.
14) The Baldwin lab’s publication (ref 13) regarding the biomimetic
(
3
118.
52) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; C
Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592.
53) Wang, T.; Hoye, T. R. Nat. Chem. 2015, 7, 641.
̈
̈
̧elebi-Olc u̧ m, N.;
(
(
synthesis of himbacine has recently been retracted. Tchabanenko, K.;
Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Org. Lett. 2015, 17,
(
3
190.
15) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron
Lett. 1999, 40, 3399.
16) Gao, L. J.; Waelbroeck, M.; Hofman, S.; Van Haver, D.;
Milanesio, M.; Viterbo, D.; De Clercq, P. J. Bioorg. Med. Chem. Lett.
002, 12, 1909.
(
(
2
(
17) Wong, L. S. M.; Sherburn, M. S. Org. Lett. 2003, 5, 3603.
(
18) Darroch, S.; Taylor, W.; Choo, L. K.; Mitchelson, F. Eur. J.
Pharmacol. 1990, 183, 1720.
H
DOI: 10.1021/jacs.5b07710
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX