Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives

Article abstract of DOI:10.1021/jacs.6b07623

We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine.

Full text of DOI:10.1021/jacs.6b07623

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Article
Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine
Via Late-Stage Oxidation of (+)-Fendleridine Derivatives
Kolby L. White, and Mohammad Movassaghi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07623 • Publication Date (Web): 10 Aug 2016
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Journal of the American Chemical Society
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Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine
Via Late-Stage Oxidation of (+)-Fendleridine Derivatives.
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Kolby L. White and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: We report the first total syntheses of (+)-
haplocidine, and its N1-amide congener (+)-haplocine. Our con-
D
N
N
19
F
E
14
A
21
O
O
C
cise synthesis of these alkaloids required the development of a
late-stage and highly selective C–H oxidation of complex aspido-
sperma alkaloid derivatives. A versatile, amide directed ortho-
acetoxylation of indoline amides enabled our implementation of
a unified strategy for late-stage diversification of hexacyclic C19-
hemiaminal ether structures via oxidation of the corresponding
pentacyclic C19-iminium ions. An electrophilic amide activation
of a readily available C21-oxygenated lactam, followed by
transannular cyclization and in situ trapping of a transiently
formed C19-iminium ion, expediently provided access to hexa-
cyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-
acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly
effective enzymatic resolution of a non-β-branched primary
alcohol (E=22) allowed rapid preparation of both enantiomeric
forms of a C21-oxygenated precursor for synthesis of these aspi-
dosperma alkaloids. Our synthetic strategy provides succinct
access to hexacyclic aspidosperma derivatives, including the an-
tiproliferative alkaloid (+)-haplocidine.
2
B
3
N
H
N
17
H
R
R
OH
(+)-haplocidine (1), R=C(O)Me
(+)-haplocine (2), R=C(O)Et
(+)-fendleridine (3), R=H
(+)-acetylaspidoalbidine (4), R=C(O)Me
N
N
O
O
O
O
N
N
H
H
MeO
Me
Et
OMe
OH
O
(+)-cimicine (5)
(–)-aspidophytine (6)
Figure 1. Structure of (+)-haplocidine (1) and (+)-haplocine (2)
and structurally related aspidosperma alkaloids.
intermediates.5,7,9 This approach has been applied to the synthe-
ses of ( )-fendleridine (3) and ( )-acetylaspidoalbidine (4),4,5 in
addition to (–)-aspidophytine (6)9 and related alkaloid (+)-
haplophytine12 starting with A-ring oxygenated starting materi-
al.7 An alternative approach secures the desired C19-oxidation
state via a cycloaddition reaction.5e,13 While this inventive solu-
tion bypasses the need for C19-methine oxidation, it does require
additional reductive steps after cycloaddition, in addition to the
use of chiral chromatographic separation to access enantiomeri-
cally enriched (+)-fendleridine (3) and (+)-acetylaspidoalbidine
(4). We aspired to develop a unified strategy for the syntheses of
(+)-haplocidine (1) and (+)-haplocine (2) that would involve re-
gioselective late-stage A-ring functionalization and highly stere-
oselective cyclization events to rapidly generate their hexacyclic
architecture.
Introduction. The structural complexity and diverse biological
activity of the aspidosperma alkaloids have long served as an in-
spiration for development and application of new chemical syn-
thesis strategies.1 A subset of these natural products are hexacy-
clic C19-hemiaminal ether aspidosperma alkaloids that include
the potent caspase-8 inhibitor (+)-haplocidine (1, Figure 1)2,3 and
the structurally related (+)-haplocine (2).2 Related natural alka-
loids include (+)-fendleridine (3)4,5 and (+)-acetylaspidoalbidine
(4) that possess the same hexacyclic structure without A-ring ox-
ygenation, along with (+)-cimicine (5)6,7 and (–)-aspidophytine
(6)7,8,9 as C21-lactone variants of the subfamily with A-ring oxy-
genation. As an outgrowth of our cyclization studies concerning
synthesis of pentacyclic aspidosperma alkaloids,10,11 we sought
the development of a versatile and unified strategy to secure the-
se hexacyclic alkaloids. Herein, we describe the first total synthe-
ses of (+)-haplocidine (1) and (+)-haplocine (2). Our synthesis
features the critical use of transiently formed pentacyclic C19-
iminium ions for securing the desired hexacyclic C19-
hemiaminal ether architecture and a final-stage palladium cata-
lyzed C17–H oxidation.
Scheme 1. Retrosynthetic analysis of (+)-haplocidine (1) and
(+)-haplocine (2)
N
N 19
19
N1-acylation
21
21
O
O
regioselective
C17–H oxidation
3
3
1
1
N
N
R
H
H
17
17
H
OH
(+)-fendleridine (3)
(+)-haplocidine (1), R=C(O)Me
(+)-haplocine (2), R=C(O)Et
intramolecular
trapping
The unique structure of C19-hemiaminal ether subfamily of as-
pidosperma alkaloids has stimulated the development of elegant
synthetic strategies.1,2,4–9 Current synthetic routes to these alka-
loids can be categorized into two groups based on the strategy for
critical C19-hemiaminal ether introduction. One solution to this
structural element is the C19-oxidation of pentacyclic
OH
21
TfO–
21
OH
+
O
N
N
19
12
5
19
transannular
cyclization
2
2
N
N
H
8
7
PMB
PMB
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Results and Discussion. Our retrosynthetic analysis of (+)-
tam ( )-14 in 78% yield.20,21 Exclusive hydration of the C20-
alkene of lactam ( )-14 via a Wacker-Tsuji oxidation,22 provided
the corresponding C21-aldehyde that was reduced in situ to give
alcohol ( )-15 in 79% overall yield (Scheme 2). The C5-
quaternary center of alkene ( )-14 is likely responsible for the
anti-Markovnikov mode of hydration.23
1
2
3
4
5
6
7
8
haplocidine (1) and (+)-haplocine (2) is illustrated in Scheme 1.
Structural comparison of these hexacyclic C19-hemiaminal ether
alkaloids with the biogenetically related aspidosperma alkaloid
(+)-fendleridine (3) highlighted the need for the development of
a final-stage C17-hydroxylation. We envisioned N1-acetylation
and N1-n-propionylation of (+)-fendleridine (3) followed by am-
ide directed C–H oxidation would provide the C17-hydroxylated
alkaloids (+)-1 and (+)-2, respectively. We identified an oppor-
Table 1. Enzymatic resolution of alcohol ( )-15a
21
21
OH
OAc
O
O
N
N
tunity to develop
a
unified strategy to secure the C19-
vinyl acetate
9
R
S
(±)-15
+
lipase, solvent
hemiaminal ether hexacycle shared by (+)-haplocidine (1), (+)-
haplocine (2), (+)-fendleridine (3), (+)-acetylaspidoalbidine (4),
and related aspidosperma alkaloids.6,8 Informed by our mecha-
nistic study of the interrupted Bischler-Napieralski reaction,14,15
we planned the spontaneous interception of the transient C19-
iminium ion of putative pentacycle 7 with the C21-alcohol to di-
rectly obtain the desired C19-hemiaminal ether found in this
hexacyclic–genre of aspidosperma alkaloids (Scheme 1). We en-
visioned transannular cyclization of lactam 8, promoted by elec-
trophilic amide activation, followed by regioselective C2-
reduction to provide the necessary pentacyclic iminium ion 7.
Given the natural occurrence of the characteristic aspidosperma
skeleton with C21-oxygenation in both enantiomeric forms,1,16
we devised a synthetic strategy that would allow for an advanced-
stage stereochemical divergence. Thus, in place of an early intro-
duction of the C5-quaternary stereocenter via asymmetric alkyla-
tion chemistry,11 we sought the resolution of a versatile substrate
to access the desired C21-hydroxylated lactam 8.
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11
12
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14
15
16
17
18
19
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22
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N
N
(–)-15
(+)-16
PMB
PMB
entry
solvent
conversion
ee of (–)-15
ee of (+)-16
lipase
–
–
–
1
2
3
4
5
CAL-B
CCL
CCL
CCL
CCL
PhMe
PhMe
44%
<15%
38%
8%
30%
49%
THF
PhMeb
t-BuOMe
65%
55%
55%
74%
60%
92%
26%
42%
50%
6
Amano PS t-BuOMe
aReagents and conditions: vinyl acetate (2.0 equiv), 23 ºC. Each resolu-
tion was monitored for 48 h or until approximately 50% conversion to
(+)-16 (HPLC analysis), whichever occurred first. Triethylamine (1.0
equiv) was utilized as an additive. CAL-B = Candida antarctica lipase B,
CCL = Candida rugosa lipase, Amano PS = Burkholderia cepacia lipase.
b
We next focused on the resolution of alcohol ( )-15 with pri-
mary interest in accessing enantiomerically enriched (–)-15 to
secure the (R)-C5-stereochemistry required for the C19-
hemiaminal ether aspidosperma alkaloids (+)-1–4 (Figure 1). Af-
ter exploring a variety of strategies using chiral auxiliaries for
preparation of alcohol (–)-15, including modifications of the
synthetic route outlined in Scheme 2 and the C21-derivatization
of alcohol ( )-15 to allow separation of diastereomers,24 we rec-
ognized the superiority of an enzymatic kinetic resolution of al-
cohol ( )-15. Whereas the kinetic resolution of primary alcohols
with β-branching and a variety of secondary alcohols is well es-
tablished,25 the resolution of non-β-branched primary alcohols is
challenging.26 The paucity of methods for the resolution of alco-
hols with remote stereochemistry notwithstanding, the accom-
modation of the polycyclic alcohol ( )-15 as a potential substrate
was of concern given the existing level of success with simpler
substrates.26 We began our investigation with Candida antarctica
lipase B (CAL-B) and a lipase from Candida rugosa (CCL) based
on their prior success with non-β-branched primary alcohols.27
Unfortunately, we saw no acetylation of alcohol ( )-15 with
CAL-B (Table 1, entry 1), likely due to the relative complexity of
alcohol ( )-15 compared to prior substrates.27 We observed an
encouraging level of acylation using alcohol ( )-15 and CCL
(Table 1, entries 2–3)26f that prompted further examination of
solvents and additive choices (Table 1, entries 4–5), resulting in
alcohol (–)-15 with modest level of enantiomeric enrichment
(74% ee) at 65% conversion. With further experimentation we
discovered that the use of a lipase from Burkholderia cepacia with
t-butyl methyl ether as solvent at 10 μM concentration of the
substrate afforded the desired alcohol (–)-15 with synthetically
useful level of enantiomeric enrichment (92% ee) at 55% conver-
sion (Table 1, entry 6).
Scheme 2. Synthesis of the C21-hydroxylated lactam ( )-15a
n-C10H21O2C
HN
Me
n-C10H21O2C
CO2H
9
+
b,c
a
I
N
N
PMB
PMB
N
11
12
PMB
d
10
21
6
OH
O
O
N
O
N
N
20
5
e
f
N
N
N
PMB
(±)-14
PMB
PMB
13
(±)-15
aReagents and conditions: (a) LDA, N,N'-dimethylpropylene urea, THF,
43%. (b) N-allyl-N-(2,2-dimethoxyethyl)-2,2,2-trifluoroacetamide, TFA,
Et3SiH, CH2Cl2, 89%. (c) NaOH, H2O, MeOH, 100 ºC, 98%. (d) Ph3P, I2,
i-Pr2NEt, CH2Cl2, 69%. (e) HG-II Ru-Cat., ClCH2CH2Cl, 80 ºC, 78%. (f)
Pd(OAc)2, p-benzoquinone, MeCN, H2O, HClO4, PhMe; NaBH4, 79%.
We recognized alcohol ( )-15 (Scheme 2) as an attractive pre-
cursor for enantiomerically enriched lactam 8 (Scheme 1), en
route to C19-hemiaminal ether alkaloids described in this report,
while offering future utility toward other aspidosperma alka-
loids16a–d via C6-alkene functionalization. Deprotonation of ester
9 with lithium diisopropylamide (LDA) in the presence of N,N'-
dimethylpropylene urea, followed by α-alkylation of the result-
ing dienolate with indole iodide 1011 afforded divinyl ester 11 in
43% yield.17 Trifluoroacetic acid (TFA) catalyzed Friedel–Crafts-
type reductive alkylation18 of indole 11 followed by tandem hy-
drolysis of the trifluoroacetamide and n-decyl ester provided the
amino acid 12 in 87% yield over two steps (Scheme 2). Slow ad-
dition of a solution of amino acid 12 and Hünig’s base in di-
chloromethane to a solution of triphenylphosphine and io-
dine11,19 in dichloromethane gave lactam 13 in 69% yield. Treat-
ment of triene 13 with Hoveyda–Grubbs II catalyst afforded lac-
With these promising conditions available for resolution of al-
cohol ( )-15, we turned our attention to further optimization
and implementation of this strategy for synthesis of the desired
lactam 8 (Scheme 1). The addition of dichloromethane as co-
solvent (10:1, v/v) and use of vinyl acetate (4.50 equiv) in resolu-
tion of alcohol ( )-15 [5 μM] with Amano PS lipase led to excel-
2
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lent selectivity (E=22), providing one of the most effective kinetic
Scheme 4. Concise syntheses of (+)-fendleridine (3),
resolutions of a complex non-β-branched primary alcohol.26
These conditions afforded the critical alcohol (–)-15 in 36% yield
(10 h, 64% conversion) with an excellent level of enantiomeric
excess (>98% ee)17 along with isolation of acetate (+)-16 (60%,
56% ee, Scheme 3).28 Furthermore, the enatiopurity of recovered
acetate (+)-16 could be readily enhanced using a CCL hydrolytic
resolution to give alcohol (+)-15 (90% ee, 46%) with excellent
potential for synthesis of the characteristic (S)-C5-aspidosperma
skeleton containing C21-oxygenation.6,8
(+)-acetylaspidoalbidine (4), and (+)-limaspermidine (20)a
1
2
3
4
5
6
7
8
TfO–
21
6
+
OH
a,b
OR
21 OR
O
O
N
N
N
19
c
3
N
N
N
PMB
(–)-15
PMB
(+)-17
R=C(O)C6H4-p-NO2
TfO– PMB
18
9
• highly stereoselective
synthesis of versatile
iminium ion 19
Scheme 3. Preparation of alcohols (–)-15 and (+)-15a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TfO–
OH
d,e
21 OR
+
N
N
19
21
21
OH
OH
OAc
• direct interception of
C19-iminium ion
O
N
O
O
N
N
5
R
S
a
2
3
+
• access to penta- or
hexacyclic strucutres
H
N
N
H
H
PMB
N
N
N
(+)-limaspermidine (20)
19
PMB
(±)-15
PMB
(–)-15
PMB
(+)-16
• late-stage N1-
derivatization
f
50% conversion (7 h): 80% ee
80% ee
TfO–
+
21 OH
• excellent selectivity
E = 22
N
19
N
O
N
preparation of alcohol (–)-15 at 64% conversion (10 h):
(–)-15, >98% ee, 36% (+)-16, 56% ee, 60%
19
21
O
g
• distal, quaternary
stereochemistry
2
3
1
N
N
R'
N
H
H
H
PMB
PMB
preparation of alcohol (+)-15 from acetate (+)-16:
• ready access to
both enantiomers
(+)-21
(+)-fendleridine (3), R'=H
(+)-acetylaspidoalbidine (4), R'=Ac
7
b
h
(+)-16, 71% ee
(+)-15, 90% ee, 46%
aReagents and conditions: (a) Amano PS Lipase (>500 U/g), vinyl acetate
(4.50 equiv), t-BuOMe, CH2Cl2, 28 °C. (b) CCL, H2O, Et3N, t-BuOMe, 21
h, 28 °C.
aReagents and conditions: (a) PtO2, H2, EtOAc. (b) p-NO2C6H4COCl,
DMAP, 82% (2-steps). (c) n-Bu3SnH, Tf2O, MeCN, –40 ºC. (d)
NaHB(OMe)3, THF, 77% from (+)-17. (e) PhSH, TFA, 55 ºC; K2CO3,
MeOH, 86%. (f) 1,8-diazabicyclo[5.4.0]undec-7-ene, MeOH, 80% from
(+)-17. (g) PhSH, TFA, 55 ºC; Et3N, MeOH, 84%. (h) pyridine, Ac2O,
CH2Cl2, 88%.
The versatility of lactam (–)-15 for the synthesis of C21-
oxygenated aspidosperma alkaloids is illustrated in Scheme 4.
Hydrogenation of lactam (–)-15 followed by p-nitrobenzoylation
of the C21-alcohol gave benzoate (+)-17 in 82% yield. The elec-
trophilic amide activation of lactam (+)-17 under our optimal
conditions11 resulted in the diastereoselective formation of dii-
minium ion 18. Regioselective C2-reduction with tri-n-butyltin
hydride in situ afforded the critical C19-iminium ion 19 as the
prelude to accessing the crucial C21-hydroxy-iminium ion 7
(Schemes 1 and 4). Importantly, the presence of the electron-
deficient C21-ester was found to be ideal for the desired transan-
nular cyclization step in preparation of iminium ion 19. The ab-
solute and relative stereochemistry of the pentacyclic C21-
oxygenated iminium ion 19 was unequivocally secured via its
conversion to aspidosperma alkaloid (+)-limaspermidine (20,
Scheme 4).5,17,29,30 Gratifyingly, mild in situ methanolysis of imin-
ium ion 19 resulted in the release of the C21-alcohol and sponta-
neous cyclization providing direct access to hexacycle (+)-21 in
80% yield from benzoate (+)-17 (Scheme 4). While unraveling of
the N1-amine afforded (+)-fendleridine (3), a subsequent N1-
acetylation provided (+)-acetylaspidoalbidine (4), in 84% and
88% yield, respectively (Scheme 4). All spectroscopic data as well
as the optical rotation data for our synthetic (+)-fendleridine (3)
We next focused on the development of our biogenetically in-
spired strategy for final-stage C17-hydroxylation of fendleridine
derivatives (Scheme 1) to provide (+)-haplocidine (1) and (+)-
haplocine (2). We envisioned the N1-amide could provide the
necessary guidance32 to afford a regioselective C–H bond oxida-
tion, offering an exciting strategy for late-stage diversification
and amplification of the molecular complexity of the C19-
hemiaminal ether aspidosperma alkaloids.
Table 2. Directed C–H oxidation of indoline ( )-22a a
Me
Me
conditions
N
N
H
H
OAc
Me
(±)-23a
Me
O
O
(±)-22a
entry
Pd(OAc)2 PhI(OAc)2
time temperature solvent
yield
1
2
4 equiv
2 equiv
38%
61%
20 mol%
24 h
24 h
70 ºC
55 ºC
HFIP
HFIP
100 mol%
3
4
5
6
7
8
20 mol%
2 equiv
24 h
23%
87%
84%
67%
0%
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
AcOH
AcOHb
AcOHb
AcOHb
2.5 equiv
2.5 equiv
2.5 equiv
2.5 equiv
2.5 equiv
100 mol%
15 mol%
5 mol%
––
12 h
9 h
(observed: [α]D24: +79 (c = 0.40, CHCl3), lit.: [α]D24: +43 (c = 1.1,
24
CHCl3)5e,31) and (+)-acetylaspidoalbidine (4) (observed: [α]D
:
12 h
12 h
13 h
+39 (c = 0.18, CHCl3), lit.: [α]D = +38 (c = 0.2, CHCl3)5e and
24
AcOHb
AcOHb,c
24
[α]D = +46 (CHCl3)4a), were consistent with the literature.4a,17
20 mol%
74%
Importantly, the application of our planned transannular cycliza-
tion followed by intramolecular trapping of a transient C19-
iminium ion 7 (Scheme 1) offered a concise and completely ste-
reoselective strategy for conversion of lactam (–)-15 to the C19-
hemiaminal ether containing alkaloids (+)-fendleridine (3) and
(+)-acetylaspidoalbidine (4) in only four and five steps, respec-
tively (Scheme 4).
b
aReactions conducted in solvent and Ac2O mixture (10:1, v/v). Reaction
conducted under O2 atmosphere. cReaction conducted without Ac2O.
Inspired by recent advances in the ortho-C–H oxidation of N-
phenylacetamides,33 we sought to develop a similar transfor-
mation for the desired C17-hydroxylation of fendleridine deriva-
tives. While conditions exist for ortho-hydroxylation of many N-
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acyl-azaheterocycles,34 N-acyl-indolines are a challenging set of
Scheme 6. First total syntheses of (+)-haplocidine (1) and
(+)-haplocine (2)a
1
2
3
4
5
6
7
8
substrates for ortho-functionalization due to the geometry and
distance between the directing amide and the target C–H bond.
Existing methods for introduction of the desired ortho-C–O
bond in simple indolines require the use of toxic lead or thallium
reagents and often give product mixtures.35 Prompted by suc-
cessful indoline ortho-C–H functionalizations to give C–C,36 C–
N,37 C–Se, and C–S bonds,38 we focused on development of the
first transition metal catalyzed indoline ortho-C–H acetoxylation.
Our most promising results involving palladium–catalyzed or-
tho-acetoxylation39 of N-acetylindoline ( )-22a as a model sub-
strate are summarized in Table 2.17 The use of hexafluoroisopro-
panol (HFIP) and acetic anhydride provided the desired acetoxy-
indoline ( )-23a even at 55 °C, but required long reaction times
and high catalyst loadings (Table 2, entries 1–2). Alternatively,
the use of acetic acid and acetic anhydride solvent mixture (10:1,
v/v) as the reaction medium at 100 °C led to faster ortho-
acetoxylation (Table 2, entries 4–6). Notably, lower yields were
observed when the reaction was not purged with dioxygen prior
to heating (Table 2, entry 3). Under optimal conditions, treat-
ment of N-acetylindoline ( )-22a with palladium acetate (15
mol%) and bisacetoxyiodosobenzene (2.5 equiv) in acetic acid
and acetic anhydride at 100 °C under an atmosphere of dioxygen
for 9 h provided acetoxy-indoline ( )-23a in 84% yield (Table 2,
entry 5). While the desired oxidation product was not formed in
the absence of palladium acetate (Table 2, entry 7), the exclusion
of acetic anhydride led to slightly lower yield of acetoxy-indoline
( )-23a (74%, Table 2, entry 8).
–
X3CCO2
+
9
N
+
O2CCX3
OH
N
N
19
O
acylation
a
–O2CCX3
N
N
N
H
H
H
17
17
R
R
R
O
O
O
(+)-4,
(+)-24,
26
25
R=Me
R=Et
9
oxidation
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X3CCO2
OH
+
O2CCX3
+
N
N
N
O
–O2CCX3
1
N
N
H
N
H
H
17
17
17
R
O
O
OH
R
R
OH
O
O
O
R=Me
R=Et
(+)-haplocidine (1),
(+)-haplocine (2),
27
28
CX3
• use of naturally occuring N1-acyl groups for directed C17-hydroxylation
• direct hydroxylation of complex hexacyclic alkaloid substrates (+)-4 and (+)-24
• efficient, final-stage regioselective oxidation to access alkaloids (+)-1 and (+)-2
aReagents and conditions: (a) TFA, TFAA, 60 ºC; Pd(OAc)2 (20 mol%),
PhI(OAc)2 (4 equiv), 75 ºC; MeOH, Et3N. R=Me, 77%. R=Et, 74%.
hydroxylation of fendleridine derivatives (Scheme 6). Initial ef-
forts towards the oxidation of (+)-acetylaspidoalbidine (4) to
(+)-haplocidine (1) by direct application of the mildest condi-
tions developed for N-acetylindoline ( )-22a (Table 2, entry 2)
only returned the starting material. We posited that an unpro-
ductive N9-amine coordination to palladium may outcompete
the N1- amide, consistent with the absence of basic nitrogens in
substrates that efficiently undergo metal-catalyzed C–H func-
tionalization.33–38,42 Thus, we envisioned a strategy to deactivate
the N9-amine by exploiting the reversible opening of the C19-
hemiaminal ether of (+)-acetylaspidoalbidine (4). Heating hexa-
cyclic alkaloid (+)-4 in a mixture of acetic acid and acetic anhy-
dride (10:1, v/v) at 100 ºC for 6 h led to quantitative conversion
to the corresponding C19-iminium acetate ester 26 (X=H,
Scheme 6).17,43 However, application of the mildest oxidation
conditions to C19-iminium acetate ester 26 (X=H) led to no ob-
served product formation. The use of more forcing conditions
with C19-iminium acetate ester 26 (X=H), involving acetic acid
as solvent at 100 ºC, also did not provide the product. Employing
a stoichiometric amount of palladium acetate provided (+)-
haplocidine (1) after hydrolysis, albeit with less than 25% conver-
sion along with recovery of (+)-acetylaspidoalbidine (4).17 At-
tempts at promoting the reaction further through increased tem-
perature, increased amounts of palladium acetate and oxidant,
use of an atmosphere of dioxygen, extended reaction times and
the use of alternate solvents did not result in greater conversion
to (+)-haplocidine (1).17
Scheme 5. Directed C–H oxidation of N-acylindolinesa
Me
Me
a
(±)-23b, R=C(O)t-Bu, 86%
(±)-23c, R=C(O)Et, 82%
(±)-23d, R=C(O)Ph, 59%
N
N
H
H
OAc
R
R
O
O
(±)-22b–d
aReagents and conditions: (a) Pd(OAc)2 (15 mol%), PhI(OAc)2 (2.5
equiv), AcOH, Ac2O, 100 ºC, O2.
Given our interest in the application of this amide–directed or-
tho-acetoxylation to fendleridine derivatives with varying N1-
amides (Scheme 1), we evaluated the relative effectiveness of in-
dolines ( )-22b–d17 as substrates under the optimal conditions
(Scheme 5). Notably, we were able to obtain the ortho-
acetoxylation products ( )-23b–d from the corresponding N-
pivaloyl, N-propionyl, and N-benzoyl indoline amides in 86%,
82%, and 59% yield, respectively.17 The oxidation products ( )-
23b–d were obtained under the standard set of conditions with
excellent level of regioselection. In the case of amide ( )-23b, the
s-cis conformer, the optimal conformer for directed ortho-
acetoxylation, was calculated to be 1.52 kcal/mol lower in energy
than the corresponding s-trans conformer.17,40 In contrast, the
preference calculated for the s-cis conformer for amide ( )-23d
was only 0.13 kcal/mol. Thus, the greater efficacy of substrate
( )-23b compared to amide ( )-23d is consistent with its en-
hanced Lewis basicity and s-cis conformational preference. This
N1-amide directed acetoxylation could be of broader utility given
the prevalence of the N-acyl indoline substructure in various bio-
active molecules and natural products.41
We surmised that the C19-iminum ion increases the energetic
barrier for the C17-electrophilic palladation step compared to
that involved in oxidation of N-acetylindoline ( )-22a. To our
delight, a dramatic increase in the efficiency of the C17-oxidation
was achieved using the C19-iminium trifluoroacetate ester 26
(X=F, Scheme 6) in place of the corresponding C19-iminium ac-
etate ester 26 (X=H, Scheme 6).17,44 We determined that the op-
timal conditions involved the use of trifluoroacetic acid as the
solvent, leading to clean palladium-catalyzed C17-acetoxylation
of C19-iminium trifluoroacetate ester 26 (X=F, Scheme 6), likely
With efficient conditions for the ortho-oxidation of N-acyl in-
dolines ( )-22a and ( )-22c at hand, we proceeded with devel-
opment of a unified strategy for the first total syntheses of (+)-
haplocidine (1) and (+)-haplocine (2) via a final-stage C17-
4
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due to more effective guidance by the N1-amide. In the event,
Corresponding Author
*Email: movassag@mit.edu
1
2
3
4
5
6
7
8
exposure of (+)-acetylaspidoalbidine (4) to trifluoroacetic acid
and trifluoroacetic anhydride (TFAA, 10:1, v/v) at 60 ºC for 4 h,
followed by addition of palladium acetate (20 mol%) and
bisacetoxyiodosobenzene (4.0 equiv) and heating at 75 °C for 16
h gave complete conversion to the desired C17-oxidation prod-
uct 27 (X=F, Scheme 6). Mild methanolysis of C17- and C21-
trifluoroacetates of iminium ion 27 and spontaneous C19-
hemiaminal ether formation of pentacycle 28 directly afforded
(+)-haplocidine (1) in 77% overall yield. All spectroscopic data as
well as the optical rotation data (observed: [α]D24: +207 (c = 0.32,
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We acknowledge financial support by NIH-NIGMS (GM089732)
and Amgen. We thank the NSF under CCI Center for Selective
C–H Functionalization (CHE-1205646) for supporting our oxi-
dation studies. K.L.W. acknowledges a National Science Founda-
tion graduate fellowship and an Amgen Graduate Research Fel-
lowship. We are grateful to Prof. Jin-Quan Yu for helpful discus-
sions. We thank Dr. Wen-Tau T. Chang (MIT) for assistance
with the DFT calculations and Dr. German F. Cabrera (MIT) for
discussions related to the Wacker-Tsuji oxidation chemistry.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
CHCl3), lit.: [α]D = +214 ±7 (c = 0.354)) for our synthetic (+)-
haplocidine (1) were in agreement with the literature.2a Further-
more, prompted by the flexibility of this oxidation reaction with
respect to the N1-amide (Table 2, Scheme 5) we prepared N-
propionylaspidoalbidine (+)-24 (Scheme 6)17 via N1-n-
propionylation of (+)-fendleridine (3). Exposure of substrate (+)-
24 to the optimal C17-oxidation conditions described above di-
rectly provided (+)-haplocine (2) in 74% yield. All spectroscopic
data as well as the optical rotation data (observed: [α]D24: +180 (c
= 0.23, CHCl3), lit.: [α]D24: +193 (CHCl3)) for (+)-haplocine (2)
were consistent with the literature.2a Importantly, the application
of this amide directed ortho-acetoxylation of indolines, com-
bined with our strategic use of the pentacyclic C19-iminium ion
26 (X=F) provided (+)-haplocidine (1) and (+)-haplocine (2) in a
single-step from (+)-acetylaspidoalbidine (4) and (+)-
propionylaspidoalbidine (24), respectively. This C–H oxidation
chemistry bodes well for future access to derivatives of these al-
kaloids.33–39,45
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7 offered a unified approach to C19-
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2014, 136, 17302. (g) Dong, J. J.; Browne, W. R.; Feringa, B. L. Angew.
Chem. Int. Ed. 2014, 54, 734.
(24) The chiral auxiliaries included 1,2-diphenylethane-1,2-diamine
and tryptophan, menthol, and camphor based carboxylate derivatives.
(25) For a selection of reviews on the use of enzymatic resolution in
synthesis see: (a) Sih, C. J.; Wu, S. H. Topics Stereochem. 1989, 19, 63. (b)
Chen, C.-S.; Sih, C. J. Angew. Chem. Int. Ed. Engl. 1989, 28, 695. (c) Bo-
land, W.; Frössl, C.; Lorentz, M. Synthesis 1991, 1049. (d) Faber, K.; Riva,
S. Synthesis 1992, 895. (e) Theil, F. Chem. Rev. 1995, 95, 2203.
(41) (a) Reina, M.; Ruiz-Mesia, W.; Lopez-Rodriguez, M.; Ruiz-Mesia,
L.; Gonzalez-Coloma, A.; Martinez-Diaz, R. J. Nat. Prod. 2012, 75, 928.
(b) Rasoanaivo, P.; Palazzino, G.; Nicoletti, M.; Galeffi, C. Phytochemistry
2001, 56, 863.
(42) For recent examples for oxidation conditions that circumvent
non-productive Lewis basic nitrogen coordination, see: (a) Howell, J. M.;
Feng, K. B.; Clark, J. R.; Trzepkowski, L. J.; White, M. C. J. Am. Chem.
Soc. 2015, 137, 14590. (b) Adams, A. M.; Du Bois, J.; Malik, H. A. Org.
Lett. 2015, 17, 6066. (c) Moretti, R. A.; Du Bois, J.; Stack, T. D. P. Org.
Lett. 2016, 18, 2528.
(26) (a) Cambou, B.; Klibanov, A. M. J. Am. Chem. Soc. 1984, 106,
2687. (b) Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupaty, M.; Leazer, J.
L.; McNamara, J. M.; Sidler, D. R.; Reider, P. J.; Grabowski, E. J. J. Org.
Chem. 1990, 55, 6252. (c) Mizuguchi, E.; Takemoto, M.; Achiwa, K. Tet-
rahedron: Asymmetry 1993, 4, 1961. (d) Soriente, A.; Laudisio, G.;
Giordano, M.; Sodano, G. Tetrahedron: Asymmetry 1995, 6, 859. (e) Ors,
M.; Morcuende, A.; Jimenez-Vacas, M. I.; Valverde, S.; Herradón, B. Syn-
lett 1996, 449. (f) Goj, O.; Burchardt, A.; Haufe, G. Tetrahedron: Asym-
metry 1997, 8, 399. (g) Isleyen, A.; Tanyeli, C.; Dogan, O. Tetrahedron:
Asymmetry 2006, 17, 1561. (h) Chen, H.; Nagabandi, S.; Smith, S.;
Goodman, J. M.; Plettner, E. Tetrahedron: Asymmetry 2009, 20, 449. (i)
(43) Conversion of (+)-acetylaspidoalbidine (4) to the corresponding
1
iminium acetate ester 26 (X=H) is consistent with the observed H NMR
deshielding of the C8-, C10-, and C21-resonances by approximately 1, 1,
and 0.5 ppm, respectively.
(44) Under similar conditions using excess Pd-catalyst and oxidant,
the acetate 26 (X=H) and the trifluoroacetate 26 (X=F) were converted
to the desired product (+)-1 to 18% and 75%, respectively.
(45) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788. (b) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.;
Tang, R.-Y.; Movassaghi, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136,
10807.
Forró, E.; Schönstein, L.; Fülöp, F. Tetrahedron: Asymmetry 2011, 22,
1255.
(27) Schönstein, L.; Forró, E.; Fu
2013, 24, 202.
̈löp, F. Tetrahedron: Asymmetry
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1
2
3
4
(9 cm x 3-1/2 cm)
5
6
7
8
9
OH
O
N
N
N
21
final-stage
oxidation
double
cyclization
19
19
O
O
21
complexity
generation
natural
product
derivatization
A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
H
H
17
R
R
17
PMB
OH
(+)-acetylaspidoalbidine,
(+)-fendleridine,
(+)-haplocidine,R=C(O)Me
(+)-haplocine, R=C(O)Et
R=C(O)Me
R=H
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