Assignment of the C5' relative stereochemistry in (+)-lepadin F and (+)-lepadin G and absolute configuration of (+)-lepadin G

Article abstract of DOI:10.1021/ol9018997

Concise assignments of the C5' stereochemistry In (+)-lepadin F and (+)-lepadin G and the absolute configuration of (+)-lepadin G via the first total syntheses of (+)-5'-epl-lepadin F, (+)-lepadin G, and (+)-5'-epMepadin G are described. This work represe

Full text of DOI:10.1021/ol9018997

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4616-4619
Assignment of the C5′ Relative
Stereochemistry in (+)-Lepadin F and
(+)-Lepadin G and Absolute
Configuration of (+)-Lepadin G
Gang Li and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received August 14, 2009
ABSTRACT
Concise assignments of the C5′ stereochemistry in (+)-lepadin F and (+)-lepadin G and the absolute configuration of (+)-lepadin G via the first total
syntheses of (+)-5′-epi-lepadin F, (+)-lepadin G, and (+)-5′-epi-lepadin G are described. This work represents an illustrative example in which a
diastereomeric pair can possess sufficient spectroscopic difference for clear assignment despite differing only at a highly insulated acyclic stereocenter.
We recently completed a total synthesis of (+)-lepadin F1-3
featuring an aza-[3 + 3] annulation4,5 of vinylogous amide
Scheme 1. C5′ Stereochemistry of (+)-Lepadins F and G
1 and iminium ion 2 (Scheme 1).6 Close spectroscopic
comparisons with those reported by Davis et al.1,7 for the
isolated sample and Blechert8 for synthetic (+)-lepadin F
(1) For Carroll’s isolation of lepadins (+)-F, (+)-G, and (+)-H: Davis,
R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65, 454
.
(2) For isolation of lepadins (+)-D, (-)-E, and (-)-F, see: Wright, A. D.;
Goclik, E.; Ko¨nig, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067
.
(3) For isolation other lepadin families, see: (a) (-)-lepadin A,Steffan,
B. Tetrahedron 1991, 47, 8729. (b) (-)-B and (-)-C, Kubanek, J.; Williams,
D. E.; de Silva, E. D.; Allen, T.; Andersen, R. J. Tetrahedron Lett. 1995,
36, 6189. (c) For total syntheses of lepadins A-E, and H, see: Pu, X.; Ma,
D. J. Org. Chem. 2006, 71, 6562. (d) Pu, X.; Ma, D. Angew. Chem., Int.
Ed. 2004, 43, 4222. (e) Kala¨ı, C.; Tate, E.; Zard, S. Z. Chem. Commun.
2002, 1430. (f) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001,
66, 3338. (g) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000, 2, 2955.
(h) Toyooka, N.; Okumura, M.; Takahata, H. J. Org. Chem. 1999, 64, 2182
.
(4) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23
(5) Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-L.;
Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435
.
.
allowed us to claim a completed total synthesis. However,
the C5′ stereocenter was never defined in the isolation
(6) For our total synthesis of (+)-lepadin F, see: Li, G.; Hsung, R. P.;
Slafer, B. W.; Sagamanova, I. K. Org. Lett. 2008, 10, 4991.
10.1021/ol9018997 CCC: $40.75
Published on Web 09/23/2009
 2009 American Chemical Society

reports.1,2 Despite our close spectroscopic comparisons, the
margin of error to ascertain the C5′ stereochemistry remains
high, especially in the absence of an authentic sample of
(+)-5′-epi-lepadin F, because the C5′ stereocenter is both
acyclic and highly insulated on the lepadin side chain. We
report here assignments of the C5′ stereochemistry in (+)-
lepadin F and (+)-lepadin G and absolute configuration of
(+)-lepadin G via concise enantioselective total syntheses
of (+)-5′-epi-lepadin F, (+)-lepadin G, and (+)-5′-epi-
lepadin G.
Total synthesis of (+)-5′-epi-lepadin F commenced with
an advanced intermediate aldehyde 6 that was used in (+)-
lepadin F synthesis (Scheme 2). Homologation of the side
Scheme 2. Synthesis of (+)-5′-epi-Lepadin F
Figure 1. NMR comparisons of synthetic (+)-lepadin F and (+)-
5′-epi-lepadin F with Carroll’s natural (+)-lepadin F.
lepadin F are in blue with ∆δ for (+)-5′-epi-lepadin F in
red. We note here that Carroll’s 1H spectra data were
collected on a 600-MHz spectrometer [150 MHz for 13C
NMR], whereas ours were collected on a 500 MHz spec-
trometer [125 MHz for 13C]. These two sets of spectroscopic
comparisons distinctly reveal that the synthetic (+)-lepadin
F is better matched with Carroll’s natural (+)-lepadin F than
(+)-5′-epi-lepadin F, thereby confirming that the relative
stereochemistry at C5′ in (+)-lepadin F should be S.
In addition, careful spectroscopic comparisons between
synthetic (+)-lepadin F and (+)-5′-epi-lepadin F were carried
out with 13C NMR differences being tabulated in the bar
graph shown in Figure 2. Intriguingly, despite differing only
chain in 6 was achieved in 90% yield through Kocienski
modified Julia olefination9 employing sulfone (R)-7.10,11
Subsequent hydrogenation of the resulting C2′-3′ olefin in 8
followed by desilylation led to alcohol 9, which could be
converted to (+)-5′-epi-lepadin F in two steps featuring
esterification under Yamaguchi conditions.
With (+)-5′-epi-lepadin F in hand, we were able to attain
comprehensive comparisons of respective spectral data. As
shown in Figure 1, both proton and carbon NMR chemical
shift differences in C6D6 between Carroll’s natural (+)-
lepadin F1 and our synthetic (+)-lepadin F6 and (+)-5′-epi-
lepadin F were tabulated, and all non-zero ∆δ values are
displayed as bar graphs along the axis indicating their
respective proton and carbon numberings: ∆δ values for (+)-
Figure 2.
13C NMR differences between (+)-lepadin F and (+)-
5′-epi-lepadin F.
at C5′, which is an acyclic and stereochemically insulated
stereocenter, (+)-lepadin F and (+)-5′-epi-lepadin F are quite
distinct spectroscopically. Their difference was further
1
manifested with the 1.93-1.75 ppm region of H NMR
(7) Wright’s data were collected from CDCl3.2 When we used K2CO3
pretreated CDCl3 to avoid protonation of the decahydroquinoline motif,
where the resonances are assigned to H4′′ and H4ꢀ (Figure
3). In comparison with Carroll’s spectra [black], our synthetic
(+)-lepadin F [red] matches the natural sample precisely,
whereas (+)-5′-epi-lepadin F [blue] does not.
The fact that two complex structures differing only at a
remote acyclic and highly insulated stereocenter can still be
differentiated spectroscopically provoked us to synthesize (+)-
lepadin G and (+)-5′-epi-lepadin G in an attempt to concisely
assign C5′ stereochemistry in (+)-lepadin G. Consequently, total
1
our 13C NMR did match Wright’s data, but H NMR comparison retains
minor variations.
(8) For total syntheses of (+)-lepadin F and (-)-lepadin G, see: Niethe,
A.; Fischer, D.; Blechert, S. J. Org. Chem. 2008, 73, 3088.
(9) (a) Kocienski, P. Phosphorous Sulfur 1985, 24, 97. (b) Kocienski,
P.; Lythgoe, B.; Watrehouse, I. J. Chem. Soc., Perkin Trans. 1 1980, 1045.
(10) For the synthesis of 7, see: (a) D’Souza, L. J.; Sinha, S. C.; Lu, S.;
Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57, 5255. (b) Blackemore, P. A.;
Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26. Also see refs 3c
and 3d
.
(11) See Supporting Information.
Org. Lett., Vol. 11, No. 20, 2009
4617

both proton and carbon NMR chemical shift differences in
C6D6 between Carroll’s natural (+)-lepadin G1 and our
synthetic (+)-lepadin G and (+)-5′-epi-lepadin G (Figure
4). Although 13C NMR comparison is less unambiguous than
Figure 3.
1H NMR spectra of Carroll’S natural (+)-lepadin F versus
synthetic (+)-lepadin F and (+)-5′-epi-lepadin F.
Figure 4. NMR comparison of synthetic (+)-lepadin G and (+)-
5′-epi-lepadin G with Carroll’S natural (+)-lepadin G.
syntheses of both (+)-lepadin G and (+)-5′-epi-lepadin G were
carried out as summarized in Scheme 3.
1H NMR, the synthetic (+)-lepadin G appears to match the
natural (+)-lepadin G better than (+)-5′-epi-lepadin G. The
Scheme 3
.
Total Syntheses of (+)-Lepadin G and
(+)-5′-epi-Lepadin Ga
1
specific difference in H NMR for (+)-lepadin G and (+)-
5′-epi-lepadin G can be again revealed in the 1.90-1.72 ppm
1
region of H NMR spectra for which the resonances are
assigned to H4ꢀ and H6′′ (Figure 5). Our synthetic (+)-
Figure 5.
1H NMR spectra of Carroll’s natural (+)-lepadin G versus
synthetic (+)-lepadin G and (+)-5′-epi-lepadin G.
a Reagents and conditions: (a) Pd(OH)2/C, 60 psi H2, 4.0 equiv (BOC)2O,
MeOH, 24 h. (b) K2CO3, MeOH, 50 °C. (c) Dess-Martin periodinane
[DMP] reagent, NaHCO3, CH2Cl2. (d) NaBH4, MeOH, -41 °C. (e) 10.0
equiv TBDPSCl·imidazole, CH2Cl2, 40 °C, 12. (f) DIBAL-H, -40 °C. (g)
DMP oxidation. (h) NaHMDS, THF, -78 °C, (R)-7 or (S)-7. (i) Pd/C, 20
psi H2, MeOH, rt. (j) TBAF, THF, 50 °C.
lepadin G [red] would again match more closely with
Carroll’s spectra [black] relative to (+)-5′-epi-lepadin G
[blue], thereby suggesting that the relative stereochemistry
at C5′ should be R for (+)-lepadin G.
With both synthetic (+)-5′-lepadin G and (+)-5′-epi-
lepadin G in hand, we were able to tabulate ∆δ values for
Finally, the absolute configuration for (+)-lepadin G could
also be assessed in an unambiguous manner. Blechert’s
4618
Org. Lett., Vol. 11, No. 20, 2009

synthesis of (-)-lepadin G led to an [R]23D value of -14.5°
While a great ideal of overlap can be seen with the cis
1-aza-decalinic core being virtually identical, they are
different particularly in all the respective side chains.
Although these are not calculations in C6D6 nor do they
represent an average conformation, we believe these readily
observable conformational differences on the side chains can
contribute to the observed spectroscopic differences.
In addition, these calculations suggest the presence of the
H-bonding between the C5′-OH and C1′′-CdO in the two
respective pairs of conformers: (+)-lepadin F [red dotted line]
versus (+)-5′-epi-(+)-lepadin F [blue dotted line], and (+)-
lepadin G [red dotted line] versus (+)-5′-epi-lepadin G [blue
dotted line]. The clear difference in the H-bonding distance
in these two pairs of conformers can contribute prominently
to their respective conformational difference, thereby provid-
ing a rationale for two complex structures to be spectroscopi-
cally distinct despite differing only at a highly insulated
acyclic stereocenter.
We have described here concise assignments of the C5′
relative stereochemistry in both (+)-lepadin F and (+)-lepadin
G, as well as the absolute configurations of (+)-lepadin G
through enantioselective total syntheses of (+)-5′-epi-lepadin
F, (+)-lepadin G, and (+)-5′epi-lepadin G. This work
documents the possibility of a diastereomeric pair possessing
sufficient spectroscopic difference for clear differentiation
even when both isomers differ only at a highly insulated
acyclic stereogenic center. These efforts support that total
synthesis remains a useful tool in stereochemical assignments
of natural products.
[c 0.26, CH2Cl2], the [R]23 value of our synthetic (+)-
D
lepadin G is +10.2° [c 0.26, CH2Cl2] with Carroll’s natural
sample being [R]23D ) +12.5° [c 0.31, CH2Cl2]. On the other
hand, both antipodes of lepadin F were reported with Wright2
documenting (-)-F and Carroll1 reporting (+)-F. Thus,
assigning the absolute configuration of lepadin F is not as
critical especially since the reported values ([R]22D ) -1.5°
[c 0.1, CHCl3] and ([R]23D ) +5.55° [c 0.12, CH2Cl2] from
Wright and Carroll, respectively) are too small to make
meaningful comparisons. Nevertheless, on the basis of the
current information, it implies that stereochemically (+)-
lepadin F and (+)-lepadin G are essentially enantiomeric at
the 1-aza-decalinic core and the alkyl side chain, while
differing only in the degree of unsaturation for the ester side
chain.
We were intrigued by the fact that these two diastereomeric
pairs possessed sufficient spectroscopic difference for clear
assignment despite differing only at a highly insulated acyclic
stereogenic center. Consequently, we carried out calculations
to analyze lowest-energy equilibrium conformers for (+)-
lepadin F and (+)-5′-epi-lepadin F as well as (+)-lepadin G
and (+)-5′-epi-lepadin G. Spartan Molecular Mechanics/
MMFF was employed for identifying the lowest-energy
conformer with Hartree-Fock/6-31G* being adopted for the
equilibrium geometry optimization. The overlapping con-
formers of (+)-lepadin F [gold] and (+)-5′-epi-(+)-lepadin
F [gray] as well as (+)-lepadin G [gold] and (+)-5′-epi-
lepadin G [gray] are shown in Figure 6.
Acknowledgment. We thank the NIH [NS38049] for
financial support. We thank Professor Craig J. Forsyth [Ohio
State University] for informative discussions that occurred
in 2003. We thank Dr. Yu Zhang [Dow AgroSciences] for
computational modeling and assistance on other aspects of
the manuscript. We are particularly grateful to Dr. Rohan
A. Davis, Dr. Anthony R. Carroll, and Professor Ronald J.
Quinn of Griffith University [Queensland, Australia] for
providing us with invaluable spectral data of lepadins F-H.
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra and characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 6. Models of (+)-lepadins and (+)-5′-epi-lepadins.
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