Total syntheses of (-)-kopsifoline D and (-)-deoxoapodine: Divergent total synthesis via late-stage key strategic bond formation

Article abstract of DOI:10.1021/ja500548e

Divergent total syntheses of (-)-kopsifoline D and (-)-deoxoapodine are detailed from a common pentacyclic intermediate 15, enlisting the late-stage formation of two different key strategic bonds (C21-C3 and C21-O-C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21-C2 bond formation) and (+)-fendleridine (C21-O-C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21-C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels-Alder reaction and stabilizing the intermediate 1,3-dipole.

Full text of DOI:10.1021/ja500548e

Article
pubs.acs.org/JACS
Total Syntheses of (−)-Kopsifoline D and (−)-Deoxoapodine:
Divergent Total Synthesis via Late-Stage Key Strategic Bond
Formation
Kiyoun Lee and Dale L. Boger*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Divergent total syntheses of (−)-kopsifoline D
and (−)-deoxoapodine are detailed from a common
pentacyclic intermediate 15, enlisting the late-stage formation
of two different key strategic bonds (C21−C3 and C21−O−
C6) unique to their hexacyclic ring systems that are
complementary to its prior use in the total syntheses of
kopsinine (C21−C2 bond formation) and (+)-fendleridine
(C21−O−C19 bond formation). The combined efforts
represent the total syntheses of members of four classes of
natural products from a common intermediate functionalized
for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to
the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation
for late-stage formation of the C21−C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a
penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying
Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the
functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a
key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels−Alder reaction and stabilizing the
intermediate 1,3-dipole.
same intermediate, albeit in the enantiomeric series and by
virtue of conversion of the C5 ethyl group primary alcohol to a
methyl dithiocarbonate, was enlisted for the total synthesis of
kopsinine (10),7,8 featuring a diastereoselective SmI2-mediated
free radical transannular conjugate addition reaction for
formation of the bicyclo[2,2,2]octane core central to its
hexacyclic ring system with C21−C2 bond formation. This
late-stage C21−C2 bond formation not only complemented
prior Diels−Alder approaches to its bicyclo[2,2,2]octane core,9
but it also represented the first synthetic approach that directly
provided kopsinine from the underlying pentacyclic Aspido-
sperma alkaloid skeleton (Figure 2).
Herein, we report full details of the use of this same key
intermediate in initial exploratory efforts that provided the
parent kopsifoline skeleton (named (−)-kopsifoline H, 8) and
the extension of these studies to the first total synthesis of a
naturally occurring kopsifoline, (−)-kopsifoline D (4).10 By
mimicking what is the likely biosynthesis of the kopsifolines,1 a
late-stage C21−C3 bond formation via a transannular enamide
alkylation of an alcohol-derived C21 iodide within the
Aspidosperma alkaloid skeleton was developed and imple-
mented to complete the assemblage of the kopsifoline skeleton
INTRODUCTION
■
The kopsifolines and their unique core hexacyclic ring system
were first disclosed in 2003 when Kam and Choo reported the
initial members of this new alkaloid class (Figure 1).1
Kopsifoline A−F (1−6) were isolated from the leaf extracts
of a previously unencountered Malaysian Kopsia species later
identified as K. fruticosa (Ker) A. DC., and their structures were
established spectroscopically.1 Subsequent exploration of K.
singapurensis led to a second isolation of kopsifoline A (1) and
characterization of a seventh kopsifoline (singaporentine A, 7).2
Related to the Aspidosperma alkaloids, their more complex
hexacyclic core structure incorporates a previously unprece-
dented C3−C21 carbon−carbon bond linking the terminal
carbon (C21) of the C5 ethyl substituent to C3 bearing a
methoxycarbonyl group such that the stereochemically rich
central six-membered ring incorporates five or six stereogenic
centers, three or four of which are quaternary.
In efforts that served to assign the natural product absolute
stereochemistry, we recently disclosed a total synthesis of
(+)-fendleridine (9, aspidoalbidine), enlisting an intermediate
in which the C5 ethyl substituent bears an oxidized terminal
C21 methyl group. Closure of this alcohol onto C19 (C21−O−
C19 bond formation) via trap of an intermediate iminium ion
provided the fendleridine tetrahydrofuran ring and completed
the assemblage of its hexacyclic ring system (Figure 2).3−6 This
Received: January 17, 2014
Published: February 5, 2014
© 2014 American Chemical Society
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primary alcohol oxygen to C19 (fendleridine)3 and C6
(deoxoapodine) or through linkage of C21 itself to C2
(kopsinine)7 and C3 (kopsifoline D) using the C21
functionality to conduct complementary nucleophilic or
electrophilic C−C bond-forming reactions (Figure 3). The
Figure 1. Kopsifolines.
Figure 3. Divergent total syntheses of a series of naturally occurring
alkaloids containing deep-seated structural differences from a common
cascade cycloaddition product.
combined efforts represent the total syntheses of members of
four different classes of natural products from a common
intermediate deliberately functionalized for late-stage formation
of four different key strategic bonds13 embedded in each unique
core structure.
RESULTS AND DISCUSSION
Figure 2. Key strategic bond disconnections for approaching the
natural products from a common precursor.
■
The basis of the approach and key to the assemblage of the
underlying Aspidosperma skeleton is a powerful intramolecular
[4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that
provides the fully functionalized pentacyclic ring system in a
single step (Scheme 1).14 Assembled in two steps from N-
benzyltryptamine and subsequent N-acylation of the amino-
1,3,4-oxadiazole 12 with 4-(2-tert-butyldimethylsilyloxy)pent-4-
enoic acid (13), thermal cyclization of 14 (230 °C, o-
dichlorobenzene (o-DCB)) provided the key pentacyclic
skeleton 15 (71%) as a single diastereomer. As disclosed in
our initial work,3 the initiating intramolecular [4 + 2]
cycloaddition15 is followed by a retro Diels−Alder loss of N2
to provide an intermediate 1,3-dipole14 stabilized by the two
substituents on the carbonyl ylide. In turn, the stabilized 1,3-
dipole undergoes a subsequent diastereoselective [3 + 2]
cycloaddition16 with the tethered indole exclusively through an
endo transition state and with an intrinsic regioselectivity that is
reinforced by the linking tether to provide the cascade
cycloadduct 15. Inherent in the approach, the C3 methyl
ester found in the kopsifolines, deoxoapodine, and kopsinine
serves as a key 1,3,4-oxadiazole substituent, activating it for
participation in the initiating Diels−Alder reaction and
stabilizing the intermediate 1,3-dipole. As detailed in our
preceding studies albeit with improvements in the originally
disclosed conversions,7 diastereoselective reductive cleavage of
(eq 1) in a route that directly provides the natural product in its
final indolenine oxidation state. The studies further established
the kopsifoline absolute configuration as enantiomeric to the
Aspidosperma alkaloids including fendleridine, but analogous to
that found within kopsinine.
An additional attribute of the approach is that the same key
intermediate was also used herein to access natural
(−)-deoxoapodine (11),11 originally isolated from Tabernae
armeniaca, by virtue of C21−O−C6 bond formation. These
efforts represent only the second total synthesis of the natural
product5 and the first to provide 11 in optically active form,
confirming the anticipated absolute configuration assign-
ment.11c Thus, a common Aspidosperma-like pentacyclic
intermediate, bearing a terminally functionalized C5 ethyl
substituent (primary alcohol), was used in the divergent total
synthesis12 of a suite of alkaloids, entailing linkage of the C21
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Scheme 1
Scheme 2. Synthesis of Kopsifoline H
enantiomer of 21 with Lawesson’s reagent19 (1.1 equiv,
toluene, 100 °C, 0.5 h) furnished the thiolactam 22 (89%).
The absolute configuration of (+)-22 was unambiguously
established by an X-ray structure determination conducted on
this intermediate containing a heavy atom (S).18b Concomitant
reduction of the thioamide and removal of the N-benzyl group
was accomplished by the treatment of (+)-22 with Raney-nickel
(Ra−Ni, H2, EtOH, 80 °C, 0.5 h) to furnish (−)-8 (70%),
which we have come to refer to as kopsifoline H, designating its
hydrogenated (H) state.
Biomimetic C21−C3 Bond Formation: 6,7-Dihydro-
kopsifoline D. The additional key question addressed in initial
studies was whether a late-stage C21−C3 bond formation via a
transannular enamide alkylation of an alcohol-derived C21
electrophile was feasible for formation of the kopsifoline core,
permitting the direct introduction of the correct C2 indolenine
oxidation state of the natural products (see eq 1). These efforts
began with 25, originally prepared in prior studies7 and bearing
a readily removable indoline N-carboxybenzyl (Cbz) group. In
efforts that impact the regioselectivity of the Chugaev
elimination,20 conversion of 16 to the corresponding Cbz
carbamate 23, followed by an improved methyl dithiocarbonate
formation (NaH, CS2 then MeI, THF, 0 to 25 °C, 3 h, 93%)
provided 24 (Scheme 3). The intermediate xanthate 24
underwent clean thermal elimination under mild reaction
conditions (toluene, 100 °C bath, 48 h or 150 °C bath, 36 h),
providing good yields (60%) of 25. Here, the indoline Cbz
carbamate (vs N-benzyl) activates C2−H for xanthate syn
elimination, favoring formation of the more substituted and
stable olefin.7
the oxido bridge in 15 (NaCNBH3, 88%) with exclusive convex
face hydride reduction of an intermediate iminium ion flanked
by two quaternary centers and subsequent methyl dithiocar-
bonate formation (NaH, CS2; MeI; 91%) provided 177 in
superb conversions.
Kopsifoline H. As our studies began, we first focused on the
synthesis of 8, the parent kopsifoline skeleton. Although 8 has
not yet been isolated as a naturally occurring substance, lacking
a Δ6,7-double bond and containing a saturated indoline, it
possesses the parent hexacyclic skeleton and represents the
tetrahydro derivative of kopsifoline D. Barton−McCombie
deoxygenation17 of methyl dithiocarbonate 17 (Bu3SnH, cat.
AIBN, toluene, reflux, 1 h, 96%) cleanly provided 18 as a single
diastereomer arising from exclusive convex face hydrogen atom
reduction of the intermediate stabilized radical and inversion of
the C3 stereochemistry (Scheme 2). Silyl ether cleavage of 18
(Bu4NF, tetrahydrofuran (THF), −78 to 25 °C, 1 h, 92%)
provided the primary alcohol 19 that in turn was converted to
the iodide 20 (Et3N, CH3SO2Cl, THF, −78 °C, 1 h then NaI,
acetone, −78 to 50 °C, 12 h, 81%), setting the stage for studies
on its cyclization to the kopsifoline skeleton. After exploration
of several alternatives, treatment of 20 with KOtBu in THF (3
equiv, −78 to 0 °C, 1 h) proved to be highly effective and
afforded 21 (95%), whose structure and stereochemistry were
confirmed with a single-crystal X-ray structure determinatio-
n.18a Initial, albeit limited, attempts to promote the cyclization
of the intermediate mesylate (0%) or corresponding tosylate
(32−36%) were not as productive. Chromatographic separa-
tion of the enantiomers of 21 (α = 1.2, 10% i-PrOH/hexane)
was carried out on a semipreparative Daicel ChiralCel AD
column, providing (+)-21 and ent-(−)-21. Treatment of each
Silyl ether cleavage in 25 (3 equiv Bu4NF, THF, 25 °C, 1 h,
98%) and conversion of the primary alcohol 26 to the primary
iodide 27 (Et3N, CH3SO2Cl, THF then NaI, acetone, 50 °C, 12
h, 80%) followed by reduction of the amide 27 to the tertiary
amine 28 (5 equiv BH3·THF, THF, 0 °C, 1.5 h, 79%) set the
stage for examination of the transannular cyclization. After
optimization of the conditions, we were delighted to find that
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installation of the Δ6,7-double bond. Toward this end, α-
phenylselenation of 25 was achieved by treatment of the lactam
enolate (lithium diisopropylamide, −78 °C) with phenylselenyl
chloride (PhSeCl, 1 equiv) to provide 31 (81%, Scheme 4).
Scheme 3. Synthesis of 6,7-Dihydrokopsifoline D
Scheme 4. Total Synthesis of (−)-Kopsifoline D
The mixture of isomeric phenylselenides (8:1, β:α) was treated
with m-chloroperoxybenzoic acid (m-CPBA, 1.5 equiv) in
CH2Cl2 at −78 °C to yield the corresponding selenoxides, and
their subsequent in situ syn elimination proceeded smoothly
(−78 to 25 °C) to afford 32 (90%). The enantiomers of 32
were easily separated (α = 1.48, 20% i-PrOH/hexane) on a
semipreparative Chiralcel OD column, affording natural (+)-32
and ent-(−)-32. Clean 1,2-reductive removal of the lactam
carbonyl was best accomplished by O-methylation of (+)-32
and subsequent reduction of the resulting methoxyiminium ion
(3 equiv Me3OBF4, 2,6-t-Bu2Py, CH2Cl2, 25 °C; NaBH4,
MeOH, 25 °C, 52%)22 to afford natural (−)-33. Nearly as
effective, direct lactam reduction of (+)-32 by treatment with
diisobutylaluminum hydride (Dibal-H, 5 equiv, THF, −20 °C,
20 min) also afforded (−)-33 (48%) in a single step.
Alternatively, treatment of (+)-32 with Lawesson’s reagent19
(1.1 equiv, toluene, 100 °C, 0.5 h, 65%), subsequent S-
methylation of the intermediate thioamide (3 equiv Me3OBF4,
2,6-t-Bu2Py, CH2Cl2, 25 °C) and reduction of the resulting S-
methyliminium ion (10 equiv NaBH4, MeOH, 0 °C, 45 min)
also provided 33 (40% overall), albeit in lower overall
conversions. Silyl ether cleavage (Bu4NF, THF, 25 °C, 1 h,
98%) followed by conversion of the primary alcohol (−)-34 to
the primary iodide (−)-35 (Et3N, CH3SO2Cl, THF, −78 °C
then NaI, acetone, 90 °C bath temperature, 12 h, 68%) set the
stage for the key transannular cyclization. Cbz deprotection and
subsequent intramolecular ring closure of 35 (BF3·OEt2, Me2S,
CH2Cl2, 25 °C, 12 h followed by treatment with Et3N, EtOAc,
25 °C, 12 h) provided (−)-kopsifoline D (4) in superb
the treatment of 28 with BF3·OEt2 and dimethyl sulfide (Me2S)
in CH2Cl2 (25 °C, 15 h)21 proceeded smoothly not only to
promote Cbz deprotection but also to afford 30 directly in 75%
yield as a single diastereomer, providing 6,7-dihydrokopsifoline
D. Shorter reaction times led to detection and isolation of the
intermediate Cbz deprotection product 29 that itself undergoes
slow cyclization to the indolenine 30 simply upon standing at
room temperature. Notably, the corresponding carbinol amine
derived from water addition to C2 of 30 could also be isolated
if the chromatographic purification (SiO2) of 30 was carried out
without the presence of Et3N (ethyl acetate (EtOAc) vs 2%
Et3N in EtOAc). Reduction of 30 (NaBH4, EtOH, 0 to 25 °C)
provided 8, confirming the structure of 30 and providing an
alternative synthesis of kopsifoline H.
Finally, limited efforts to convert 8 to 30 by oxidation
+
(MnO2, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Me2 S−
Cl, KMnO4) to the C2 imine have not yet proved productive
(Scheme 3), suggesting that direct indolenine introduction
from intermediates such as 28 may constitute a more effective
approach.
Total Synthesis of (−)-Kopsifoline D. Adoption of the
approach for the total synthesis of kopsifoline D required
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conversion (79%) and identical in all respects compared to
those of the authentic material1 except for its distinctly different
optical rotation ([α]D −69 (c 0.08, CHCl3) vs reported [α]D
−27 (c 0.09, CHCl3)1b). Use of the intermediate mesylate (0%)
and corresponding tosylate (22%) was less effective than the
primary iodide 35, and its intramolecular ring closure to
provide 4 was slower than that providing 30, requiring a longer
reaction time and deliberate base treatment (Et3N) for
completion. Initial concerns over the discrepancy in the optical
rotations between our synthetic 4 versus that reported for
natural 4 led us to explore several origins of the distinctions and
entailed repeated preparations of synthetic material. In the
course of these efforts, the water addition product to
kopsifoline D (kopsifoline D hydrate, 4a) was also isolated
and characterized (Scheme 4). Unexpectedly, the optical
rotation of this synthetic hydrate, which could be deliberately
prepared by simply stirring a solution of 4 in THF−H2O (95%,
25 °C, 3 h), perfectly matched that reported for kopsifoline D
([α]D −26 (c 0.08, CHCl3) vs reported [α]D −27 (c 0.09,
CHCl3)1b). This suggests that, while the spectroscopic
characterization of natural kopsifoline D was effectively
conducted with 4, the optical rotation itself was measured on
a sample that had undergone hydration. The ease of kopsifoline
D hydration also suggests that this corresponding hydrate is a
natural product as well and that it likely will be isolated and
characterized in the years ahead. The unambiguous assignment
of the absolute configuration of 4 was accomplished with a
single-crystal X-ray structure determination conducted on the
natural enantiomer of the primary alcohol derived from 23,18c
which was correlated with (+)-32 (see Supporting Information
[SI]).
and cyclization. In contrast, silyl ether deprotection under
acidic conditions conducted by treatment of (+)-32 with HF·
pyridine (3 equiv, THF, 0 °C, 2 h) afforded only the
deprotected primary alcohol (84−95%) with little or no
cyclization even under prolonged reaction times (10 h).
Reductive removal of the lactam carbonyl of (−)-36 upon
treatment with BH3·THF (THF, 0 °C, 1.5 h) provided (−)-37
(70%) and subsequent cleavage of the Cbz group (BF3·OEt2,
Me2S, 25 °C, 5 h, 82%)21 afforded natural (−)-deoxoapodine
(11, [α]D −522 (c 0.17, CHCl3) vs [α]D −432 (c 0.76,
CHCl3)11a and [α]D −593 (CHCl3)11b), which proved identical
in all respects to those of the natural product. By virtue of the
crystallographic assignment of the absolute configuration of
intermediates in route to 11 ((+)-2318c and (+)-32), the
correlation serves to unambiguously confirm the anticipated
absolute configuration for the natural product.11c
CONCLUSIONS
■
Divergent total syntheses of (−)-kopsifoline D and (−)-deox-
oapodine that unambiguously established their absolute
stereochemistry are detailed from a common pentacyclic
intermediate 15 with the late-stage formation of two different
key strategic bonds unique to their hexacyclic ring systems,
complementing its prior use in the total syntheses of kopsinine
and (+)-fendleridine. The combined efforts represent the total
syntheses of members of four different classes of natural
products from a common intermediate functionalized for late-
stage formation of four different key strategic bonds uniquely
embedded in each natural product core structure. The basis of
the approach and central to the assemblage of the underlying
skeleton is a powerful intramolecular [4 + 2]/[3 + 2]
cycloaddition cascade of a 1,3,4-oxadiazole.14,23−32 This
reaction provided the C21 functionalized pentacyclic ring
system 15 in a single step in which the C3 methyl ester found
in the natural products served as a key 1,3,4-oxadiazole
substituent, activating it for participation in the initiating
Diels−Alder reaction and stabilizing the intermediate 1,3-
dipole.
Total Synthesis of (−)-Deoxoapodine. With the natural
enantiomer (+)-32 in hand, our efforts turned to the divergent
total synthesis of (−)-deoxoapodine (Scheme 5). Comple-
Scheme 5. Total Synthesis of (−)-Deoxoapodine
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and copies of H/13C NMR spectra.
1
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
boger@scripps.edu
■
Notes
The authors declare no competing financial interest.
mentary to the approach to kopsifoline D, silyl ether
deprotection prior to lactam carbonyl removal was anticipated
to permit the requisite C21−O−C6 strategic bond formation
by conjugate addition of the primary alcohol. Silyl ether
deprotection upon treatment of (+)-32 with Bu4NF (3 equiv)
in THF at −5 °C (6 h) under basic conditions smoothly
provided only the primary alcohol conjugate addition product
(−)-36 (70%) as a single diastereomer without the detection or
isolation of the intermediate alcohol. Higher reaction temper-
atures (0−25 °C) led to generation of an additional minor
diastereomer of the conjugate addition product, whereas lower
reaction temperatures (−40 °C) resulted in little deprotection
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Institutes of Health (CA042056, DLB). We thank Raj. K.
Chadha for the X-ray crystal structures of 21 and (+)-22 and
Professor A. Rheingold (UCSD) for the X-ray structure
determination of the free alcohol of (+)-23.
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(18) (a) The structure and stereochemistry of 21 were confirmed
with a single crystal X-ray structure determination conducted on white
monoclinic crystals of 21 obtained from Et2O (CCDC 977766). (b)
The structure, stereochemistry, and absolute configuration of (+)-22
(natural enantiomer) were established with a single crystal X-ray
structure determination conducted on a colorless parallelpiped crystal
obtained from acetone (CCDC 978175). (c) The enantiomers of 23
were separated by chiral phase HPLC (Chiracel OD, 2 cm × 20 cm,
20% i-PrOH/hexane, 7 mL/min, α = 1.8) and the structure,
stereochemistry, and absolute configuration of the natural enantiomer
((+)-23) were established with a single-crystal X-ray structure
determination conducted on crystals of the corresponding primary
alcohol obtained from MeOH (CCDC 977767).
3317
dx.doi.org/10.1021/ja500548e | J. Am. Chem. Soc. 2014, 136, 3312−3317