Total synthesis of (±)-gelsemoxonine

Article abstract of DOI:10.1021/ja403823n

Gelsemoxonine (1) is a Gelsemium alkaloid incorporating an unusual azetidine. Its total synthesis was achieved employing a novel ring contraction of a spirocyclopropane isoxazolidine to furnish a β-lactam intermediate. This β-lactam ring was further elabo

Full text of DOI:10.1021/ja403823n

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Communication
Total Synthesis of (±)-Gelsemoxonine
Stefan Diethelm, and Erick M Carreira
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja403823n • Publication Date (Web): 21 May 2013
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O
NO2
NO2
O
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OH
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CHO
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b
O
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O
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O
O
NH
O
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N
OH
OH
d
c
H
H
OTMS
O
O
7
O
5
3
CO2Et
8
CO2Et
OEt
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Total Synthesis of ()-Gelsemoxonine
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Stefan Diethelm, Erick M. Carreira*
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Eidgenössische Technische Hochschule Zürich, HCI H335, 8093 Zürich, Switzerland
Supporting Information Placeholder
In contrast to other small saturated heterocycles such as ox-
etanes or epoxides, azetidines have only been found in a handful
ABSTRACT: Gelsemoxonine (1) is a Gelsemium alkaloid incor-
porating an unusual azetidine. Its total synthesis was achieved
employing a novel ring contraction of a spirocyclopropaneisoxa-
zolidine to furnish a β-lactam intermediate. This β-lactam ring
was further elaborated into the azetidine of Gelsemoxonine. In
addition, the synthesis includes a highly diastereoselective re-
ductive Heck cyclization for the installation of the oxindole ring
system as well as a directed hydrosilylation of an alkyne to ac-
cess the ethyl ketone of the natural product.
of natural products to date.6 In a prior approach to Gelsemoxo-
nine, Fukuyama employed a biomimetic strategy for the for-
mation of this unusual motif in which epoxide ring opening at
C(15) is coupled to azetidine formation (Figure 1a).7 Our interest
in small saturated heterocycles and their utility in modifying the
underlying physicochemical properties of a scaffold in drug
discovery have prompted us to examine novel strategies for their
synthesis.8 The occurrence of the embedded azetidine in Gelse-
moxonine provided an opportunity to examine less common
methods for azetidine synthesis in more complex settings.
Plants from the genus Gelsemium have proven to be a rich
source of structurally diverse monoterpenoid indole alkaloids.1
The compact structures of these natural products have inspired
multiple generations of chemists to develop strategies for their
synthesis.2 Of the three known Gelsemium species, extracts of
Gelsemium elegans have found use in traditional Asian medicine
for over a thousand years.3 It is from this source that in 1991
Clardy isolated the alkaloid Gelsemoxonine (1) (Figure 1).4 Revi-
sion of the originally proposed structure based on X-ray crystal-
lographic analysis revealed that it includes an azetidine embed-
ded within a compact polycyclic scaffold.5 Furthermore, Gelse-
moxonine harbors six contiguous, densely packed stereocenters,
including a quaternary carbon at the spirocyclic junction and a
fully substituted carbon within the azetidine. These features,
along with its medical relevance, render it a veritable target for
study. Herein, we report a total synthesis of Gelsemoxonine that
utilizes a strategic ring contraction of a spirocyclopropane isoxa-
zolidine to provide access to the azetidine (Figure 1b). An addi-
tional salient feature of the synthesis is the introduction of the
congested quaternary oxindole stereocenter at C(7) by a dia-
stereoselective reductive Heck cyclization.
In our retrosynthetic analysis of the targeted natural product,
we envisioned late-stage construction of the oxindole by aryla-
tion at C(7) (Figure 2). β-Lactam 2 was envisioned as a key in-
termediate in the route for the construction of the Gelsemoxo-
nine tricyclic core. However, it was not clear how implementa-
tion of conventional approaches to the synthesis of β-lactams
would enable an access route to 2.9 A synthesis plan was devised
that centered on the use of an uncommon ring contraction of N-
alkylated spirocyclopropane isoxazolidines to form the corre-
sponding β-lactam (I→II) first reported by Brandi.10 The success-
ful implementation of this transform would offer access to the
azetidine ring at the heart of Gelsemoxonine.
Figure 2. Retrosynthetic Strategy for Gelsemoxonine (1) and key
ring contraction.
The initial reports on the intriguing ring contraction reaction
to β-lactams was limited to a handful of simple substrates. Thus,
we first conducted prospecting experiments to establish the
operational parameters of the transformation, its generality, and
potential use in the context of the target alkaloid. As shown in
Scheme 1, we observed ring contraction to the corresponding β-
lactam product for two relevant model substrates in excellent
yield. It is noteworthy that nitrogen protecting groups were not
Figure 1. Gelsemoxonine (1) and strategies for azetidine for-
mation.
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required for the transformation. The success of the model sys-
h; then anhydrous CeCl3, 30 min; then 7, BF3∙OEt2, THF, ‒78°C, 2
h, 78%.
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tems compelled us to examine the ring contraction towards the
synthesis of Gelsemoxonine. However, as discussed below, we
ultimately opted for a more complex pyran substrate than those
suggested by the model systems in Scheme 1.
With a short route to spirocyclopropane isoxazolidine 8 se-
cured, the key ring contraction to the projected β-lactam could
now be addressed, as shown in Scheme 3. We were curious to
know whether the densely functionalized intermediate 8 would
undergo the desired reaction. To our delight, when 8 was treat-
ed with TFA at 80°C, the system underwent ring contraction to
yield the highly substituted β-lactam 9 in 40-45% after complete
consumption of 8.15 The structure of 9 was unambiguously con-
firmed by X-ray crystallographic analysis of its carbonate deriva-
tive 10. The rearrangement of 8 to 9 along with the model sys-
tems are noteworthy as it underscores the generality of the
transformation and the compatibility with a number of function-
al groups, including alcohol, alkyne, ether, and ester.
Scheme 1. Model Studies for the Ring Contraction
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Scheme 3. Ring Contraction of Isoxazolidine 8
The synthesis route commenced with the construction of a
suitably substituted precursor for the key ring contraction as
depicted in Scheme 2. A key difference to the model systems for
the ring contraction reaction is that the targeted pyran
incorporates a substituent at C(3), as shown for 8. To this end,
aldehyde 311 was subjected to a Henry reaction with lithiated
nitromethane, furnishing secondary alcohol 4 in 70% yield. This
intermediate was then treated with Boc2O in the presence of
DMAP delivering isoxazoline 5 via a sequence consisting of alco-
hol activation, elimination, dehydrative formation of a nitrile
oxide followed by intramolecular dipolar cycloaddition.12 Epoxi-
dation of the enol ether 5 using DMDO13 produced an unstable
epoxide intermediate, which was immediately subjected to
nucleophilic opening by ketene silyl acetal 6 under Lewis acid
catalysis to furnish alcohol 7 in 56% yield. Although the epoxida-
tion proceeded to give a 2:1 mixture of epoxide diastereomers in
favor of the desired epoxide isomer, careful tuning of the reac-
tion conditions allowed for differential opening of only the major
epoxide isomer, with the minor diastereomer remaining unreac-
tive. With isoxazoline 7 in hand, introduction of an alkyne as a
surrogate for the ethylketone was subsequently addressed.
Accordingly, addition of 1-propynyllithium to 7 in the presence
of anhydrous CeCl3 and BF3∙OEt2 furnished diastereomerically
pure oxazolidine 8 in 78% yield.14 Interestingly, the free second-
ary alcohol in 7 proved essential for the addition to proceed. We
speculate that the hydroxyl group is involved as a directing
group for the incoming organometal species.
The next hurdle in the synthetic effort was the methenylation
of β-lactam 9 (Scheme 4). To this end, amide 9 was first protect-
ed using Boc2O to furnish the corresponding imide in 85% yield.
Exposure of this substrate to Petasis’ olefination conditions16 led
to clean conversion to strained enecarbamate 11, obtained in
77% yield. The stereocenter at C(5) was then installed by a hy-
droboration reaction. In this transformation we observed that
the strained olefin in 11 reacts exclusively from the exo-face.
Thus, following oxidative workup (NaBO3) primary alcohol 12 is
obtained in 92% yield as a single diastereomer as determined by
NMR spectroscopy. With the full carbon backbone of the Gelse-
moxonine core in place, closure of the seven membered carbo-
cycle was pursued. A variety of conditions were examined to
displace the derivatives of the primary alcohol at C(6) by the
ester derived enolate, without success. Finally, we decided to
explore an aldol condensation approach to achieve the requisite
ring closure. To this end, dialdehyde 13 was prepared by DIBAL
reduction of 12 followed by oxidation of the intermediate diol
under Swern conditions. When 13 was treated with 20 mol% of
proline, aldol product 14 was isolated as a single diastereomer in
82% yield. Notably, no elimination of the secondary alcohol was
observed under these conditions. A sequence consisting of Pin-
nick oxidation/esterification in the presence of a free secondary
alcohol delivered the corresponding methyl ester in 91% yield.
Finally, elimination of the alcohol using TFAA furnished unsatu-
rated ester 15 in 94% yield. In addition to full 2D NMR spectro-
scopic characterization, the structure of 15 was unambiguously
confirmed by X-ray crystallographic analysis.
Scheme 2. Synthesis of Isoxazolidine 8a
aReagents and conditions: (a) MeNO2, LDA, 30 min; then 3, THF,
‒78°C to rt, 2 h, 70%, (b) Boc2O, DMAP, toluene, rt, 12 h, 79%. (c)
DMDO, CH2Cl2/ acetone (1:1), 0°C, 2 h; then 6, InBr3 (5 mol%),
CH2Cl2, ‒60°C to rt, 2 h, 56%. (d) 1-bromo-1-propene, nBuLi, 1.5
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Scheme 4. C(6)-C(7) Ring Closurea
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aReagents and conditions: (a) Me3SnOH, 1,2-dichloroethane,
80°C ,24 h. (b) (COCl)2, DMF (cat.), CH2Cl2, rt, 1 h; then N-(2-
bromophenyl)hydroxylamine, NaHCO3, Et2O/CH2Cl2 (3:1), 0°C,
45 min, 58% (85% brsm, 2 steps). (c) PdCl2(MeCN)2 (10 mol%),
1,2,2,6,6-pentymethylpiperidine, HCOOH, DMF, 60°C, 1.5 h,
72%. (d) NaH, MeI, DMF, 0°C to rt, 45 min, 92%. (e) K2CO3,
MeOH, 50°C, 30 min, 87%. (f) (Me2SiH)2NH, 50°C, 2.5 h; then
{[RuCl2(C6H6)]2} (20 mol%), CH2Cl2, rt, 17 h, 58%. (g) KHF2, Ac2O,
H2O2, DMF, rt, 12 h, 65%. (h) 3M HCl, EtOAc, 0°C, 10 min, 97%.
aReagents and conditions: (a) Boc2O, NEt3, DMAP, CH2Cl2, rt, 30
min, 85%. (b) Cp2TiMe2, pyridine, toluene, 70°C, 8 h, 77% (85%
brsm). (c) 9-BBN dimer, THF, rt, 45 min; then NaBO3∙4H2O,
THF/H2O (1:1), rt, 1 h, 92%. (d) DIBAL-H, THF/CH2Cl2 (2:1), ‒
78°C, 75 min, 81%. (e) (COCl)2, DMSO, 15 min; then diol sub-
strate, 45 min; then NEt3, CH2Cl2, ‒78°C to rt, 1 h, 73%. (f) DL-
proline (20 mol%), DMSO, rt, 12 h, 82%. (g) NaClO2,
NaH2PO4∙2H2O, 2-methyl-2-butene, tBuOH/H2O (4:1), rt, 20
min; then TMSCH2N2, CH2Cl2/MeOH (9:1), rt, 10 min, 91%. (h)
TFAA, DBU, THF, rt, 30 min, 94%.
With the introduction of the oxindole secured, installation of
the ethylketone remained as the final task in the synthesis route.
To this end, a protocol involving hydroxyl directed hydrosilyla-
tion of the triple bond was employed.23 Following this strategy,
the C(14) Boc carbonate could be selectively cleaved using K2CO3
in MeOH in 87% yield. The resulting secondary alcohol was sub-
jected to hydrosilylation conditions employing {[RuCl2(C6H6)]2}
as catalyst to furnish vinylsilane 19 in 58% yield as an inconse-
quential mixture of double bond isomers.24 Oxidation of this
mixture under Tamao-Fleming conditions25 delivered ethyl
ketone product in 65% yield. Final removal of the N-Boc carba-
mate using 3M HCl delivered the natural product Gelsemoxonine
(1) in 97% yield. The characterization data of the synthetic mate-
rial matched the reported data for natural Gelsemoxonine5 in all
respects.
With the tricyclic core scaffold of Gelsemoxonine in hand, we
focused on the introduction of the spiro-fused oxindole at C(7)
(Scheme 5). The stereoselective construction of the quaternary
oxindole stereocenter has proven to be a major challenge in
many syntheses of Gelsemium alkaloids.2 The system investigat-
ed herein proved resistant to a number of intermolecular aryla-
tion attempts with various derivatives of 15. Hence, we turned
our attention to the intramolecular addition of aryl nucleophiles
to the α,β-unsaturated carbonyl. Thereby, an intramolecular
reductive Heck reaction would offer an attractive approach to
achieve such a transformation. Although the Heck reaction has
been commonly used for the construction of quaternary stereo-
centres, including oxindole ring systems,17 the envisioned reduc-
tive variant of this transformation posed a few challenges when
applied to projected substrate 16. Given that a putative arylpal-
ladium intermediate would need to add regiospecifically to the
congested C(7) carbon, the stereochemical outcome could not
be predicted on steric grounds.18 Additionally, the reductive
quenching of the resulting alkylpalladium species could be com-
plicated by a variety of undesired competing side reactions. This
includes reopening of the oxindole ring, β-hydride elimination,
side reactions involving the adjacent azetidine ring and potential
cleavage of the N-O bond in 16. In order to test the strategy,
hydroxamic acid 16 was prepared following hydrolysis of ester
15 using Me3SnOH.19 The resulting carboxylic acid was then
converted into the acid chloride and coupled to N-(2-
bromophenyl)hydroxylamine.20 Gratifyingly, upon exposure of
aryl bromide 16 to reductive Heck conditions,21 employing for-
mic acid as reductant, the formation of oxindole 17 was ob-
served in 72% yield and as a single diastereoisomer.22 The N-
hydroxyl in 17 was methylated to deliver N-methoxy oxindole 18
in 92% yield.
In summary, we have achieved the total synthesis of Gelse-
moxonine (1) in a sequence of 21 linear steps starting from alde-
hyde 3. The synthesis relies on the ring contraction of a spirocy-
clopropane isoxazolidine to deliver a β-lactam intermediate,
which was further used to build up the azetidine ring of Gelse-
moxonine. Additional salient features of the synthesis include a
diastereoselective reductive Heck cyclization for the construc-
tion of the oxindole ring and directed hydrosilylation of a triple
bond to generate the ethylketone. Over the course of the syn-
thesis, we have established the use of the ring contraction reac-
tion of spirocyclopropane isoxazolidine to give a β-lactam in a
complex setting. This little-studied, mechanistically intriguing
reaction is sure to find additional tactical applications in the
synthesis of complex structures incorporating azetidines.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all reac-
tions and products, including 1H and 13C NMR spectra. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 5. Completion of the Synthesisa
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that the cyloaddition has to occur from an unsaturated nitrile oxide
AUTHOR INFORMATION
intermediate incorporating a Z-double bond, as indicated in Scheme 2.
(13) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661.
(14) Uno, H.; Terakawa, T.; Suzuki, H. Chem. Lett. 1989, 1079.
(15) When the reaction was stopped at 50% conversion the product
could be isolated in 35% yield, or 70% brsm.
1
2
3
4
Corresponding Author
carreira@org.chem.ethz.ch
Notes
5
6
7
8
The authors declare no competing financial interests.
(16) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(b) Martínez, I.; Howell, A. R. Tetrahedron Lett. 2000, 41, 5607.
(17) (a) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130. (b) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.;
Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054.
(18) We speculated that the ether bridge adjacent to the reactive C(7)
carbon might be able to govern the stereoselective approach of the aryl
nucleophile through coordination to the arylpalladium intermediate. For
recent examples of ethers as directing groups in palladium catalyzed
reactions see: (a) Li, G.; Leow, D.; Wan, L.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2013, 52, 1245. (b) Jamieson, A. G.; Sutherland, A. Org. Biomol.
Chem. 2005, 3, 735.
(19) (a) Furlán, R. L. E.; Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett.
1996, 37, 5229. (b) Nicolaou, K. C.; Nevalainen, M.; Zak, M.; Bulat, S.;
Bella, M.; Safina, B. S. Angew. Chem. Int. Ed. 2003, 42, 3418.
(20) (a) Gupta, V. K.; Tandon, S. G. J. Indian. Chem. Soc. 1969, 46, 831.
(b) Smissman, E. E.; Corbett, M. D. J. Org. Chem. 1972, 37, 1947.
(21) Trost, B. M.; Thiel, O. R.; Tsui, H.-Ch. J. Am. Chem. Soc. 2003, 125,
13155.
ACKNOWLEDGMENT
9
We dedicate this manuscript to Prof. Dr. Scott E. Denmark in
honor of his 60th birthday. We are grateful to Dr. B. Schweizer
and M. Solar for X-ray crystallographic analysis, and to Dr. M.-O.
Ebert, R. Arnold, R. Frankenstein and P. Zumbrunnen for NMR
measurements. S.D. acknowledges the Stipendienfonds
Schweizerische Chemische Industrie (SSCI).
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Brandi, A. J. Am. Chem. Soc. 2000, 122, 8075.
(11) Aldehyde 3 was prepared in 5 steps according to: Ferrara, M.;
Cordero, F. M.; Goti, A.; Brandi, A.; Estieu, K.; Paugam, R.; Ollivier, J.;
Salaün, J. Eur. J. Org. Chem. 1999, 2725.
(12) Elimination of the secondary alcohol occurs before cycloaddition
as indicated by TLC analysis of the reaction and isolation of the nitroal-
kene intermediate. When this intermediate is subjected to the same
reaction conditions, enol ether 5 is obtained. We therefore speculate
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