A tandem, nitroalkene conjugate addition/[3+2] cycloaddition approach to the synthesis of the pentacyclic core of (±)-scandine

Article abstract of DOI:10.1002/adsc.200600301

The complete pentacyclic core of the melodinus alkaloid scandine has been synthesized. The synthetic strategy features two key steps: (1) a tandem nitroalkene conjugate addition/[3+2] cycloaddition of the resulting silyl nitronate and (2) an intramolecula

Full text of DOI:10.1002/adsc.200600301

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DOI: 10.1002/adsc.200600301
A Tandem, Nitroalkene Conjugate Addition/[3+2] Cycloaddition
G
Approach to the Synthesis of the Pentacyclic Core of
(ꢀ)-Scandine
Scott E. Denmarka,* and Jeromy J. Cottella
a
245 Roger Adams Laboratory, Box 18, Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana,
IL 61801, USA
Phone: (+1)-217-333-0066; Fax: (+1)-217-333-3984; e-mail: denmark@scs.uiuc.edu
Received: June 22, 2006; Accepted: August 28, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The complete pentacyclic core of the mel-
odinus alkaloid scandine has been synthesized. The
synthetic strategy features two key steps: (1) a
plan 3, needed to be both 2,2-disubstituted and bear a
geminal diester function next to the reactive center.[7]
Not unexpectedly, orienting experiments on a simpli-
fied analogue of 3 failed to show the expected [4+2]
cycloaddition regardless of the dipolarophile or Lewis
acid employed.[8] Thus, an alternative strategy that in-
troduced the C(7) aryl moiety (scandine numbering)
at a later stage was envisioned.
tandem nitroalkene conjugate addition/[3+2] cyclo-
A
addition of the resulting silyl nitronate and (2) an
intramolecular Heck reaction of an aryl iodide with
a g-disubstituted allylic alcohol which set a highly
congested, quaternary stereogenic center with the
concomitant formation of an aldehyde. Intramolec-
ular reductive amination with this aldehyde com-
pleted the pentacyclic core.
The second generation strategy took good advant-
age of the tandem [4+2]/
A
tion, but it was still necessary to devise a method to
Keywords: conjugate addition; [3+2] cycloaddition;
A
nitroalkenes; quaternary stereogenic centers; silyl
nitronates
(+)-Scandine (1) is a member of the Melodinus alka-
loid family,[1] and is biosynthetically related to the
Aspidosperma class of natural products.[2] Embedded
in the pentacyclic core of the molecule resides a cen-
tral cyclopentyl ring C containing all four of the resi-
dent stereocenters, three of which are quaternary
(Scheme 1).[3] Its densely functionalized structure pro-
vided an intriguing challenge to extend the use of the
tandem [4+2]/[3+2] nitroalkene cycloaddition pro-
A
cess for total synthesis of complex alkaloids.[4,5]
Following a well established analysis for the con-
struction of indolizidines from the tandem cycloaddi-
tion of functionalized nitroalkenes,[6] it was envisioned
that the core structure of 1 could be assembled by the
addition of a chiral vinyl ether to the nitroalkene 3
(Route A, Scheme 1). The application of an intermo-
lecular [4+2]/intramolecular [3+2] approach would
not only provide the central cyclopentyl ring, but
would also create two of the necessary quaternary
centers. However, the requisite nitroalkene for this Scheme 1.
Adv. Synth. Catal. 2006, 348, 2397 – 2402
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install the C(7) aryl unit and thus create the third most likely results from the conjugate addition of the
quaternary stereogenic center. Both radical-based[9] silyl ketene acetal, followed by silyl group migration
and Pd-mediated[10] reactions have proven to be relia- to provide an intermediate silyl nitronate 9. Upon
ble methods for the construction of sterically congest- warming, this nitronate then undergoes an intramo-
ed quaternary centers. Thus, an unsaturated precursor lecular [3+2] cycloaddition with the tethered dipolar-
such as intermediate 4 (Scheme 1) could make use of ophile to provide the silyl nitroso acetal 11.
either of these strategies for the synthesis of (+)-
The construction of nitroso acetal 11 could be
scandine, where intramolecular cyclization would pro- streamlined to a one-pot procedure by replacing the
vide the desired lactam (Route B). Interestingly, in no silyl ketene acetal of methyl acetate with its lithium
previous study had an indolizidinone been generated enolate, (to effect a Michael-type addition) followed
directly from the cycloaddition product because that by the in situ silylation of the lithium nitronate inter-
would require the use of a ketene acetal as the dieno- mediate with TESCl (Scheme 3). This process also al-
phile. The construction of the nitroso ortho esters lowed for the incorporation of tert-butyl acetates,
such as 5, was unexplored within the context of the which were unreactive as the corresponding ketene
tandem nitroalkene cycloaddition. Given the need for acetals. With this modified procedure, the silyl nitroso
a highly reactive dienophile to overcome steric en- acetal 11 was prepared in high yield, as a 6:1mixture
cumbrance, the obvious opportunities to investigate of two diastereomers. The two diastereomers differed
the use of chirally modified ketene acetals, and the di- only in the configuration of the C(6) stereocenter [fa-
versity of transformations available to convert 4 to voring the HC(7)-HC(21) (scandine numbering) trans
the scandine core, we were stimulated to reduce this relationship] suggesting that the diastereoselectivity
plan to practice.
A simple model study was undertaken first to dem- Although, this center will be lost in intermediate 4, it
onstrate the feasibility of tandem [4+2]/[3+2] nitroal- will play a role in the ability to form the lactam pre-
arises from the facial approach of the dipolarophile.
AHCTREUNG
kene cycloaddition with ketene acetals. Nitroalkene 7 cursor (vide infra).
was chosen as the test substrate (Scheme 2). If suc-
cessful, the resulting cycloadducts would also allow in-
vestigation into the late-stage intramolecular aryla-
tion. Combination of the TBS ketene acetal of methyl
acetate with 7 in the presence of MAD as the Lewis
acid afforded none of the desired nitroso orthoester 8.
Instead, two non-isomeric compounds were isolated;
the first was identified as the conjugate addition prod-
uct 10[11] and the second clearly showed the loss of
the starting diene and the formation of a monosubsti-
tuted alkene. Spectroscopic characterization of this
compound revealed that a diastereomeric mixture of
the silyl nitroso acetals 11 had formed. This product
Scheme 3.
The mixture of diastereomeric nitroso acetals was
carried forward to the intermediate 12 via hydrobora-
tion/oxidation of the terminal alkene, followed by to-
sylation of the resulting primary alcohol. Unexpected-
ly, in the case of the methyl acetate derived series, hy-
drogenation of the nitroso acetal under standard con-
ditions with Raney nickel at 360 psi did not provide
the desired tricyclic lactam. Instead the bicyclic amino
ester 13 was isolated in good yield. Subsequent at-
Scheme 2.
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Synthesis of the Pentacyclic Core of (ꢀ)-Scandine
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tempts to induce lactamization provided only trace
amounts of the cyclization product, suggesting that
the C(7) configuration of the major diastereomer of
the nitroso acetal was not suited for closure to an all
cis fused tricyclic lactam. This assumption was proven
correct by X-ray crystallographic analysis of the N-
benzoyl derivative.[12]
Although the stereostructure of 13 did not lend
itself to the direct construction of the third ring of the
scandine core via intermediate 4, it was still suitable
for probing the central question of introducing the
C(7) quaternary stereogenic center through intramo-
lecular arylation. The synthetic plan was revised to ac-
commodate the preparation of bicyclic a,b-unsaturat-
ed ester 16 (Scheme 4). This approach allows for the
correction of the C(7) stereocenter, which will be re-
Scheme 5.
generated during the formation of the quaternary less of the conditions employed. Therefore, the Pd-
center. Protection of both the alcohol and amine func- mediated cyclization was investigated.
tions provided 14, which was then dehydrogenated by
The carbopalladative cyclization of 16 cannot pro-
a two-step selenylation/oxidation procedure to yield ceed by the usual Heck mechanism because of the
15, as 4:1 Z/E mixtures of geometrical isomers. Inter- lack of neighboring hydrogen atoms to allow for b-hy-
estingly, the selenide had to be prepared using a silyl dride elimination and catalyst regeneration.[13] In this
ketene acetal intermediate at ꢁ1108C to prevent frag- case the process should lead to a palladium enolate,
mentation of the cyclopentyl ring. Furthermore only which could be hydrolyzed upon work-up. However,
the major selenide diastereomer underwent clean oxi- the addition of a stoichiometric amount of palladium
dation to the corresponding olefin.
acetate provided only the 7-endo cyclization product
18, and none of the desired 6-exo derived lactam 17
(Scheme 6). Despite an expected kinetic preference
for the 6-exo pathway,[10b] the reversibility of the ini-
tial cyclization allows for the formation of the 7-endo
derived intermediate III (Scheme 6). Upon b-hydride
elimination to provide 18 (Scheme 7), this pathway is
no longer reversible and the reaction is funneled
through the 7-endo intermediate.[14] The 6-exo inter-
mediate II can be trapped by the addition of sodium
formate,[14] however the desired lactam was isolated
in low yield with significant amounts of the deiodinat-
ed starting material.
Scheme 4.
Scheme 6.
The arylation precursor 16 was prepared by selec-
tive amidation of the sterically more accessible me-
thoxycarbonyl group of 15, followed by methylation
To solve the problem of reversed regioselectivity,
of the resulting amide. Initial attempts to create the we clearly needed to provide a rapid and irreversible
quaternary center were investigated though the gener- capture of the kinetically preferred 6-exo cyclization
ation of an aryl radical (Scheme 5). Unfortunately, intermediate. This could be accomplished by conver-
only minor amounts of the arylation product 17 were sion of the tert-butyl ester to a primary alcohol or de-
observed. Instead, the reduction of the aryl halide rivative. Heck type reactions of allylic alcohols and
was found to be the major reaction pathway, regard- ethers are well precedented and proceed directly to
Adv. Synth. Catal. 2006, 348, 2397 – 2402
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Scott E. Denmark and Jeromy J. Cottell
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products could be influenced by changes in solvent,
base, ligand, and additive as illustrated in Table 1.
The beneficial effect of ammonium salts is well docu-
mented in Heck reactions[16] and here, tetrabutylam-
monium chloride was most effective. The best condi-
tions, entry 6, cleanly provided a 4:1mixture favoring
the desired lactam 21.
Table 1. Optimization of intramolecular arylation of 20.
Scheme 7.
aldehydes or enol ethers by b-hydride eliminatio-
n.[10a,15] If this pathway is competitive with reversal,
the ratio of observed products could be altered. Hy-
drolysis of the tert-butyl ester to the parent acid was
required to allow selective reduction to allylic alcohol
19 in the presence of both methyl ester and anilide
functions (Scheme 8). The alcohol was then converted
to its TBS ether 20 under standard conditions.
The intramolecular arylation of 20 was evaluated
under a variety of conditions. As was the case with
the corresponding ester, a mixture of both the 6-exo
(21) and 7-endo (22) derived products was observed
along with ketone 23 which arose from arylation of
the methyl ester. However, the ratio of the two Heck
Heck reactions of unprotected allylic alcohols are
known to provide aldehydes in good yields.[10a,14]
Direct use of the primary alcohol would eliminate a
protection and deprotection step in the synthesis and
the aldehyde would be the ideal intermediate for the
subsequent reductive amination step to close the last
ring. Thus, exposure of allylic alcohol 19 to the opti-
mized arylation conditions (Table 1) provided the de-
sired 6-exo cyclization product 24 in good yield in a
20:1ratio with the 7- endo derived lactam (Scheme 9).
Construction of the final ring system could now be
readily effected by debenzylation and in situ reductive
amination, thus providing the first synthesis of the
complete core structure of scandine. X-ray crystal
Scheme 8.
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Synthesis of the Pentacyclic Core of (ꢀ)-Scandine
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brine (10 mL). The aqueous layers were back extracted with
Et2O (2”10 mL). The organic layers were combined, dried
over MgSO4, and concentrated under vacuum to provide 20
(yield: 0.451, 88%) as a colorless oil. An analytical sample
was obtained by recrystallization (hexanes/EtOAc, ꢁ208C),
providing 24 as colorless prisms.
Analytical Data for 24: mp 145–1478C (hexanes/EtOAc);
1H NMR (500 MHz, CDCl3): d=9.39 [s, 1H, HC(2’v)], 7.00–
G
7.30 [m, 9H, HC
3.49 [s, 3H, HC(2’)], 3.45 [m, 2H, HC
3H, HC(12)], 3.09 [m, 4H, HC(11a), HC(10), HC
(1’v)], 2.85 [ABX, 2H, HC(7)], 2.46 [dt, J=3.2, 13.9 Hz, 1H,
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
HC(10)], 2.27 [dt, J=5.6, 9.3 Hz, 1H, HC(7a)], 1.48 [tt, J=
2.9, 11.2 Hz, 1H, HC(9)], 1.38 [m, 1H, HC(9)], 0.97 [s, 9H,
HC
13C NMR (125 MHz, CDCl3): d=201.68 [C
[C(1’)], 168.22 [C(6)], 139.41 [C(11c)], 138.19 [C
128.84 [C(3’’’)], 128.34 [C(4’’’)], 128.23 [C(1)], 128.02 [C-
(5’’’)], 127.17 [C(3)], 126.58 [C(4a)], 123.10 [C(2)], 115.19
[C(4)], 68.89 [C(11a)], 65.21 [C(8)], 63.14 [C(1’’’)], 59.09
[C(6a)], 53.35 [C(2’)], 52.92 [C
(1’v)], 41.85 [C(12)], 41.40
[C(10)], 34.88 [C(7a)], 31.51 [C(7)], 30.74 [C(11b)], 27.07
[C(9)], 26.07 [C(2’’)], 18.38 [C (3’’)], ꢁ4.78 [C-
(1’’)], ꢁ4.52 [C
(3’’)]; IR (CDCl3): n=2952 (m), 2926 (m), 2854 (w), 1731
A
G
U
AHCTREUNG
Scheme 9.
A
ACHTREUNG
analysis of the amine 25 confirmed the expected con-
nectivity, as well as its relative stereostructure.[12]
In conclusion, we have developed a novel conjugate
addition/intramolecular [3+2] cycloaddition sequence
that proceeds in high yield and with good diastereose-
lectivity. This development was necessitated by ob-
AHCTREUNG
ACHTREUNG
AHCTREUNG
AHCTREUNG
G
ACHTREUNG
AHCTREUNG
(s), 1716 (s), 1659 (s), 1600 (m), 1471 (m), 1458 (s), 1373 (s),
served limitations in the tandem [4+2]/[3+2] nitroal-
A
1249 (s), 1051 cmꢁ1 (m); MS (ESI): m/z=577 (M+, 100);
kene cycloaddition methodology resulting from the
steric bulk of the diene. The preparation of the ni-
troso acetal 11 allowed for the exploration of an intra-
molecular aryl cyclization to form a very sterically
congested vicinal quaternary center. Currently the
completion of the synthesis of (ꢀ)-scandine is under
study from 25, as is the development of an enantiose-
TLC: Rf =0.21(CH Cl2/MeOH, 18/1, UV); anal. calcd. for
2
C33H44N2O5Si (576.80): C 68.72%, H 7.69%, N 4.86%;
found: C 68.67%, H 7.86%, N 4.96%.
Acknowledgements
lective variant of the conjugate addition/[3+2] cyclo-
A
addition step for the total synthesis of (+)-scandine.
We are grateful to the National Institutes of Health for gener-
ous financial support (GM30938).
Experimental Section
References
Key Intramolecular Heck Cyclization of 19 to 24.
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The reaction was conducted in a 35 mL (one-neck) round-
bottom flask, with a gas Intel, septum, stir bar, and reflux
condenser, under an atmosphere of argon. To a mixture of
Bu4NCl·H2O (0.493 g, 1.77 mmol, 2.0 equivs.), Pd
A
(0.020 g, 0.089 mmol, 0.1equiv.), and triphenylphosphine
(0.046 g, 0.177 mmol, 0.2 equivs.) was added a solution of 19
(0.625 g, 0.89 mmol) in acetonitrile (18 mL). To the yellow
solution was added triethylamine (0.23 mL, 1.78 mmol, 2.0
equivs.), and the solution was heated to reflux (858C, bath
temperature) for 12 h. During this time the reaction color
became light brown, and a black precipitate began to form.
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(15 mL), and brine (15 mL). The aqueous layers were com-
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0.1 ! 8/2/0.1) to give a slightly yellow oil. The oil was dis-
solved in Et2O (15 mL) and was washed with a saturated
aqueous solution of Na2S2O3 (10 mL), H2O (10 mL), and
Adv. Synth. Catal. 2006, 348, 2397 – 2402
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charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre,
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N
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