Total synthesis of (±)-leuconolam: Intramolecular allylic silane addition to a maleimide carbonyl group

Article abstract of DOI:10.1039/c3sc00056g

A concise total synthesis of the plant alkaloid (±)-leuconolam (1) has been achieved. A regio- and diastereoselective Lewis-acid mediated allylative cyclization was used to establish, simultaneously, two adjacent tetrasubstituted carbon centers. Furthermore, an essential arene cross-coupling to a hindered haloalkene was enabled by the use of a novel 2-anilinostannane.

Full text of DOI:10.1039/c3sc00056g

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Total synthesis of (ꢀ)-leuconolam: intramolecular allylic
silane addition to a maleimide carbonyl group†
Cite this: Chem. Sci., 2013, 4, 2262
*
Enver Cagri Izgu and Thomas R. Hoye
Received 8th January 2013
Accepted 13th March 2013
A concise total synthesis of the plant alkaloid (ꢀ)-leuconolam (1) has been achieved. A regio- and
diastereoselective Lewis-acid mediated allylative cyclization was used to establish, simultaneously, two
adjacent tetrasubstituted carbon centers. Furthermore, an essential arene cross-coupling to a hindered
haloalkene was enabled by the use of a novel 2-anilinostannane.
DOI: 10.1039/c3sc00056g
www.rsc.org/chemicalscience
benzenoid ring. Therefore, the molecule is axially chiral around
the arene–alkene C14b–C14a bond. Moreover, the relative
Introduction
Leuconolam (1) is a monoterpenoid bis-lactam alkaloid that has
an interesting and complex polycyclic molecular architecture
shown in panel A of Fig. 1. Goh and co-workers reported the
isolation of 11 from the Leuconotis plants L. griffithii and L.
eugenifolia located in Malaysia.2 This open-ring indole is a
member of the aspidosperma class of anti-mitotic alkaloids.3
Two closely related analogues of 1, rhazinilam4a-c and rhazinal,4d
are shown in panel B. There has been a signicant level of
interest in developing synthesis strategies to construct the
carbon frameworks of the latter alkaloids.5 Leuconolam (1)
distinguishes itself from these pyrrole embedded natural
products by possessing a functionalized a,b-unsaturated car-
binolamide subunit (highlighted in gray, panel A). Some of the
key structural features of 1 are revealed more explicitly by its
single crystal X-ray structure.1b In particular, the styrenyl moiety
and the acetanilide functional group are non-coplanar with the
conguration of the two adjacent stereogenic tetrasubstituted
carbons presents an additional challenge from the perspective
of synthetic chemists.
In 2006 Banwell and co-workers reported the only total
synthesis of 15g [via the PCC oxidation of rhazinilam, which
proceeded to give both 1 and 12a-epi-1 (1 : 1.7 ratio)]. To
establish the complex carbinolamide motif in 1, we envisioned
a Sakurai type6 intramolecular 1,2-addition of an allylic silane to
a maleimide (see 3 to 2, Scheme 1). Such a transformation, if
achieved in a regio- and diastereoselective fashion, would be an
Fig. 1 Structures of leuconolam (1) and analogues rhazinilam and rhazinal.
Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis,
MN 55455, USA. E-mail: hoye@umn.edu; Tel: +1 612-625-1891
† Electronic supplementary information (ESI) available: Experimental procedures
for preparation of, full characterization data for, and copies of NMR spectra of new
compounds. See DOI: 10.1039/c3sc00056g
Scheme 1 Retrosynthetic analysis of 1.
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especially productive disconnection because the two adjacent
The Ireland–Claisen rearrangement was used to install the
tetrasubstituted carbon centers as well as the ethylene branch of desired C–C double bond at the b-position of the silyl moiety.
the monoterpenoid would be formed in a single step. Herein we In situ trapping of the lithium enolate (LDA/HMPA/THF) with
describe our efforts that led to a concise total synthesis of TBSCl9 was followed by facile (#ambient temperature) [3,3]-
(ꢀ)-leuconolam (1). Our strategy for construction of 1 included sigmatropic rearrangement, which gave the TBS-ester 11 aer
the following (Scheme 1): Ireland–Claisen rearrangement of 4 an aqueous workup. The E-conguration of the alkene was
followed by Mitsunobu displacement to give maleimide 3, determined by nOe experiment. One pot ethoxyethyl (EE)
intramolecular allylative ring closure within 3 to provide 2, cleavage-methyl esterication was done by treatment of 11 with
arylation
macrolactamization.
(arene–alkene
cross-coupling)
of
2,
and methanolic HCl. Mitsunobu displacement of the resulting
alcohol 12 with either of the furan protected maleimide
derivatives 13a or 13b afforded, following thermolysis, 3a or
3b, each in $80% yield. Initial attempts to succeed a direct
displacement with the parent maleimides gave considerably
Results and discussion
lower yields of 3a (41%) and 3b (13%), possibly due to their
propensity to oligomerize under the somewhat basic reaction
conditions.10
Our synthesis commenced with construction of the Ireland–
Claisen rearrangement precursor 4 from methallyl alcohol (6,
Scheme 2). SN2-Alkylation occurred at the more reactive allylic
position of the dianion of 67 (the C-terminus) with bromide 5.8
We transformed the primary alcohol 8 to the ester 4 by
employing a 3-step procedure: (i) Swern oxidation; (ii) 1,2-
addition of (trimethylsilyl)methylmagnesium chloride (7, cf.
Scheme 1) to the resulting aldehyde; and (iii) acetylation of the
secondary alcohol 9. The acetate 4 was prepared on an ca. 10
gram scale and in 66% overall yield from 8.
We then turned to a study of the critical cyclization reaction
between allylic silane and maleimide moieties. Unimolecular
Sakurai-type6a C–C bond forming processes are known, but
have rarely been used to construct adjacent (vicinal) tetrasub-
stituted centers.11 To nd robust and functional group tolerant
allylative ring closure conditions, we screened various Lewis-
acid activators using 3a as the test substrate (Table 1). This
symmetrical imide was particularly useful for analyzing
the reaction outcomes because the allylation step was not
confronted by any regioselectivity issues, as in the case for the
3-substituted maleimides 3b–e. One obstacle we encountered
during the optimization of the ring closure was the formation
of the protodesilylation12 by-product 15 (entries 2–4).
Gratifyingly, use of MeAlCl2 (4 equiv., entry 5)13 facilitated the
desired 1,2-addition of the allylic silane onto the maleimide
carbonyl group in excellent yield (88%) and diastereoselectivity
(42 : 1 by 1H NMR). Subsequent cyclizations on the
substituted analogs 3b–e also proceeded with good to excellent
levels of diastereoselectivity (Scheme 3). The relative congu-
ration of the major diasteromer, although not conrmed until
the completion of the synthesis and correlation with the leu-
conolam structure, was predicted to be that shown in
Table 1 Screening Lewis acids for the key allylative cyclization
Scheme 2 Synthesis of the allylative ring closure precursors. Reagents and
conditions: (a) n-BuLi (2.2 equiv.), TMEDA (2.0 equiv.), Et2O, ꢁ78 to ꢁ10 ꢂC, 12 h; 5
(1.1 equiv.), ꢁ78 to 0 ꢂC, 12 h, 52%; (b) (COCl)2 (1.2 equiv.), DMSO (1.3 equiv.),
Et3N (3.0 equiv.), CH2Cl2, ca. ꢁ65 ꢂC, 85%; (c) 7 (1.3 equiv.), Et2O, ꢁ10 ꢂC, 80%; (d)
AcCl (1.2 equiv.), pyr (1.5 equiv.), DMAP (0.2 equiv.), CH2Cl2, 0 ꢂC, 97%; (e) LDA
(1.2 equiv.), HMPA (1.0 equiv.), TBSCl (1.2 equiv.), THF, ꢁ78 ꢂC, 85%; (f) AcCl (1.0
equiv.), MeOH, rt, 81%; (g) 13a or 13b (1.3 equiv.), DIAD (1.5 equiv.), PPh3 (1.5
equiv.), THF, ꢁ10 ꢂC; (h) toluene, 100 ꢂC, 80–82% over 2 steps. (i) o-(Tributyl-
stannyl)nitrobenzene (1.5 equiv.), Pd2(dba)3$CHCl3 (0.1 equiv.), AsPh3 (0.4 equiv.),
DMF, rt, 91%; (j) o-(tributylstannyl)aniline (1.3 equiv.), Pd2(dba)3$CHCl3 (0.1
equiv.), AsPh3 (0.4 equiv.), DMF, rt, 82%; (k) NaI (5.5 equiv.), acetone, reflux, 94%;
TMEDA ¼ N,N,N0,N0-tetramethylethylenediamine, DMAP ¼ 4-(dimethylamino)
pyridine, LDA ¼ lithium diisopropylamide, HMPA ¼ hexamethylphosphoramide,
TBSCl ¼ tert-butyldimethylsilyl chloride, DIAD ¼ diisopropyl azodicarboxylate.
Entry
LA (equiv.)
Time (min)
14a
15
1
2
3
4
5
Ti(O-iPr)4 (10)
TiCl4 (2)
TMSOTf (2)
BF3$OEt2 (2)
MeAlCl2 (4)
60
15
15
15
10
no reaction
0%
0%
0%
43%
95%
80%
0%
88% (dr 42 : 1)
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the enone system (cf. dHa ¼ 6.17 vs. dHb ¼ 6.86 ppm,
respectively). Therefore, we turned our attention to cyclization
of the halogenated maleimide substrates 3b and 3e, the latter
of which was prepared from the former by treatment with NaI
in reuxing acetone17 (cf. Scheme 2). Each of these substrates
efficiently closed to the desired b-halo-carbinolamide 14b or
14e, respectively, in ca. 85% yield and, more importantly, with
high levels of both regio- and diastereoselectivity (Scheme 3,
panel B). As mentioned earlier, the geometry depicted in panel
C serves to rationalize the preferred mode of addition. We
speculate that s-inductive effect of the halogen substituent
activates the adjacent carbonyl.
We next focused on the arylation of the hindered
halides 14b and 14e with the Stille cross-coupling partners 17–
20 (Scheme 4). The bromide 14b proved to be an
ineffective substrate under all conditions we examined. Simi-
larly, the iodide 14e failed to provide any of the nitro- or
BocHN-derivative 14c or 14f using the known organostannanes
1715 and 18,18 respectively. A trace of the required aniline
product 14d19 was observed using the more electron-rich ani-
linostannane 19.16 Gratifyingly, using the sterically less bulky
Stille donor o-(trimethylstannyl)aniline (20),16 which we
expressly designed for this application, we were successful in
arylation of 14e to furnish 14d in 74% yield. The near-neutral
conditions used for this cross-coupling [Pd2(dba)3$CHCl3/
AsPh3 at room temperature] were tolerant of the base-sensitive
iodo-carbinolamide 14e. This novel organostannane (20)
allowed for direct introduction of the ortho-aminophenyl
substituent in unprotected form, a transformation of broader
interest.
To prepare 14d for the macrolactamization, it was necessary
to saponify the methyl ester. Reagents used previously to
perform late-stage methyl ester hydrolysis in rhazinilam
syntheses [namely, NaOH,5c,e,j KOH,5g Ba(OH)25h] or potassium
trimethylsilanolate (KOTMS) proved ineffective, presumably
because of the base sensitivity of the carbinolamide in 14d.
Gladly, use of a limited amount of LiOH-monohydrate (3 equiv.)
in aqueous THF served to effect this transformation cleanly,
Scheme 3 Panel A. Cyclizations of maleimides containing an aromatic substit-
uent (3c and 3d) proceed with undesired regioselectivity. Panel B. Cyclizations of
maleimides containing a halogen substituent (3b and 3e) proceed with desired
regioselectivity (and diastereoselectivity). General procedure for the allylative ring
closure: imide (3b–e, 1.0 equiv., 0.05 M), MeAlCl2 (4.0 equiv.), CH2Cl2, rt, 10–15
min, then NH4Cl quench. Panel C. Proposed geometry of cyclization for the
LA-activated intermediates 16.
structures 14a–e by the transition state geometry 16 in panel C furnishing the corresponding amino acid in excellent yield
of Scheme 3.14
(>90%, Scheme 5). Although carbodiimide mediated
We initially explored a retrosynthetic plan slightly different
from that shown in Scheme 1. In particular, we investigated
whether the allylative cyclization could be effected on a
substrate already having the arene appended to the maleimide.
Accordingly, we prepared the 2-nitrophenyl and 2-aminophenyl
substrates 3c and 3d (cf. Scheme 2) by Stille coupling of
bromide 3b with o-(tributylstannyl)nitrobenzene15 or o-(tribu-
tylstannyl)aniline,16a respectively. The rst of these cyclized
under the action of MeAlCl2 in excellent yield, but gave,
exclusively, a carbinolamide having the undesired regioiso-
meric relationship (i.e., iso-14c, Scheme 3, panel A). Similarly,
the anilino substrate 3d gave mostly the unwanted constitu-
tional isomer although some of the desired 14d (Scheme 3,
panel B) was observed at room temperature. Presumably, the
bulky aromatic substituent inhibits allyl addition in the
Scheme 4 Arylation (cross-coupling) studies of the iodoalkene 14e to provide
the anilino esters 14c–d. Reagents and conditions for the synthesis of 14d: 20 (1.2
desired trajectory. The ratio of 14 to iso-14 was determined by
1
the well-separated H NMR signals of the a- and b-protons of equiv.), Pd2(dba)3$CHCl3 (0.1 equiv.), AsPh3 (0.4 equiv.), DMF, rt, 74%.
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and A. Chatterjee, Phytochemistry, 1970, 9, 1491–1493; (c)
K. T. De Silva, A. H. Ratcliffe, G. F. Smith and G. N. Smith,
Tetrahedron Lett., 1972, 13, 913–916. For isolation of
rhazinal, see: (d) T.-S. Kam, Y.-M. Tee and G. Subramanian,
Nat. Prod. Lett., 1998, 12, 307.
5 For synthesis of rhazinilam, see: (a) A. H. Ratcliffe, G. F. Smith
and G. N. Smith, Tetrahedron Lett., 1973, 14, 5179–5184; (b)
G. Hugel, B. Gourdier, J. Levy and J. L. Men, Tetrahedron,
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12, 4224–4227; (j) L. McMurray, E. M. Beck and M. J. Gaunt,
Angew. Chem., Int. Ed., 2012, 51, 9288–9291. For synthesis of
rhazinal, see: (k) M. G. Banwell, A. J. Edwards, K. A. Jolliffe,
J. A. Smith, E. Hamel and P. Verdier-Pinard, Org. Biomol.
Chem., 2003, 1, 296–305; also see ref. 5g; (l) A. L. Bowie Jr
and D. Trauner, J. Org. Chem., 2009, 74, 1581–1586; (m) For
synthesis of the related alkaloid rhazinicine, a pyrrole amide
analog of rhazinilam, see: E. M. Beck, R. Hatley and
M. J. Gaunt, Angew. Chem., Int. Ed., 2008, 47, 3004–3007.
6 (a) D. Schinzer, Synthesis, 1988, 263–273; (b) For a recent and
elegant study, where an intermolecular Sakurai reaction was
used to form a macrocycle, see: M. R. Gesinski and
S. D. Rychnovsky, J. Am. Chem. Soc., 2011, 133, 9727–9729.
7 A similar allylic C-alkylation [with 2-(2-bromoethoxy)-2H-
tetrahydropyran] has been reported: H.-Y. Lee and Y. Kim,
J. Am. Chem. Soc., 2003, 125, 10156–10157.
Scheme 5 Completion of the total synthesis of (ꢀ)-1. Reagents and conditions:
(a) LiOH$H2O (3 equiv.), THF–H2O (2 : 1), rt, 92%; (b) HATU (1.5 equiv.), DIPEA (1.5
equiv.), DMAP (0.2 equiv.), DMF, rt, 71%; (c) H2 (50 psi), Pd/C (1 equiv.), EtOH, rt,
95%; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexa-
fluorophosphate, DIPEA ¼ N,N-diisopropylethylamine.
lactamization (EDCI$HCl) proved inefficient, we successfully
achieved the desired lactam formation in 71% isolated yield by
treating a DMF solution (0.05 M) of the amino acid derived from
14d with HATU, DIPEA, and DMAP. The resulting macrolactam
21 was smoothly converted by chemoselective hydrogenation
with H2 (50 psi) over Pd/C to provide the target alkaloid leuco-
nolam (1) in 95% yield.
Conclusion
In summary, we have achieved an efficient total synthesis of
(ꢀ)-leuconolam (1). Key features include: (i) the Ireland–Claisen
rearrangement of acetate ester 4 to produce the E-trisubstituted
alkene in 11, (ii) the use of furan-protected maleimide 13b as a
superior partner in Mitsunobu installation of the maleimide
moiety in 3, (iii) the regio- and diastereoselective Lewis-acid
mediated allylative cyclization of the allylic silane onto the a-
halogenated carbonyl group in 3e, (iv) the use of the novel
o-(trimethylstannyl)aniline 20, designed as an effective cross-
coupling donor to engage the hindered iodoalkene in 14e, and
(v) the nal establishment of the ethyl group by selective
hydrogenation of the vinyl unit in 21, which arose during
cyclization of the allylic silane 3e.
8 R. K. Boeckman and K. J. Bruza, Tetrahedron, 1981, 37, 3997–
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9 (a) Initial attempts using TMSCl resulted in essentially
full recovery of the acetate 4 and a trace amount of the alcohol
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Chem. Soc., 1976, 98, 2868–2877; (c) S. R. Wilson and
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Acknowledgements
This research was supported by the U.S. Department of Health
and Human Services National Institute of General Medical
Sciences (GM-65597) and National Cancer Institute (CA-76497).
10 M. Azechi, N. Toyota, K. Yamabuki, K. Onimura and T. Oishi,
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Notes and references
1 (a) S. H. Goh, C. Wei and A. R. M. Ali, Tetrahedron Lett., 1984, 13 Me2AlCl was also effective for achieving this allylation but
25, 3483–3484; (b) C. Wei, A. R. M. Ali, S. H. Goh, E. Sinn and
TBAF11 induced substrate decomposition.
R. J. Butcher, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 14 An asymmetric variant of this transformation (as well as in
1986, 42, 349–351.
2 In old Malayan medicine, these plants were used to treat
simpler model systems) would be of interest, but this has
not yet been pursued.
dermatologic infections by applying topically on the 15 M. Kosugi, T. Ohya and T. Migita, Bull. Chem. Soc. Jpn., 1983,
infected skin.3
56, 3855–3856.
3 S. H. Goh, A. R. M. Ali and W. H. Wong, Tetrahedron, 1989, 16 (a) E. C. Izgu and T. R. Hoye, Tetrahedron Lett., 2012, 53,
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4938–4941; (b) Aspects of the scope and generality as well
as the comparitive performance of stannane reagents 17–
20 are discussed in ref. 16a.
4 For isolation of rhazinilam, see: (a) H. H. A. Linde, Helv.
Chim. Acta, 1965, 48, 1822; (b) A. Banerji, P. L. Majumder
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17 R. S. Coleman, M. C. Walczak and E. L. Campbell, J. Am.
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18 M. Iwao, H. Takehara, S. Furukawa and M. Watanabe,
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that served as sources of acetaldehyde, which was
incorporated into 14d leading to 22. Therefore, use
of Et3N-pre-treated silica gel to purify 14d was
avoided.
19 A by-product, the hemiaminal 22, was observed during
an early attempt to purify the amino ester 14d by
column chromatography on silica gel that had been
pre-treated with Et3N. We presume that the Et3N
contained small amounts of auto-oxidation products
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