Enantioselective total synthesis of lycopodine

Article abstract of DOI:10.1021/ja803613w

The first enantioselective total synthesis of lycopodine has been completed. Key steps include a highly diastereoselective organocatalyzed cyclization of a keto sulfone to establish the key C₇ and C₈ stereocenters and a tandem 1,3-su

Full text of DOI:10.1021/ja803613w

Published on Web 06/27/2008
Enantioselective Total Synthesis of Lycopodine
Hua Yang, Rich G. Carter,* and Lev N. Zakharov†
Department of Chemistry, Oregon State UniVersity, 153 Gilbert Hall, CorVallis, Oregon 97331
Received May 14, 2008; E-mail: rich.carter@oregonstate.edu
The lycopodium family of alkaloids has garnered considerable
attention over the years because of their wide-ranging biological
activity and structural complexity.1 The parent member of this
family, lycopodine (1), was isolated 125 years ago by Bo¨deker
(Figure 1).2 Beneficial medicinal properties, such as antipyretic3
and anticholinesterase activity,4 have been attributed to lycopodine
and other lycopodium alkaloids. To date, seven racemic total
syntheses and two racemic formal syntheses of 1 have been
reported.5 Herein, we report the first enantioselective total synthesis
of 1. Our retrosynthetic strategy is shown in Figure 1. Key to this
strategy is the diastereoselective intramolecular Michael addition
of 4 and the Heathcock-inspired5d Mannich cyclization to form
tricycle 2.
Figure 1. Retrosynthetic strategy for lycopodine.
Scheme 1. Synthesis of the Keto Sulfone Subunit
The synthesis commenced with the known ester 6,6 which is
readily accessible in two steps from commercially available acyl
sultam 5 (Scheme 1). Next, one-pot treatment of commercially
available 1,4-dibromobutane (7) with NaSO2Ph in DMF followed
by NaN3 and H2O generated the sulfone 8 in reasonable yield.
Double deprotonation of 8 with lithium tetramethylpiperidide
(LiTMP) followed by addition of the chiral ester 6 yielded keto
sulfone 9 in 74% yield. It should be noted that use of lithium
diisopropylamide or n-BuLi resulted in a significant reduction in
the yield of this transformation. We have previously observed the
superior performance of LiTMP during our synthetic efforts toward
the bisspiroketal azaspiracid-1.7 Next, we turned our attention to
the cross metathesis of 9 and 3-penten-2-one (10). The presence
of the azide moiety as well as an internal nucleophile (the C8 keto
sulfone moiety) and Michael acceptor (the C5-C7 enone) within
product 4 imparted unique challenges for the cross metathesis. We
were gratified to find that use of the highly active second-generation
Grubbs-Hoveyda (GH-II) catalyst8 did generate the desired product
4 in good yield (63%, 88% on the basis of recovered starting
material). Also key to this metathesis was the specific choice of
the enone 10.9 Replacement of 10 with methyl vinyl ketone led to
a significant reduction in the efficiency of the transformation.
analysis revealed that the desired stereochemical outcome 3 had
instead been observed. One possible explanation for this fortuitous
diastereoselectivity may be a 1,2-steric interaction between the large
substituents at C7 and C8 that forces them to adopt a pseudoaxial
conformation in the transition state, a feature that would disfavor
transition state 11. Conversion of the methyl ketone 3 into the
Mannich cyclization precursor 14 was accomplished in one pot via
Staudinger reduction followed by tert-butyldimethylsilyl (TBS) enol
ether formation.
Our attention then turned to the key intramolecular Michael
addition of keto sulfone 4 (Scheme 2). We had initially hypothesized
that the C15 stereogenic center would disrupt the desired stereo-
chemical outcome at the C7 and C8 positions by placing the larger
phenyl sulfone and methyl ketone in pseudoequatorial positions in
the transition state 11 shown. Consequently, our strategy had
intended to explore a suitable organocatalyst for facilitating this
reaction while overriding what we perceived to be the favored
pathway. Prior to embarking on this investigation, we felt it would
be prudent to confirm the inherent stereochemical preference in
the system. Treatment of keto sulfone 4 with i-Pr2NH in a mixed-
solvent system (4:1 i-PrOH/dichloromethane) at room temperature
led to clean conversion to a single product that crystallized out of
the reaction in 89% yield. Interestingly, X-ray crystallographic
We next turned to the key Mannich cyclization step (Scheme
3). To this end, treatment of silyl enol ether 14 with Zn(OTf)2(96 °C,
ClCH2CH2Cl, 16 h) generated a new compound. One might have
expected product 2 to be formed; however, X-ray crystallographic
analysis established that the rearranged tricycle 19 had been
constructed. Product 19 was the result of a net 1,3-rearrangement
of the sulfone moiety from the expected C8 position to the C14
position. While a limited number of examples of 1,3-rearrangements
of allylic sulfones have appeared in the literature,10 we believe this
result is the first example of an R-sulfonyl imine undergoing such
a shift. This rearrangement likely occurs via initial complexation
of the imine nitrogen followed by imine/enamine interconversion
to form intermediate 16. Next, the 1,3-transposition of the sulfonyl
moiety might occur via either heterolytic cleavage of the C-S bond
to a tight ion pair11 or homolytic cleavage followed by recombina-
tion at C14 to produce the axial sulfone 17. An alternate mechanism
would invoke a 2,3-sigmatropic rearrangement to the sulfinate ester
† Director of the X-ray Crystallographic Facility of the Departments of Chemistry
at Oregon State University and the University of Oregon.
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9238 J. AM. CHEM. SOC. 2008, 130, 9238–9239
10.1021/ja803613w CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Diastereoselective Intramolecular Michael Addition and
ORTEP Representation of Keto Sulfone 3
tion of Heathcock’s original conditions [t-BuOK (6 equiv), Ph2CO
(18 equiv), PhH, 110 °C, sealed tube, 50 min].5d These improved
conditions suppressed a retro-Michael pathway that competitively
produced the tricycle 20. Finally, reduction using Stryker’s reagent14
yielded 1, which matched the reported spectral data.5f,15 Impor-
tantly, comparison of the optical rotation {[R]D ) -23.2° (c )
0.22, 100% EtOH)} with the literature value16 {[R]D ) -24.5° (c
) 1.10, 100% EtOH)} allowed us to confirm the assigned absolute
configuration of 1.
In conclusion, we have completed the first enantioselective total
synthesis of lycopodine. This approach should open the door to
accessing other lycopodium alkaloids. Further synthetic studies will
be reported in due course.
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM63723). The authors would like
to thank Professor Clayton Heathcock (UC-Berkeley) for providing
an authentic sample of 1 and Professor Max Deinzer and Dr. Jeff
Morre´ (OSU) for mass spectral data. Finally, the authors are grateful
to Professor James D. White (OSU), Professor Paul R. Blakemore
(OSU), and Dr. Roger Hanselmann (Rib-X Pharmaceuticals) for
helpful discussions.
Supporting Information Available: Complete experimental pro-
1
cedures, including H and 13C spectra, for all of the new compounds,
and crystallographic data and CIF files for 3 and 19. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Total Synthesis of Lycopodine
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