Total Synthesis of the Norhasubanan Alkaloid Stephadiamine

Article abstract of DOI:10.1021/jacs.8b01918

(+)-Stephadiamine is an unusual alkaloid isolated from the vine Stephania japonica. It features a norhasubanan skeleton, and contains two adjacent α-tertiary amines, which renders it an attractive synthetic target. Here, we present the first total synthes

Full text of DOI:10.1021/jacs.8b01918

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Article
Total Synthesis of the Norhasubanan Alkaloid Stephadiamine
Nina Hartrampf, Nils Winter, Gabriele Pupo, Brian M. Stoltz, and Dirk Trauner
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01918 • Publication Date (Web): 11 Jun 2018
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Total Synthesis of the Norhasubanan Alkaloid Stephadiamine
a
a
c
d
a,b*
Nina Hartrampf, Nils Winter, Gabriele Pupo, Brian M. Stoltz, and Dirk Trauner
a
Department of Chemistry, University of Munich, Butenandtstraße 5ꢀ13, Munich 81377, Germany
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Department of Chemistry, New York University, 100 Washington Square East, Room 712, New York, NY 10003,
Email: dirktrauner@nyu.edu
c
University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.
d
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
Supporting Information Placeholder
which contains the benzylic oxygen often found in hasuꢀ
banan alkaloids.
ABSTRACT: (+)ꢀStephadiamine is an unusual alkaloid
isolated from the vine Stephania japonica. It features a
norhasubanan skeleton, and contains two adjacent αꢀ
tertiary amines, which renders it an attractive synthetic
target. Here, we present the first total synthesis of stephꢀ
adiamine, which hinges on an efficient cascade reaction
to implement the aza[4.3.3]propellane core of the alkaꢀ
Scheme 1. Natural products related to stephadiamine
and retrosynthesis.
loid. The
αꢀaminolactone moiety in a highly hindered
position was installed via Tollens reaction and Curtius
rearrangement. Useful building blocks for the asymmetꢀ
ric synthesis of morphine and (nor)hasubanan alkaloids
are introduced.
INTRODUCTION. Morphine and hasubanan alkaloids
have inspired synthetic chemists for decades. Following the
[1]
pioneering work of Gates in 1952, more than 30 total and
[
2]
formal syntheses of morphine (1) have been published,
[3]
some of them very recently. Many syntheses of hasuꢀ
banonine (2) and its congeners have appeared in the literaꢀ
ture since the isolation of the first hasubanan alkaloid was
reported by Konto et al. in 1951. Therefore, it is surprisꢀ
ing that one of the most beautiful and challenging moleꢀ
cules in the series, viz. stephadiamine (3), has been virtualꢀ
ly ignored by the synthetic community.
[4]
INITIAL SYNTHETIC PLAN. Motivated by these unuꢀ
(
+)ꢀStephadiamine (3) was isolated from the snake vine
sual structural features and our general interest in hasuꢀ
Stephania japonica in 1984 by Taga et al. and is the only
example of a norhasubanan alkaloid, which features a conꢀ
tracted Cꢀring. The absolute configuration of the natural
product was elucidated by single crystal Xꢀray analysis of a
benzoylated derivative of 3. Although S. japonica is used in
traditional Chinese medicine to treat asthma, fever and
[8]
banan alkaloids, we set out to explore the synthesis of
stephadiamine (3). Our initial strategy called for the instalꢀ
[5]
lation of both
αꢀtertiary amines and the [4.3.3]ꢀ
azapropellane core through a lateꢀstage and intramolecular
cisꢀ1,2ꢀdiamination (Scheme 1). The requisite diamination
substrate 4, a cyclopentene carboxylate, could be traced
back to conjugated ester 5 via reductive aldol condensation.
[6]
digestive disorders, the biological activity of stephadiaꢀ
mine (3) has yet to be established due to a paucity of mateꢀ
rial. Structurally, 3 features a unique pentacyclic skeleton
arranged around an aza[4.3.3]propellane core. It bears a
total of four stereocenters, including a benzylic quaternary
carbon and two adjacent αꢀtertiary amines in a cisꢀ1,2 relaꢀ
Ketone 5, in turn, could be accessed from the known
βꢀ
[9]
tetralone 6. Tetralones with this substitution pattern are
popular intermediates in the synthesis of hasubanan and
[
10
]
morphinan alkaloids, but most reported preparations are
lengthy, require expensive catalysts and starting materials,
[7]
tionship. One of these is part of an
αꢀamino
δ
ꢀlactone
[ ]
9
or are difficult to scale up. We therefore first set out to
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develop a oneꢀpot procedure starting from the commercialꢀ
ly available carboxylic acid 7.
sary in this reaction to prevent competing cyclization to the
corresponding benzofuranone by participation of the adjaꢀ
1
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6
[11]
cent methoxy group. Alkylation of 6 with bromoacetoniꢀ
[12]
Scheme 2. Synthesis of tetralone 8 and attempted
aldol condensation.
trile under Stork conditions, followed by conversion to
the enol carbonate and decarboxylative Tsuji allylation
yielded tetralone 8 as a racemate with the benzylic quaterꢀ
[13]
nary stereocenter in place. A subsequent cross metathesis
with methyl acrylate then provided the conjugated ester 5
[14]
in excellent yield.
DISCOVERY OF A CASCADE REACTION. With ester
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in hand, we investigated a reductive aldol reaction to
[15]
form the fiveꢀmembered ring.
Using Stryker’s reagent,
we only isolated the 1,4ꢀreduction product (11) accompaꢀ
nied by lactone 9, which is presumably formed by attack of
a tertiary alkoxide onto the nitrile followed by hydrolysis,
and trace amounts of the anticipated aldol product 10. Alꢀ
ternative hydride sources such as
LꢀSelectride,
Rh(cod) OTf/PPh /H , and a copper hydride formed in situ
2
3
2
from Cu(OAc) , TMDS, and racꢀBINAP only increased the
2
yield of 9 (Scheme 2 and SI). The single crystal Xꢀray
structure of 9 revealed a perfect antiꢀperiplanar arrangeꢀ
ment of the C–Hꢀbond next to the methyl ester and the
lactone C–O bond. Despite this, we were unable to promote
an elimination to the corresponding cyclopentene carboxꢀ
ylate.
Next, we attempted the aldol addition under conditions,
a
Reagents and conditions: (a) oxalyl chloride (1.2 eq.), DMF (cat.),
which could enable the clean isolation of
βꢀhydroxy ketone
CH
32 °C, 6 h, 48% over 2 steps; (c) pyrrolidine (1.3 eq.), toluene, MgSO
100 °C, 24 h, then BrCH CN (1.6 eq.), 100 °C, 28 h, 89%; (d) NaH
1.1 eq.), THF, 0 °C, 30 min, then allyl chloroformate (1.0 eq.), 0 °C, 1 h,
8%; (e) Pd (dba) (2.5 mol%), PPh (6.25 mol%), r.t., 12 h, 84%; (f) HG
II (7 mol%), methyl acrylate (15 eq.), toluene, 48 h, 97%; (g)
Cu(OAc) ·H O (0.5 eq.), racꢀBINAP (0.5 eq.), TMDS (1 eq.), THF, r.t.,
HCl, r.t., 1 h, 60%. BINAP = 2,2'–Bis(diphenylphosphino)–
2 2 3
Cl , 0 °C, 10 min, then r.t., 3 h; (b) AlCl (6 eq.), ethene (1 atm),
1
0 with the nitrile intact (Scheme 2). In preparation for this,
−
4
,
we hydrogenated 5 to obtain the saturated ester 11. Upon
exposure of 11 to in situ generated sodium methoxide in
methanol at 75 °C, we isolated two new products in excelꢀ
lent combined yield. To our pleasant surprise, these were
identified as the pyrrolidinone 16 and its C7ꢀepimer 17,
both of which contain the aza[4.3.3]propellane core of
stephadiamine (3) (Scheme 3). They are formed in a reacꢀ
tion cascade that presumably involves a transiently formed
2
(
9
2
3
3
2
2
2
1
4 h → 1 M
,1'–binaphthyl; dba = dibenzyliꢀdeneacetone, HG II = Hoveyda−Grubbs
nd
cat. 2 generation, TMDS = 1,1,3,3ꢀtetramethyldisiloxane
Conversion of 7 to the corresponding acyl chloride, folꢀ
ester
enolate
12.
lowed by treatment with AlCl under an ethene atmosphere
3
provided tetralone 6 in good overall yield and on a multiꢀ
[ ]
9
gram scale (Scheme 2). Low temperatures were necesꢀ
Scheme 3. Cascade reaction for the construction of the aza[4.3.3]propellane core.
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a
Reagents and conditions: (a) PdꢀC (10wt%), H
mmol scale.
2
(1 atm), EtOAc, r.t., 12 h, 97%; (b) Na (1.2 eq.), MeOH, 75 °C, 24 h, 91% on 24 mmol scale, 99% on
3
1
2
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7
8
9
alcohol smoothly gave the Cbzꢀprotected cisꢀ1,2ꢀdiamine
21.
Intramolecular aldol addition then affords alkoxide 13,
which undergoes addition to the nitrile, elimination of the
intermediary imidate (14→15), and conjugate reꢀaddition
in an azaꢀMichael reaction to yield the diastereomeric pyrꢀ
Scheme 4. Installation of the diamine.
rolidinones. This sequence of events resembles a casca[d16e]
that was used in Inubushi’s synthesis of cepharamine,
although in our case we construct a different heterotricyclic
system with an additional stereocenter in a remarkably
efficient overall reaction.
1
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INSTALLATION OF THE DIAMINE. At this point,
completion of stephadiamine (3) formally required Nꢀ
methylation,
αꢀamination and closure of the lactone via
benzylic functionalization. While the first task could be
achieved by treating the diastereomeric mixture of lactams
1
6 and 17 with NaH and MeI, the second turned out to be
exceedingly difficult due to the steric hindrance of the
azapropellane system.
Attempted deprotonation of 16/17 and exposure to a variety
of electrophilic amination reagents failed to give any idenꢀ
tifiable products and mostly resulted in the recovery of
starting materials. Similarly, carboxylation under a variety
of conditions, which was intended to enable a Curtius rearꢀ
rangement for the installation of the second
αꢀtertiary
amine, were unsuccessful. In addition, all efforts to epimerꢀ
ize the ester and to form a silyl ketene acetal failed, sugꢀ
gesting that the deprotonation step was the source of our
frustrations.
In an attempt to increase the acidity of the αꢀhydrogen, we
reduced the ester moiety to the corresponding aldehyde 18
using DIBALꢀH. Again, we only observed either decompoꢀ
sition or no reaction when we tried αꢀaminations or carꢀ
boxylation reactions. We therefore decided to resort to
chemistry that would employ one of the smallest base and
electrophile combinations possible: the Tollens reaction
(aldol reaction followed by crossed Cannizzaro
[17]
reaction). Exposure of aldehyde 18 to an excess of KOH
and formaldehyde at elevated temperatures over two days
afforded diol 19, which features a quaternary carbon in a
highly congested position.
a
Reagents and conditions: (a) NaH (1.2 eq.), MeI (1.2 eq.), DMF, 30 °C,
To convert the 1,3ꢀdiol into the αꢀamino lactone moiety we
1
4 h, 91%; (b) DIBALꢀH (2.5 eq.), CH
(10 eq.), formaldehyde (10 eq.), MeOH, 50 °C, 48 h, 41% (d) DDQ
10 eq.), AcOH (10 eq.), 4Å MS, DCE, 75 °C, 5 h, 92%; (e) TPAP
(0.05 eq.), NMO (10 eq.), 4Å MS, CH Cl , r.t., 1 h, 93%; (f) NaClO
(9.2 eq.), NaH PO (9.2 eq.), 2ꢀmethylꢀ2ꢀbutene, tꢀBuOH/H O, r.t., 3 h,
6%; (g) DPPA (1.5 eq), NEt (3 eq.), toluene, r.t., 1 h, then 100 °C, 1 h,
then BnOH (5 eq.), 100 h, 14 h, 84%; (h) BF  OEt (30 eq.), Ac O, 0 °C
2 2
Cl ,  78 °C, 3.5 h, 79%; (c) KOH
tried to oxidize it to the corresponding malonate or carboxy
lactone. This failed, as did our efforts to selectively protect
one of the two primary alcohols. Therefore, we decided to
differentiate them via benzylic oxidation. After screening
multiple conditions, this could be accomplished using DDQ
(
2
2
2
2
4
2
9
3
3
2
2
[18]
to r.t., 6.5 h, 84%; (i) Boc
r.t., 17 h, 65%; (j) Cs CO
(0.02 eq.), NMO (4.5 eq.), 4Å MS, CH
10 eq.), MeCN, r.t., 24 h, 91 %; (m) I (10 eq.), KOH (10 eq.), MeOH,
r.t., 15 min, 94 %. Cbz = carboxybenzyl, DIBALꢀH = diisobutylaluminum
hydride, DDQ = 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone,
2
O (2 eq.), NEt
(0.5 eq.), MeOH, r.t., 12 h, 96%; (k) TPAP
Cl , r.t., 20 min, 80%; (l) I
3
(2 eq.), DMAP (0.1 eq.), THF,
and AcOH at elevated temperatures yielding pyrane 20.
2
3
[18]
2
2
2
.
With one hydroxymethyl group isolated, we turned to
(
2
the implementation of the second αꢀtertiary amine. To this
end, the primary alcohol 20 was converted to the carboxꢀ
[19]
MS = molecular sieves, TPAP = tetrapropylꢀammonium perruthenate,
NMO = NꢀMethylmorpholine Nꢀoxide, DPPA = diphenylphosphoryl
ylic acid using Ley’s conditions followed by a Pinnick–
[20]
Lindgren oxidation.
Formation of the acyl azide and
.
azide, Boc = tertꢀbutyloxycarbonyl, DMAP = 4ꢀdimethylaminopyridine.
subsequent Curtius rearrangement in the presence of benzyl
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Scheme 5. Completion of the synthesis.
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a
2 3
Reagents and conditions: (a) NBS (1.05 eq.), H O/THF, 0 °C, 90 min. then r.t., 90 min., 50%; (b) Bu SnH (10 eq.), AIBN (1 eq.), benzene, 90 °C, 3 h,
9
8%.; (c) DMS
BH (10 eq.), THF, 0 °C to r.t., 20 h, then 0 °C, AcOH, 57%, 99% brsm; (d) TFA, DCM, 0 °C, 90 min, <90%. NBS = Nꢀ
3
bromosuccinimide, AIBN = α,α′ꢀazoꢀisobutyronitrile.
ble conformation of the ester. Using NBS in the presence
COMPLETION OF THE SYNTHESIS. At this stage,
the completion of the synthesis would only require reducꢀ
tion of the lactam in 21, oxidation of its tetrahydropyran
to a lactone and deprotection of the primary amine. Altꢀ
hough we were aware that chances were slim due to the
presence of a benzylic C,Hꢀbond and a very electronꢀrich
rich aromatic ring, we first explored the oxidation under a
variety of conditions (RuO , KMnO , CrO , DMDO,
of H O, however, we were able to regioꢀ and stereoselecꢀ
2
tively install an intermediate bromohydrin 27, characterꢀ
ized by mass spectrometry, which subsequently underꢀ
[24]
went lactonization. The secondary bromide of the reꢀ
sultant halolactone 28 was removed under radical condiꢀ
tions to obtain the pentacyclic lactone 29, the structure of
which was confirmed by single Xꢀray analysis. In the
final steps of the synthesis, the lactam moiety in 29 was
reduced to the corresponding pyrrolidine using borane
4
4
3
White–Chen catalyst).
[25]
dimethyl sulfide complex.
Close monitoring of the
Since none of the conditions led to any isolable products,
we abandoned the direct oxidation of the ether 21 and
decided to cleave the C11–O bond and oxidize C8 to the
corresponding carboxylic acid followed by reclosure of
the heterocycle. The reductive opening of benzylic ethers
is a common transformation that can be achieved via
reaction was crucial to avoid competing reduction of the
strained yet sterically hindered sixꢀmembered lactone.
Acidic deprotection of the primary amine finally gave
racemic stephadiamine (3). The deprotection step was
carried out in deuterated dichloromethane and monitored
by NMR as slow cleavage of the lactone was observed
upon exposure to TFA. The analytical data of synthetic 3
were in complete agreement with the limited data availaꢀ
ble from the original publication.
hydrogenation or Lewis acid activation and hydride transꢀ
[21]
fer.
However, exposure of 21 to PtO /H , PdꢀC/H ,
2 2 2
TFA/Et SiH or AcOH/Et SiH failed to promote the reducꢀ
3
3
tive cleavage of the C,O bond. We thus investigated difꢀ
ferent conditions for the conversion of the benzyl ether
into the corresponding styrene via elimination. Since a
variety of Lewis acids (TMSOTf, TMSCl, BF ·OEt ) in
different solvents did not afford the desired product, we
reasoned that the elimination could be reversible and
ASYMMETRIC APPROACH. In parallel to our raceꢀ
mic synthesis, we investigated an asymmetric approach to
(+)ꢀstephadiamine. Since the benzylic quaternary stereoꢀ
center directs the formation of all others stereocenters, we
focused on the asymmetric allylation of 3. Formation of a
chiral imine/enamine and reaction with a variety of elecꢀ
3
2
added TFAA and Ac O to passivate the pendant alcohol.
2
[26]
TFAA decomposed the starting material, but the use of
trophiles was unsuccessful.
Therefore, we turned toꢀ
excess BF ⋅OEt in acetic anhydride allowed for the isolaꢀ
ward modern transition metal catalysis to install the benꢀ
3
2
[27]
tion of oxazolidinone 22. This compound was treated then
zylic quaternary stereocenter (Scheme 4).
metric Tsuji allylation was investigated with a variety of
chiral ligands such as (S)ꢀtꢀBuꢀPHOX (L1), (S)ꢀCF ꢀtꢀBuꢀ
The asymꢀ
with Boc O anhydride and then hydrolyzed to yield Bocꢀ
2
[22]
protected amino alcohol 23.
3
PHOX (L2), (S)ꢀQUINAP (L3), (R,R)ꢀ and (S,S)ꢀDACHꢀ
Phenyl Trost ligand (L4), (R,R)ꢀDACHꢀNaphthyl Trost
ligand (L5) and (R,R)ꢀANDENꢀPhenyl Trost ligand (L6,
Table 1). These were used in different solvents and at
varying concentrations and temperatures. In an initial
screening, we found that a 1:2 mixture of toluene and
hexane was the best solvent, providing the highest ee
value across all ligand classes. The starting material was
consumed in all cases and no sideꢀproducts were obꢀ
served.
The completion the synthesis required careful orchestraꢀ
tion of redox reactions carried out on highly hindered and
sensitive substrates. Ley oxidation of primary alcohol 23
to the corresponding aldehyde 24, followed by attempted
iodine mediated oxidation in acetonitrile, yielded the
unusual oxazolidinone acetal 25. Multiple standard oxidaꢀ
tion conditions, led to similar products or resulted in deꢀ
composition. However, treatment with iodine in methanol
[23]
cleanly yielded methyl ester 26. Since this ester could
not be hydrolyzed under a variety of conditions, we atꢀ
tempted the direct cyclization to lactone 28 or 29. Acidꢀ
catalyzed lactonization and conventional halolactonizaꢀ
tions were unsuccessful, presumably due to an unfavoraꢀ
The ligand (S)ꢀtꢀBuꢀPHOX only gave 6% ee, whereas the
electronꢀdeficient congener (S)ꢀCF
ꢀtꢀBuꢀPHOX provided
3
38% ee (entries 1 and 2). (S)ꢀQUINAP gave a very low ee
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of 11% (entry 3), whereas the C ꢀsymmetric (R,R)ꢀ
DACHꢀPhenyl Trost ligand gave the highest ee value
2
7
0.03
−10
−10
120
66%
66%
L6
1
2
3
4
5
6
7
8
9
(entry 6). Related Trost ligands resulted in a decrease of
ee values (entries 4 and 5). Therefore, we decided to opꢀ
timize the reaction for the DACHꢀPhenyl Trost ligand. It
was found that keeping the ligand/Pd (dba) ratio exactly
8a)b)
0.003
5
ent-L6
a
b
(
R)ꢀ8 was observed as the major enantiomer. Conditions: enol carꢀ
bonate (1.0 equiv), Pd
4−10 mol%), ligand (7−12 mol%) in 1:2 toluene:hexane, in glovebox.
the reaction gave the desired (R)ꢀenantiomer in 97% yield. The enantioꢀ
meric excess of this sample could be enriched to 98% ee after recrystalꢀ
lization
2
3
2 3 2 3 3
(dba) or Pd (dba) ꢁCHCl
to 2.2:1 was crucial to obtain a good ee (entry 5). In addiꢀ
tional experiments, we determined that when using this
ligand, the reaction went to completion within minutes
and therefore the reaction time could be shortened to 5
min (entry 6). Ultimately, treatment of the allylic carꢀ
bonate 31 with Pd (dba) in the presence of chiral bisꢀ
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In an effort to improve the enantioselectivity of the reacꢀ
tion, we turned our attention towards enol catalysis,
which was recently introduced by List and coꢀworkers
and allows for the direct regioꢀ and enantioselective funcꢀ
tionalization of unsymmetrical ketones. This is achieved
by employing a chiral phosphoric acid, which selectively
forms the most substituted enol, followed by asymmetric
reaction with an appropriate electrophile. Under the preꢀ
viously reported conditions,
um (0) source and (S)ꢀTRIP (cat. A) as a catalyst, 32
reacted smoothly with allyl methyl carbonate (>95%
conversion, entry 1, Table 2). The desired product (S)ꢀ8
was isolated in 84% enantiomeric excess. Upon switching
2
3
phosphine entꢀL6 gave (R)ꢀ8 in 97% yield and 66% ee
[29]
[28]
(
see SI for details). After a single recrystallization we
obtained an almost enantiomerically pure product, the
absolute configuration of which could by established by
Xꢀray crystallography.
Table 1 Optimization of conditions for the asymꢀ
metric decarboxylative Tsuji allylation.
[27b]
which employ a palladiꢀ
to (S)ꢀH ꢀTRIP (cat. B) as a catalyst, we were able to
increase the enantioselectivity to 86% ee (entry 3).
8
Table 2 Optimization of conditions for the direct
asymmetric αꢀallylation via enol catalysis.
time
Entry
[M]
T [°C]
ee
ligand
[
min]
120
120
120
120
120
120
1
0.03
0.03
0.03
0.03
0.03
0.03
rt
rt
6%
L1
L2
L3
L4
L5
L6
time
cata-
lyst
Entrya)
T [°C]
ee
[M]
[min]
2
38%
11%
29%
27%
59%
3a)
rt
rt
rt
1
2
3
4
0.05
0.025
0.05
rt
rt
rt
rt
18
18
18
36
84%
85%
86%
88%
A
A
B
B
4
5
6
−10
0.025
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Page 6 of 7
Corresponding Author
dirktrauner@nyu.edu
5
B
0.01
0.025
0.025
0.01
rt
96
96
96
96
96
89%
89%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
*
6
15
15
15
10
B
B
ORCID
Dirk Trauner: 0000ꢀ0002ꢀ6782ꢀ6056
7b)
8c)
9d)
88.5%
93%
Brian M. Stoltz: 0000ꢀ0001ꢀ9837ꢀ1528
Nina Hartrampf: 0000ꢀ0003ꢀ0875ꢀ6390
Gabriele Pupo: 0000ꢀ0003ꢀ3084ꢀ3888
B
0.02
90%
ent-B
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
2 3
Conditions: allyl carbonate (1.0 equiv), Pd (dba) (2.5 mol%), chiral
acid catalyst A or B (10 mol%), tꢀBuXPhos (11 mol%) in cyclohexane.
Full conversion by HꢀNMR was observed unless otherwise noted. (a)
Methylcyclohexane was used as solvent; (b) 63% conversion (deterꢀ
mined by 1H NMR), 63% isolated yield; (c) 85% conversion (deterꢀ
mined by 1H NMR), 81% isolated yield
Upon further optimization of the reactions conditions, the
desired product was isolated in 63% yield (97% brsm)
and 93% ee (entry 8) or in 81% yield (96% brsm) with
Notes
1
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We would like to acknowledge Dr. Anastasia Hager and
Dr. Dominik Hager for their contributions in the early
stages of this project. The authors thank Dr. Hong−Dong
Hao and Dr. Julius R. Reyes for experimental assistance,
Dr. Scott Virgil and René Rahimoff for assistance with
HPLC and Dr. Peter Mayer for Xꢀray structure analysis.
Additionally, we acknowledge the Deutsche Telekom
Foundation (Ph.D. fellowship to N.H.), the LMUMentorꢀ
ing program (fellowship N.H.), the Otto Bayer Scholarꢀ
ship (fellowship to N.H.) as well as the Deutsche Forꢀ
schungsgemeinschaft (SFB 749 and CIPSM) for generous
9
0% ee (entry 9).
CONCLUSIONS. In summary, we have achieved the
first synthesis of the unusual alkaloid stephadiamine (3),
in racemic form. Our synthesis is marked by a practical βꢀ
tetralone synthesis, the facile construction of the benzylic
quaternary center through twofold alkylation, and a reꢀ
markably efficient cascade to forge the azapropellane core
of 3. The installation of the αꢀamino lactone moiety
proved to be difficult but could eventually be achieved
using a very small base and electrophile. It also required a
carefully orchestrated sequence of oxidation and reducꢀ
tions in a densely functionalized setting. Finally, we have
elaborated a pathway for the asymmetric synthesis of
stephadiamine. The building blocks developed in this
context, (R)ꢀ8 and (S)ꢀ8, could serve as valuable intermeꢀ
diates in the synthesis of a variety of hasubanan and morꢀ
phine alkaloids, respectively.
funding.
B.M.S.
thanks
the
NIHꢀNIGMS
(
R01GM080269) for partial financial support of this proꢀ
ject. Dr. Felix Hartrampf and Dr. Julius R. Reyes are
acknowledged for excellent support in the course of this
project and with the preparation of this manuscript.
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