Total synthesis of stemaphylline N-oxide and related c9a-epimeric analogues

Article abstract of DOI:10.1002/chem.201302669

Winning the relay: The first total synthesis of stemaphylline N-oxide has been completed utilizing a bistandem relay ring-closing-metathesis (RRCM) strategy, necessitated by the conformation of the requisite tetraene. This effort also gave unnatural 9a-ep

Full text of DOI:10.1002/chem.201302669

COMMUNICATION
DOI: 10.1002/chem.201302669
Total Synthesis of Stemaphylline N-Oxide
and Related C9a-Epimeric Analogues
Michael L. Schulte,[b] Mark L. Turlington,[b] Sharangdhar S. Phatak,[b] Joel M. Harp,[b]
Shaun R. Stauffer,[b] and Craig W. Lindsley*[a]
The Stemona alkaloids represent a class of more than
eighty structurally diverse alkaloids isolated from plants be-
longing to the Stemonaceae family.[1] Structurally these alka-
loids are characterized by the conserved pyrroloACTHNUTRGNE[UNG 1,2-a]aze-
pine core usually linked to a terminal lactone. These plants
have been used in folk medicine in East Asia for thousands
of years to treat the symptoms of bronchitis, pertussis, and
tuberculosis and have been used as antiparasitics in humans
and animals.
Recently, Lie and co-workers disclosed the structures of
two new Stemona alkaloids from the root extracts of Stemo-
na aphylla: stemaphylline (1) and stemaphylline N-oxide
Figure 1. PyrroloACTHUNTGRNEUNG[1,2-a]azepine core and stemaphylline (1) and stema-
phylline N-oxide (2).
(2), featuring the central pyrroloACTHUNTGRNEUNG[1,2-a]azepine core linked
to a 3,5-disubstituted g-lactone moiety (Figure 1).[2] Stema-
phylline was found to have low acetylcholinesterase (AChE)
inhibitory activity, pronounced insecticidal activity, weak an-
timicrobial activity against Escherichia coli, Staphylococcus
aureus, Pseudomonas auruginosa and weak antifungal activi-
ty against Candida albicans.
Due to the unique properties of azabicyclic containing
natural products, our group has developed general methods
for their asymmetric synthesis and applied these methods to-
wards the total synthesis of azabicycle containing natural
products (Scheme 1).[3] This method utilizes nucleophilic ad-
dition of a Grignard reagent containing a protected alde-
hyde to an Ellman chiral aldimine (3),[4] acid-mediated de-
protection and acetal cleavage, and subsequent reductive
amination to form the pyrrolidine ring (4).[4b] Ring-closing
metathesis (RCM) gives the azabicyclic ring system (5).
Scheme 1. Approach for the enantioselective synthesis of azabicyclic ring
systems.[3]
Based on this approach, we planned an enantioselective
total synthesis of stemaphylline, which would allow further
evaluation of its biological activity and the preparation of
unnatural analogues. In addition to construction of the aze-
pine ring through RCM, our retrosynthetic analysis included
concomitant cyclization of the g-lactone from tetraene 7 to
form 6, which would give stemaphylline (1) upon olefin re-
duction. Chiral tetraene 7 would be formed from chiral N-
sulfinyl imine 8, as outlined in Scheme 2. Intermediate 8
represented an attractive point of entry into the preparation
of unnatural analogues, because the nitrogen stereocenter
can be inverted by preparation of the opposite chiral
Ellman N-sulfinyl imine. Preparation of both diastereomers
of aldimine 8 would also provide an opportunity to study
the ability of the chiral Ellman auxiliary to control the
asymmetric Grignard addition to a substrate possessing a
significant Felkin–Anh substrate bias. The C10 and C9 ster-
eogenic centers in intermediate 8 could be installed by oxa-
[a] Prof. C. W. Lindsley
Departments of Pharmacology and Chemistry
Vanderbilt Center for Neuroscience Drug Discovery
12415D MRBIV, Vanderbilt University Medical Center
Nashville, TN 37232-6600 (USA)
Fax : (+1)615-345-6532
E-mail: craig.lindsley@vanderbilt.edu
[b] Dr. M. L. Schulte,+ Dr. M. L. Turlington,+ Dr. S. S. Phatak,
Dr. J. M. Harp, Dr. S. R. Stauffer
Department of Chemistry, Vanderbilt University
7330 Stevenson Center, Station B 351822
Nashville, TN 37235 (USA)
[+] Contributed equally to this work.
Supporting information for this article contains full experimental de-
tails and is available on the WWW under http://dx.doi.org/10.1002/
chem.201302669.
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 2. Retrosynthetic analysis of stemaphylline (1). TBDPS=tert-bu-
tyldiphenylsilyl.
zolidine-mediated asymmetric conjugate addition followed
by asymmetric a-allylation of a,b-unsaturated ester 9. A
Nagao aldol reaction would be used to install the allylic al-
cohol stereogenic center at C12.[5]
Our synthesis began with the precedented Nagao aldol re-
action of thiazolidine thione 10 with acrolein (90% yield
and 5:1 diastereomeric ratio (d.r.)),[5] and was followed by
silyl protection of the allylic alcohol to afford 11. Removal
of the chiral auxiliary with LiBH4, Swern oxidation, and
Horner–Wadsworth Emmons olefination with triethyl phos-
phonoacetate by using the conditions of Masamune and
Roush[6] led to the rapid construction of a,b-unsaturated
ester 12 in 82% yield over three steps. Ester hydrolysis and
coupling of the resultant carboxylic acid with Evans auxili-
ary 13 led to oxazolidinone 9. After some experimentation,
conjugate addition of mono-organocuprate species Li-
Scheme 3. Synthesis of aldimines 8 and 18. a) TiCl4, DIEA, CH2Cl2,
À458C; then acrolein, À788C, 90%, d.r. 5:1; b) TBDPSCl, imidazole,
CH2Cl2, 08C to RT, 92%; c) LiBH4, THF/MeOH, 08C, 93%; d) (COCl)2,
DMSO, Et3N, CH2Cl2, À788C to RT, 98%; e) DBU, LiCl, triethyl phos-
phonate, MeCN, RT, 90%; f) LiOH, THF/H2O (3:1), 558C, 89%;
g) Et3N, PivCl, THF, À788C to 08C; then 13, nBuLi, THF, 788C to 08C,
ACHTUNGTRENNUNG[MeCuI] in the presence of TMSI, as was developed by
Bergdahl,[7] was found to provide better stereocontrol than
the addition of higher-order cuprates, and successfully instal-
led the C10 methyl stereocenter in 90% yield and 17:1 d.r.
Subsequent enolate formation with LiHMDS in the pres-
ence of HMPA and allylation with allyl iodide gave inter-
mediate 14 in 87% yield and 15:1 d.r. (Scheme 3).
À
95%; h) CuI DMS, MeLi, TMSI, THF, À788C, 90%, d.r. 17:1;
i) LiHMDS, HMPA, THF, À788C; then allyl iodide, À458C, 87%, d.r.
15:1; j) H2O2, LiOH, THF/H2O (3:1), 08C to RT, 96%; k) LAH, THF/
Et2O (4:1), 08C, 84%; l) TPAP, NMO, 4 ꢁ molecular sieves, CH2Cl2,
85%; m) (S)- or (R)-tert-butanesulfinamide, Ti
ACHTUNGTRENNUNG
Removal of the oxazolidine chiral auxiliary and reduction
to the primary alcohol in the presence of LiBH4 or LAH
proved to be problematic. Poor yields were obtained (ca.
30%), and degradation of starting material was observed,
presumably due to the steric congestion adjacent to the oxa-
zolidinone. A similar observation was made by Wee and co-
workers with a sterically encumbered substrate, and circum-
vented through adoption of a two-step protocol involving
saponification to the carboxylic acid in the presence of
LiOH/H2O2 and LAH reduction to the desired alcohol.[8]
Employing this procedure proved to be effective for sub-
strate 14, affording the desired primary alcohol in 81%
yield over two steps. Serendipitously, in our efforts to
modify oxazolidine 14, we isolated ring-opened intermediate
15, which could be crystallized to give X-ray suitable crys-
tals. This crystal structure confirmed the correct configura-
tion of the C9, C10, and C12 stereocenters (Figure 2).
TBDPS=tert-butyldiphenylsilyl; DBU=1,8-diazabicyclo
AHCTUNGTRENNUNG
ene; Piv=pivaloyl; DMS=dimethyl sulfide; LiHMDS=lithium bis(tri-
methylsilyl)amide; HMPA=hexamethylphosphoramide; LAH=lithium
aluminum hydride; TPAP=tetrapropylammonium perruthenate; NMO=
N-methylmorpholine oxide.
Ley oxidation and condensation with (S)- and (R)-tert-bu-
tanesulfinamides provided access to chiral N-sulfinyl imines
8 and 18 (Scheme 3). With these substrates in hand, we next
studied the effect of Felkin–Anh substrate control in the
Ellman asymmetric Grignard addition. Initial efforts re-
vealed the large degree of Felkin control for this substrate,
because formation of (2-(1,3-dioxan-2-yl)ethyl)magnesium
bromide (19) in THF and addition to N-sulfinyl imine 8
gave poor selectivity (d.r. 1:1, Scheme 4). In contrast, addi-
tion to N-sulfinyl imine 18, proceeded with much improved
selectivity (d.r. 10:1). These observations are consistent with
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Total Synthesis of Stemaphylline N-Oxide
COMMUNICATION
Table 1. Conditions for Grignard addition of 19 to aldimine 8.[a]
Entry Aldimine 8 [m] RMgX
RMgX [m] Yield [%] d.r.
(20a/20b)
solvent
1
2
3
4
5
0.2
0.2
0.2
0.2
0.1
THF
Et2O
THF
2-MeTHF 3.0
2-MeTHF 3.0
1.0
1.0
3.0
90
n.r.
61
83
86
1:1
–
1:1.5
1:2.7
1:4
[a] In all cases, to a solution of aldimine 8 in CH2Cl2 at À458C was added
Grignard reagent 19 followed by warming to RT and stirring for 18 h.
n.r.=no reaction.
Figure 2. Crystal structure of 15 and confirmation of C9, C10, and C12
stereocenters. CCDC-949920 (15) contains the supplementary crystallo-
graphic data (excluding structure factors) for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
tivity for the undesired stereoisomer 20b (Table 1, entry 4),
and increased dilution of aldimine 8 in CH2Cl2 exacerbated
this effect (Table 1, entry 5). These results suggest that non-
coordinating solvents may deteriorate or reverse the selec-
tivity of the Ellman chiral auxiliary in substrates such as 8.
Unable to improve the selectivity for desired Grignard
addition product 20a, we moved forward with our effort
toward the total synthesis of stemaphylline, as shown in
Scheme 5. Silyl deprotection with TBAF, followed by ester
formation with methacryclic anhydride gave intermediate
22. Nitrogen deprotection and concomitant acetal cleavage
with TFA/H2O, followed by reductive amination in the pres-
[3a,4b]
ence of PS-BH
G
and pyrrolidine allylation with
allyl iodide gave tetraene 7 in 47% yield for the three-step
sequence. The corresponding stereoisomer 23 containing the
opposite amine stereocenter was also synthesized in analo-
gous fashion with similar yield.
With tetraene pyrrolidines 7 and 23 in hand, we began ex-
ploring conditions for the tandem RCM to construct the
azepine ring and g-lactone. Having larger quantities of tet-
Scheme 4. Asymmetric Grignard addition to aldimines 8 and 18. a) 19
(1.0m solution in THF), THF, À458C to RT, 86%. TBDPS=tert-butyldi-
phenylsilyl.
the known sense of stereoinduction observed when employ-
ing (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide 19[3b,4b]
and the Felkin control dictated by the C9 stereocenter in al-
dimines 8 and 18. In an attempt to improve the selectivity
with aldimine 8 to obtain increased quantities of desired
stereoisomer 20a, we further investigated the asymmetric
Grignard reaction (Table 1). Hypothesizing that the chelat-
ing ability of the solvent could play a role in stereocontrol,
we attempted to form Grignard reagent 19 in less-coordinat-
ing Et2O,[4b] but were unsuccessful. Minimizing the amount
of THF present by increasing the concentration of the
Grignard reagent to 3.0m and performing the reaction in
CH2Cl2 led to a slight increase in selectivity (1:1.5); howev-
er, in favor of the undesired stereoisomer. Switching to for-
mation of Grignard 19 in 2-MeTHF further increased selec-
Scheme 5. Synthesis of pyrrolidines 7 and 23. a) TBAF, THF, 08C to RT,
97%; b) methacrylic anhydride, Et3N, DMAP, CH2Cl2 RT, 82 %;
c) i) TFA/H2O, (95:5); ii) PS-BHACHTUNTRGENNUG(OAc)3, DCE, RT; iii) allyl iodide,
K2CO3, DMF, RT, 47% over three steps. DMAP=4-dimethylaminopyri-
dine; DCE = dichloroethane; PS=polymer supported.
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11849

C. W. Lindsley et al.
raene 23 from our studies on
the asymmetric Grignard addi-
tion, we chose to first explore
the tandem RCM with this
substrate. RCM of amine con-
taining substrates are known
to be difficult and require the
use of acid additives to prevent
coordination of the amine to
the ruthenium, which can
result in catalyst poisoning.
Previously, we have successful-
ly employed Grubbs II catalyst
in the presence of TFA and
heating to close azabicylic ring
systems.[3c]
Scheme 6. Tandem RCM of 23. a) TFA (1 equiv), toluene; then 24 (15 mol%), RT; b) 24 (25 mol%), toluene,
908C, 26% yield over two steps; c) CSA (2 equiv), toluene; then 24 (10 mol%), RT, 65%; d) 24 (2ꢂ
10 mol%), 908C, 52% yield over two steps. TFA=trifluoroacetic acid; CSA=camphorsulfonic acid; Mes=
mesityl.
Unfortunately, these condi-
tions were unsuccessful. Al-
though consumption of starting
Table 2. Acid screen for tandem ring-closing reaction.
material and formation of a product corresponding to the
mass of a single ring closure was observed by LC/MS, no
progression toward the desired bis-ring closure product was
observed, and significant decomposition of starting material
occurred.
Entry
Acid [pKa]
G
Ratio 25/23
1
2
3
4
5
6
–
no conv.
1:4.5
1:2.2
>1:20
1:1.3
>20:1
TFA (À0.25)
PTSA (À2.8)
AcOH (4.76)
CSA (1.2)
CSA (1.2)
Grela and co-workers have reported Ru catalyst 24 with
improved reactivity and mild reaction conditions for chal-
lenging RCM reactions including a protected nitrogen-con-
taining azepane ring, as well as a trisubstituted a,b-unsatu-
rated d-lactone.[9] Based on these reports, we hoped to selec-
tively form the azepine ring system by reaction at room tem-
perature, and then to close the g-lactone under elevated
temperatures. Excitingly, this proved to be successful, be-
cause reaction with Grela catalyst 24 in the presence of
TFA (1 equiv) stirring first at room temperature and then at
908C gave the desired bis-ring closure product in 26% yield
(Scheme 6). With this result, we next studied the effect of
the acid on the closure of the azepine ring, examining acids
with a range of pKa values (Table 2). Without an acid addi-
tive, the reaction did not progress, and CSA with a pKa
value in the middle of the acids surveyed was found to pro-
vide the greatest degree of conversion, as was measured by
LC/MS (Table 2, entry 5). Doubling the amount of CSA to
two equivalents was found to greatly improve the efficiency
of the reaction, resulting in complete consumption of tet-
raene 23 within 6 h, and affording 65% isolated yield of pyr-
roloazepine 25.
[a] To as solution of tetraene 23 in toluene, acid was added. After stirring
for 10 min, Grela catalyst (10%) was added, and stirring was continued
at RT for 7 h.
and exhibited comparable activity. Thus, reaction of tetraene
23 in the presence of CSA (2 equiv) and Grela catalyst 24
(3ꢂ10 mol%) gave 26 in 52% isolated yield (Scheme 6).
As shown in Scheme 7, intermediate 26 was carried for-
ward to unnatural analogue 9a-epi-stemaphylline 27 through
olefin reduction employing Pearlmanꢃs catalyst,[10] which
also set the final C14 stereocenter in 95% yield and 7:1 d.r.
Reaction of 27 in the presence of O3 led to the correspond-
ing N-oxide 28 (53% yield).[11]
With successful conditions for the tandem RCM reaction,
we turned our attention toward the synthesis of stemaphyl-
line, subjecting pyrrolidine tetraene 7 to the optimized
With optimized conditions for closure of the azepine ring,
we applied these conditions (Table 2, entry 6) to the tandem
ring closure of tetraene 23, heating the reaction to 908C
after complete conversion to 25. Although conversion to
bis-ring closure product was observed by LC/MS (ca. 20%
conversion), the use of additional catalyst (2ꢂ10 mol%)
and extended heating was required for full conversion of 25
to 26. A small selection of metathesis catalysts were
screened with these optimized conditions (Hoveyda–-
ACHTUNGTRENNUNG
Scheme 7. Synthesis of 9a-epi-stemaphylline and 9a-epi-stemaphylline N-
oxide. a) Pd(OH)2/C, H2, THF, RT, 95%; b) O3, CH2Cl2, À788C, 54%.
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Total Synthesis of Stemaphylline N-Oxide
COMMUNICATION
ed epimerization. Recently,
Hoye and co-workers have de-
veloped a relay ring-closing-
metathesis (RRCM) strategy[13]
to accelerate reactivity for dif-
ficult substrates, and as
a
means to preload the rutheni-
um-metathesis catalyst at a de-
sired olefin to improve selec-
tivity. By incorporating dienes
Scheme 8. Tandem RCM of 7. a) CSA (2 equiv), 1,4-benzoquinone (50 mol%) toluene; then Hoveyda–Grubb-
s II (3ꢂ10 mol%), RT, 48%; b) Hoveyda–Grubbs II (2ꢂ10 mol%), 908C. CSA=camphorsulfonic acid.
tandem RCM reaction conditions with the Grela catalyst
(Scheme 8). Surprisingly, the ring closure proceeded more
slowly, and upon isolation an inseparable mixture of prod-
ucts was obtained. In consideration that olefin migration
could be leading to epimerization, we tested the addition of
1,4-benzoquinone reported to suppress undesirable olefin
migration;[12] however, a mixture of bis-ring closure prod-
ucts, in which the C12 carbon of the lactone was epimerized,
was still observed.
To elucidate when the suspected epimerization was occur-
ring, the reaction was stopped after closure of the azepine
ring in the presence of Hoveyda–Grubbs II, CSA, and 1,4-
benzoquinone at room temperature. Isolation of mono-ring
closure product 29 demonstrated that a single product was
formed and that closure of the g-lactone was the problemat-
ic step (Scheme 8). Unfortunately, subjection of 29 to a vari-
ety of acid additives and RCM catalysts were ineffective in
suppressing the formation of the mixture of products.
In an attempt to gain insight into the differences in reac-
tivity between tetraene 7 and 23 and azepeines 29 and 25,
the four compounds were sketched and minimized using the
MMFF force field to an energy gradient of <0.01 while pre-
serving the stereochemistry. These calculations were per-
formed by using MOE (v2012.10; Chemical Computing
Group; www.chemcomp.com). The resulting global minima
3D structures revealed that tetraene 23 possesses an intra-
molecular hydrogen bond, which could preorganize the sub-
strate for RCM. In contrast, tetraene 7 possesses a more dis-
ordered conformation with the olefins splayed apart provid-
ing a possible rationale for the lower reactivity of tetraene 7
in the RCM reaction. Examination of azepines 25 and 29 re-
vealed a striking difference in the orientation of the a,b-un-
saturated ester and its proximity to the olefin RCM partner.
Although the two olefins in intermediate 25 are in close
proximity, the reacting olefins in 29 are pointed away from
one another. This disfavorable orientation of the g-lactone
in 29 then allows competing reaction pathways or epimeriza-
tion of the C12 stereocenter during the course of the reac-
tion (Figure 3). These data suggest a conformational bias
that supports the observed experimental outcomes; howev-
er, there are many freely rotatable bonds, and solvation is
not accounted for, thus, this ground-state analysis is laden
with caveats, yet provides a partial explanation for the dif-
ferential substrate reactivity.
Figure 3. Energy-minimized 3D structures of 23 (top left), 7 (top right),
25 (bottom left), and 29 (bottom right).
30[14] and 32[15] into intermediate 20a (Scheme 9), we formed
RRCM substrate 33 to determine if directing the formation
of the ruthenium alkylidene would prove beneficial. Reac-
tion at room temperature revealed significant amounts of
truncation products, presumably intermediates 7 and 29.
However, vigorous reflux and argon spurge led to rapid for-
mation of the desired RCM product 6, and excitingly with
only minor epimerization (10:1). Reduction with Pearlmanꢃs
catalyst[10] gave stemaphylline in 62% yield and with 4:1 se-
lectivity at the C12 stereocenter. Spectral and rotation data
of the synthetic material was generally in agreement with
that reported for the natural product 1, though complicated
by the presence of 4:1 ratio of inseparable diastereomeric
products.[2] Further confirmation was achieved by conversion
to stemaphylline N-oxide 2. Attempts to form the N-oxide
in the presence of O3 was ineffective; however, formation
with mCPBA in CH2Cl2 at 08C gave stemaphylline N-oxide
2 in 74% yield, isolated as a single isomer by reverse-phase
chromatography. The synthetic 2 was in complete agreement
with the spectral and rotation data reported, thus complet-
ing the first total synthesis of 3 and, by inference, 2.[2]
From this analysis, we began investigation of methods to
expedite the closure of the g-lactone to prevent the suspect-
Chem. Eur. J. 2013, 19, 11847 – 11852
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11851

C. W. Lindsley et al.
Acknowledgements
The authors acknowledge the Vanderbilt Department of Pharmacology,
VUMC, and the NIH for funding our research, and in particular the
MLPCN (U54MH084659) for the Vanderbilt Specialized Chemistry
Center. The financial support from the Warren Foundation in the form of
the William K. Warren, Jr. Endowed Chair is gratefully acknowledged.
Keywords: alkaloids
·
metathesis
·
stemaphylline
·
stemaphylline N-oxide · total synthesis
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Scheme 9. Synthesis of RRCM substrate 33 and synthesis of stemaphyl-
line 1 and stemaphylline N-oxide 2. a) TBAF, THF, 08C to RT, 97%;
b) 30, MNBA, Et3N, DMAP, CH2Cl2, reflux, 98%; c) i) TFA/H2O, (95:5);
ii) PS-BHACHTUNGTRENNUNG(OAc)3, DCE, RT; iii) 32, K2CO3, DMF, RT, 40% over three
steps; d) CSA (2 equiv), toluene, RT; then Hoveyda–Grubbs II
(20 mol%) reflux, argon spurge, 37%; e) Pd(OH)2/C, H2, THF, RT, 62%;
f) mCPBA, CH2Cl2, 08C, 74%. MNBA=2-methyl-6-nitrobenzoic acid.
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In conclusion, we have completed the first total synthesis
of both stemaphylline 1 (19 steps) and stemaphylline N-
oxide 2 (20 steps) through a tandem bis-RCM strategy, as
well as unnatural 9a-epi-stemaphylline 27 and 9a-epi-stema-
phylline N-oxide 28. The linear tetraene substrate leading to
27 and 28 was suggested by modeling to be preorganized for
the bis-tandem RCM and smoothly gave the desired unnatu-
ral products; however, the tetraene corresponding to natural
1 and 2 was disorganized, leading to lower reactivity and
ruthenium alkylidene-mediated epimerization. Thus, adopt-
ing a RRCM strategy enabled access to 1 and 2. Biological
evaluation of both natural and unnatural analogues is under-
way and will be reported in due course.
[15] S. J. Meek, S. J. Malcolmson, B. Li, R. R. Schrock, A. H. Hoveyda, J.
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Received: July 9, 2013
Published online: August 16, 2013
11852
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Chem. Eur. J. 2013, 19, 11847 – 11852