Fully substituted carbon centers by diastereoselective spirocyclization: Stereoselective synthesis of (+)-lepadiformine C

Article abstract of DOI:10.1021/ja104250b

Reductive lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A_1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.

Full text of DOI:10.1021/ja104250b

Published on Web 06/25/2010
Fully Substituted Carbon Centers by Diastereoselective Spirocyclization:
Stereoselective Synthesis of (+)-Lepadiformine C
Matthew A. Perry, Matthew D. Morin, Brian W. Slafer, Scott A. Wolckenhauer, and
Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine, California 92697-2025
Received May 24, 2010; E-mail: srychnov@uci.edu
Scheme 1. Stereoselective Reductive Spirocyclizations
Abstract: Reductive lithiation of N-Boc R-amino nitriles generated
R-amino alkyllithium reagents with unexpected selectivity. The
intermediate radical prefers to align with the nitrogen lone pair,
and this interaction leads to an A1,3-strain effect that biases the
conformation of the radical. In cyclohexane rings with R-substit-
uents the net effect is an inversion of configuration on reductive
lithiation. In the presence of a tethered electrophile the alkyllithium
cyclizes to produce a spiro compound, again with inversion of
configuration. The overall result is retention of configuration in
the cyclization reaction. The same overall selectivity is found with
R-oxygen alkyllithium cyclizations, but in this case both steps
proceed with retention. The difference can be explained by careful
consideration of the intermediate geometries. The R-amino
spirocyclization was utilized in a concise and stereoselective
synthesis of lepadiformine C.
Stereoselective construction of fully substituted carbon atoms is
a challenge that is often at the heart of a successful complex natural
product synthesis. Several years ago we reported a synthesis of
spirocycles that was based on stereoselective generation of alkyl-
lithium reagents arising from anomeric stabilization of radical
intermediates.1,2 Herein we describe studies on the generation of
R-hetero alkyllithium reagents where classic anomeric stabilization
Figure 1. Synthetic analysis of lepadiformine C.
is not relevant, but that still show highly stereoselective transforma-
tions. This new stereoselective strategy leads to fully substituted
carbon atoms and is illustrated with a concise synthesis of
lepadiformine C.3
Lepadiformine C is an alkaloid isolated from the tunicate
ClaVelina moluccensis along with lepadiformine B.3 These alkaloids
have an effect on the cardiovascular system and block the cardiac
inward rectifying K+ channel. Lepadiformine C is the simplest of
the alkaloids in this class11 and appears to be a suitable synthetic
target for the spirocyclization reaction described above. Our
synthetic analysis is shown in Figure 1. Reductive lithiation and
cyclization of nitrile 9 would generate the spirocycle 8. Compound
9 could arise from a Strecker reaction of the corresponding
cyclohexanone, but preliminary investigation suggested that the
equilibrium was unfavorable.12 A more interesting approach would
generate the cyclohexane ring by sequential alkylation2a,d,13 of
amino nitrile 10 with a dibromide 11. This strategy rapidly
introduces all three rings from acyclic precursors.
The synthesis of lepadiformine C is presented in Scheme 2. The
known optically pure alcohol 1214,15 was coupled with 5-((tert-
butyldimethylsilyl)oxy)pentanal (13) and oxidized to generate
ketone 14. Enantioselective reduction of the propargyl ketone using
Noyori’s method,15 hydrogenation, deprotection, and bromination
produced the dibromide 16 in good overall yield. The assembly of
the ring system began with alkylation of amino nitrile 17 with
dibromide 16. The two reagents were combined and treated with
an LDA solution in portions until no more of the monoalkylated
product was visible by TLC analysis. Cyclohexane 18 was isolated
Reduction of N-protected R-amino nitriles with Freeman’s
reagent (LiDBB)4 is an effective strategy to generate tertiary
R-amino alkyllithium reagents.5 An N-alkyl 2-cyano piperidine
generally leads to the alkyllithium with high selectivity, but when
the nitrogen atom is protected as a Boc carbamate the alkyllithium
is produced as a 1.5:1 mixture of isomers.6 The reductive lithiation
of N-Boc piperidine 1 in Scheme 1 was investigated to probe the
reactivity of the Boc-protected R-amino alkyllithium reagent.
Although the lithiation is not stereoselective, both alkyllithium
isomers cyclize effectively at -78 °C to produce the bicycle 2 in
excellent yield. These tertiary N-Boc R-amino alkyllithium reagents
are expected to be conformationally stable at -78 °C, with inversion
barriers of ca. 20 kcal/mol.7 This experiment demonstrated that
tertiary N-Boc alkyllithium reagents may cyclize with retention
(SEret) or inversion (SEinv) and that suitably constrained systems
can produce single isomers in high yields.8,9
The spirocyclizations of nitriles 3 and 5 were highly stereose-
lective. Both cyclizations proceed with overall retention at the fully
substituted center,10 and the heteroatom ends up in the equatorial
position. The rationale for the selectivity is not obvious, but the
transformation could be useful in synthesis.
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J. AM. CHEM. SOC. 2010, 132, 9591–9593 9591

C O M M U N I C A T I O N S
Scheme 2. Synthesis of Lepadiformine C
Scheme 3. Stereoselective Reductive Lithiation and Protonation
Control Experiments
efficient cyclization of nitrile 1 to bicycle 2 demonstrates that these
N-Boc alkyllithium reagents may cyclize efficiently with either
retention21 or inversion7 of configuration. Coordination of the Boc
nitrogen to the lithium atom in 27 would restrict the conformation,
and the phosphate is well positioned to react from the back of the
alkyllithium in an SEinv pathway. The spirocyclization is highly
stereoselective and proceeds through an unanticipated double
inversion sequence.
as a single isomer with the nitrile in the axial position.16 The TBS
ether was exchanged for a diethylphosphate leaving group, and
subsequent reduction of phosphate 19 with Freeman’s reagent
(LiDBB)4 produced the cyclic product as a single isomer in
excellent yield. Deprotection of the TIPS group led to the crystalline
alcohol 21, and X-ray analysis confirmed the expected relative
configuration of the stereogenic centers.17 The synthesis was
completed by converting the alcohol to a mesylate and removing
the Boc group.18 Upon neutralization, the amine cyclized to form
the final ring of lepadiformine C, which was isolated as its
hydrochloride salt. The characterization data (1H and 13C NMR,
HRMS, optical rotation, IR) for lepadiformine C matched that
reported for the natural product.3a The synthesis features a rapid
and stereoselective assembly of the tricyclic structure from acyclic
dibromide 16 and amino nitrile 17.
The cyclization of nitrile 5 to spirocycle 6 shows the same sense
of selectivity, but the underlying sequence diverges. In this case
reductive lithiation of the corresponding TBS ether 28, followed
by protonation, proceeds with retention of configuration.19,22
Presumably the axial radical 29 is stabilized by the lone pairs on
the adjacent oxygen, with the alkyl substituent adopting a gauche
alignment reminiscent of an exoanomeric effect. Cyclization also
takes place with retention of configuration1,23 in the reaction with
nitrile 5. The oxygen and N-Boc substrates present an interesting
contrast, where superficially similar selectivities result from stere-
ochemically complementary intermediates.
The origin of the selectivity in the reductive lithiation and
cyclization of nitriles 3, 5, and 19 was explored (Scheme 3). All
of the alkyllithium intermediates are expected to be configurationally
stable under the reaction conditions.7 The configuration of the
alkyllithium intermediates was assessed by protonation, which is
assumed to proceed with retention of configuration.7b Reductive
lithiation and protonation of TBS ether 18 gave the cis disubstituted
cyclohexane 26.19 The lithiation proceeds with an unanticipated
inversion of configuration. One explanation is that the initially
formed radical intermediate 23 is stabilized by interaction with the
nitrogen electrons, and the resulting steric crowding of the equatorial
R′ group generates a conformational isomerization to produce
radical 24.20 Further reduction of radical 24 would produce
alkyllithium 25, which upon protonation would lead to carbamate
26. The lithiation of nitrile 19 presumably follows the same course,
with intermediate alkyllithium 27 arising from inversion of con-
figuration. The subsequent cyclization of 27 also proceeds with
clean inversion of configuration to produce spirocycle 20. The
These stereoselective spirocyclization reactions provide an
interesting new tool for assembling fully substituted carbon centers.
In the case of lepadiformine C, the nitrile in substrate 17 facilitates
two alkylation reactions followed by a stereoselective reductive
lithiation and cyclization. Thus all the carbon-carbon bonds in the
most highly substituted atom were assembled late in the synthesis
in an effective but unconventional strategy.
Acknowledgment. This project was supported by a generous
gift from the Schering-Plough Research Institute. Initial studies were
supported by NIGMS GM-65338. S.A.W. acknowledges Amgen
for a predoctoral fellowship. M.D.M. acknowledges Eli Lilly for
fellowship support. M.A.P. acknowledges Vertex Pharmaceuticals
for a Vertex Scholar fellowship. We thank Prof. Jean-Francois Biard
for providing authentic spectra for lepadiformine C and Dr. Joe
Ziller for solving the crystal structure of carbamate 21.
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C O M M U N I C A T I O N S
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