Total synthesis and absolute configuration of laurenditerpenol: A hypoxia inducible factor-1 activation inhibitor

Article abstract of DOI:10.1021/jm7011062

The absolute stereo structure of the natural product laurenditerpenol (1S, 6R, 7S, 10R, 11R, 14S, 15R) has been accomplished from eight plausible stereoisomers by its first asymmetric total synthesis in a highly convergent and flexible synthetic pathway.

Full text of DOI:10.1021/jm7011062

J. Med. Chem. 2007, 50, 6299–6302
6299
Total Synthesis and Absolute Configuration
of Laurenditerpenol: A Hypoxia Inducible
Factor-1 Activation Inhibitor
Amar G. Chittiboyina,† Gundluru Mahesh Kumar,†
Paulo B. Carvalho,† Yang Liu,‡ Yu-Dong Zhou,‡
Dale G. Nagle,‡ and Mitchell A. Avery*,†,§,
UniVersity of Mississippi, UniVersity, Mississippi 38677-1848
ReceiVed September 5, 2007
Abstract: The absolute stereo structure of the natural product lauren-
diterpenol (1S, 6R, 7S, 10R, 11R, 14S, 15R) has been accomplished
from eight plausible stereoisomers by its first asymmetric total synthesis
in a highly convergent and flexible synthetic pathway. Six stereoisomers
of laurenditerpenol were synthesized and evaluated for their biological
activity.
Figure 1. Originally proposed (1) and absolute stereochemical
assignment (1c) of laurenditerpenol from eight possible stereoisomers.
Scheme 1. Retrosynthetic Analysis of Laurenditerpenol
The rapid proliferation of cells within a tumor mass quickly
outpaces the capability of existing vasculature to supply oxygen
and nutrients. In cancer patients, the extent of tumor hypoxia
correlates with advanced disease stages and an overall poor
prognosis.1 Presently, there is no drug that specifically targets
hypoxic tumor cells. The transcription factor hypoxia-inducible
factor 1 (HIF-1a), a heterodimer of the bHLH-PAS proteins HIF-
1R and HIF-1ꢀ/ARNT, functions as a master regulator of
hypoxia-induced gene expression when mammalian cells are
subjected to oxygen-deprived conditions.2 Inhibition of HIF-1
production/function in animal models significantly reduces
tumor growth,3 and small molecule HIF-1 inhibitors represent
potential tumor hypoxia-selective anticancer drug leads.4
Bioassay-guided fractionation of the lipid extract of the red
alga Laurencia intricata yielded a structurally novel bicyclic
diterpene, laurenditerpenol 1.5 Laurenditerpenol was the first
marine natural product found to inhibit hypoxia (1% O2)-induced
HIF-1 activation and potently inhibited HIF-1 activation in T47D
breast tumor cells by hypoxia with an IC50 value of 0.4 µM.5
Mitochondrial respiration studies suggest that laurenditerpenol
is the first member of a structurally novel class of marine natural
product-based mitochondrial inhibitors that block mitochondrial
oxygen consumption and promote the degradation of HIF-1R
protein under hypoxic conditions.5
relative syn-configuration of the 7-oxabicyclo[2.2.1]heptane ring
methyl chiral centers at C11, C14, and C15, as well as their
trans relationship to C10, the configurations of the stereocenters
at C6 and C7, including the issue of absolute stereochemistry
at C10, C11, C14, and C15, remained unknown. These
uncertainties prompted us to initiate a total synthesis of
laurenditerpenol to determine its absolute stereochemistry. We
describe herein an inaugural total assignment of the absolute
configuration of laurenditerpenol from one of eight possible
stereoisomers of 1 (Figure 1) through the first asymmetric total
synthesis.
Our retrosynthetic analysis of the basic skeleton of lauren-
diterpenol is depicted in Scheme 1. This envisioned analysis is
a result of preliminary studies with racemic materials that have
eliminated many obvious construction strategies, leading to a
rather straightforward sulfone-mediated C-C bond formation
between bromide 4 and hindered bicyclic sulfone 5. This
disconnection approach provides a flexible strategy to incor-
porate either enantiomer of sulfone 5, and the C7 configuration
could be introduced by adopting appropriate stereoselective
transformations. The double Michael/Diels–Alder addition of
methyl crotonate to the furanone enolate can provide adduct
(()-6 and could be converted into olefin 3 with all the essential
substituents and the correct relative configuration, including a
trans relationship between the methyl and carboxylic acid
substituents.
The intriguing biological properties of laurenditerpenol with
the structural complexity of the molecule, including an unprec-
edented 7-oxabicyclo[2.2.1]heptane ring system and contiguous
stereogenic centers at C1, C6, and C7, pose a significant
synthetic challenge. Although previous spectroscopic studies
permitted the identification of the structure of the natural
product, including the absolute configuration at C1 and the
* To whom correspondence should be addressed. Prof. Mitchell A. Avery,
417 Faser Hall, Department of Medicinal Chemistry, School of Pharmacy,
University, MS 38677-1848. Tel.: (662) 915-5879. Fax: (662) 915-5638 .
E-mail: mavery@olemiss.edu.
†
Department of Medicinal Chemistry.
Department of Pharmacognosy.
National Center for Natural Product Research.
The synthetic venture commenced with an “anion-assisted”
Diels–Alder reaction/sequential Michael addition of lithium
enolate 7 with methyl crotonate, which remarkably produced
6-exo-ketoester (()-6 as a single diastereomer (Scheme 2).6 The
assignment of the 6-exo configuration was made based on NMR
experiments, as shown in the Scheme 2. Racemic ketoester (()-6
was protected as the thioketal and hydrolyzed into acid (()-9.
‡
§
Department of Chemistry and Biochemistry.
Abbreviations: HIF-1, hypoxia inducible factor 1; bHLH, basic-
a
helix–loop–helix; PAS, Per-Arnt-Sim; Arnt, AhR nuclear translocator; AhR,
aryl hydrocarbon receptor; pHRE, putative hypoxia response element; TK-
luc, thymidine kinase-luciferase.
10.1021/jm7011062 CCC: $37.00
2007 American Chemical Society
Published on Web 11/16/2007

6300 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Letters
Scheme 2. Synthesis of Chiral 7-Oxabicyclo[2.2.1]-heptane
Scheme 3. Fragment Coupling and Synthesis of Keto-sulfone 2
(X ) SO2Ph)a
Ring Systema
a Reagents and conditions: (a) LDA, Et2O/cyclohexane, –78 °C, then
methyl crotonate, 69%; (b) (i) ethanedithiol, p-TsOH, benzene, reflux; (ii)
LiOH, aq MeOH, 92%, two steps; (c) TEA, trimethylacetyl chloride, LiCl,
(S)-(–)-4-benzyl-2-oxazolidinone, CH2Cl2, rt, separation of diastereomers
by silica gel chromatography: (–)-10, 40%, (+)-10, 42%; (d) (i) Raney Ni,
EtOH, reflux, 98%; (ii) LiBH4, THF, 0 °C, (-)-11, 95%, (+)-11 96%; (e)
Ph3P, I2, imidazole, CH2Cl2, rt, (-)-12, 94%, (+)-12, 92%; (f) PhSO2Na,
DMF, 60 °C, (–)-5, 90%, (+)-5, 91%. ORTEP representation of the
N-acyloxazolidinone (-)-10 (H atoms are omitted for clarity).
a Reagents and conditions: (a) (CH2OH)2, CSA, benzene, reflux, 24 h,
73% (dr 92:8); (b) NBS, Yb(OTf)3, TMSCl, CH2Cl2, 0 °C, 15 min, 48%;
(c) (-)-5, n-BuLi, HMPA, THF, –40 °C, 40 min, then 4, 2 h, 98% (dr
95:5); (d) (i) BH3.S(CH3)2, THF, 10 h; (ii) H2O2, NaOH, 0 °C, 87%; (e) (i)
PhSSPh, (n-Bu3)P, toluene, rt, 94%; (ii) Raney Ni, EtOH, reflux, 90%; (f)
PdCl2(CH3CN)2, acetone, rt, 30 min, 92%. In ORTEP representation of
one of the two crystallographically independent molecules of 2 (H atoms
and cocrystallized ether molecules are omitted for clarity).
With the ambiguity in the relative configuration of the bicyclic
moiety, we decided to alter our synthesis to obtain both the
(+)- and (-)-bicyclic intermediates of 5. Seeking a higher level
of convergence, the best resolution of racemic acid (()-9 has
been achieved by converting it into N-acyloxazolidinone dia-
stereomers (-)-10 and (+)-10 employing standard coupling
conditions PivCl/Et3N/LiCl in 82% yield.7 The crystal structure
of oxazolidinone (-)-108 confirmed the soundness of NMR
experiments analysis on ketoester (()-6 and established the
absolute configuration of the 7-oxabicyclo[2.2.1]heptane ring
system. With completely characterized diastereomers (-)-10 and
(+)-10 in hand, each isomer was separately converted into its
corresponding enantiomeric sulfone in a four-step reaction
sequence. Thus, reductive elimination of the thioketal function-
ality followed by reductive removal of the chiral auxiliary with
LiBH4 provided alcohol (-)-11. Direct iodination of alcohol
(–)-11 with TPP/I2/imidazole9 followed by sulfonylation with
PhSO2Na produced sulfone (-)-5. Following the same reaction
sequence sulfone (+)-5 was also prepared from oxazolidinone
(+)-10.
Following the synthetic strategy, an acid-catalyzed ketaliza-
tion of R-(+)-pulegone accompanied by double bond migration
introduced the C6 stereogenic center to produce diequatorial
ketal 13 in high diastereoselectivity.10 Regioselective allylic
bromination of ketal 13 with NBS employing Yamanaka
conditions11 afforded bromide 4 in moderate yields, while
classical radical bromination disappointingly produced an
inseparable plethora of products. Stereoselective alkylation of
allyl bromide 4 with sulfone (-)-5 was successfully achieved
in 98% yield with high diastereoselectivity (dr 95:5). Direct
hydrogenation12 of olefin 3 proved to be unsuccessful in our
hands, while stereoselective hydroxylation of the olefin moiety
occurred under routine conditions employing a hydroboration/
oxidation13 sequence. The resultant anti-Markovnikov alcohol
14 was formed as expected while introducing the C7 methyl
stereocenter. As anticipated, the hydroxy sulfone 14 was
produced with excellent regio- and stereoselectivity, which could
be explained in terms of electrophilic borane addition by the
Felkin-Anh-Houk paradigm (Figure A).14 Sulfinylation of 14
with PhSSPh/Bu3P15 followed by reductive elimination afforded
methyl sulfone 15 in excellent yield. Deketalization of 15 with
PdCl2(CH3CN)2/acetone16 efficiently produced ketosulfone 2 in
Scheme 4. Synthesis and Absolute Configuration of
Stereoisomers of Laurenditerpenol 1a and ent-1ga
a Reagents and conditions: (a) Na-Hg (10%), MeOH, rt, 68%; (b) (i)
LDA, PhSeCl, THF, -78 °C; (ii) Py, H2O2, CH2Cl2, H2O, 0 °C, 78%; (c)
CeCl3, NaBH4, MeOH, 0 °C, 72%.
92% yield with no epimerization at C6 (Scheme 3), whereas
longer reaction times under the same conditions or other acid-
catalyzed deketalization conditions17 resulted in C6 epimeriza-
tion in minor quantities. X-ray crystallographic analysis18 of
ketosulfone 2 revealed 7R-configuration at the C7 methyl center
and supported the evolution of C7 configuration as anticipated
by the Felkin-Anh-Houk model of electrophilic hydroboration.
Having established the absolute configuration of ketosulfone
2, reductive desulfonylation19 as originally planned was ac-
complished using Na-Hg in MeOH to produce ketone 16 with
traces of the C6 epimerized product.20
Regioselective enolization of 2 with lithium diisopropylamide
at –78 °C followed by addition of PhSeCl produced a mixture
of diastereomers,20 which was further subjected to oxidative
elimination to afford R,ꢀ-unsaturated ketone 18.21Regioselective
22
reduction of the R,ꢀ-unsaturated ketone with CeCl3-NaBH4
produced chromatographically separable C1 epimers, ent-1g and
1a in a 2:3 ratio. Thus, we have synthesized two stereoisomers
of laurenditerpenol in a single pot (Scheme 4), one with the
desired 1S-configuration and one is the enantiomer of the
probable eight isomers (Figure 1).
The 1H NMR spectroscopic data and the physical parameters
(TLC and specific rotation) of the stereoisomer 1a did not match
with an authentic sample of natural product 1, whereas the ent-
1
1
1g H NMR spectrum was closely similar. H NMR spectral
data analyses of these C-1 epimers were clearly characteristic
of the natural product, which in turn reduced the synthetic

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6301
Scheme 5. Total Synthesis of Laurenditerpenola
maneuver required to identify the correct stereoisomer of
laurenditerpenol. The 1H NMR spectrum of 1a showed the H2
proton resonance at δ 5.39 ppm as a broad singlet, and the H1
proton appeared at 4.03 ppm as a broad multiplet, whereas the
1H NMR spectrum of ent-1g showed the H2 resonance at 5.64
ppm as a doublet (J ) 4.0 Hz) and H1 at 4.11 ppm as a broad
singlet. When a comparison was made of this spectral data with
reported spectral data of similar systems,23 we concluded that
1,6-syn-cyclohex-2-en-1-ol and 1,6-anti-cyclohex-2-en-1-ol sys-
1
tems exhibit this characteristic H NMR signal difference in
chemical shift values.24 Based on this characterization and
comparison of the H2 and H1 proton chemical shift values of
natural product 1 with ent-1g, it is clear that laurenditerpenol
must possess a 1,6-syn-cyclohex-2-en-1-ol system within its
structure. This analysis eliminates all of the remaining 1,6-anti-
cyclohex-2-en-1-ol isomers 1b,1e, 1f and leaves 1,6-syn-
cyclohex-2-en-1-ol isomers.
a Reagents and conditions: (a) Na-Hg, MeOH, rt, 6 h, 78%; (b) (i)
BH3 ·DMS, THF followed by H2O2, NaOH, 0 °C, 86%; (c) (PhS)2, n-Bu3P,
toluene, rt, 90% (21a/21b 3:1); (d) (i) Raney Ni, EtOH, reflux, 94%, 92%;
(ii) PdCl2(CH3CN)2, acetone, rt, 30 min, 92%, 90%; (e) KOH, MeOH, rt,
12 h, 30% epimerization, 35% epimerization; f) (i) 21a/21b, LDA, –78°C,
HMPA, THF, 1 h, PhSeCl, 2 h; (ii) H2O2, THF, 30 min, 72%, 68%; (g)
CeCl3, NaBH4, MeOH, 0 °C, 84% (2:3 1d/ent-1f), 80% (2:3 1c/ent-1e).
The representative yields in italics are corresponds to the 7S-isomer.
Thus, the first successful synthesis of stereoisomers of
laurenditerpenol 1a and ent-1g has limited the possibility of
the natural product from its eight stereoisomers 1a-1h to three
stereoisomers 1c, 1d, and 1h (Figure 1).
At this stage, we advanced to synthesize the remaining target
stereoisomers with sulfone (–)-5. Following the developed
synthetic technology, we altered the reaction sequence to
maneuver the synthesis of both the C7 stereoisomers. Thus,
sulfone 3 was desulfonylated to culminate the observed stereo-
induction in the hydroboration reaction due to phenylsulfone
functionality, which in turn facilitates access to both the 7R-
and 7S-hydroxy compounds 20a and 20b, respectively. Because
these diastereomers are chromatographically difficult to separate,
the mixture was further subjected to sulfinylation to provide
the corresponding phenylsulfides 21a and 21b as a chromato-
graphically separable mixture of diastereomers. Reductive
elimination of phenylsulfide 21a followed by deketalization
afforded ketone 16.
The desired C1-C6 syn stereoselectivity was achieved by
epimerization of ketone 16 to 22, and the diastereomers were
separated by silica gel flash chromatography.25 Dehydrogenation
of ketone 22 to enone 23 using a two-step protocol, followed
by regioselective reduction under Luche conditions, produced
stereoisomers of laurenditerpenol 1d and ent-1f in a 2:3 ratio
as a chromatographically separable mixture of isomers (Scheme
5). As anticipated, stereoisomer 1d closely matched the 1H NMR
spectral data of the natural product, but the carbon values varied
moderately, and the TLC Rf did not match with an authentic
sample of the natural product. Following the same synthetic
transformations, stereoisomer 1c also synthesized from phenyl-
sulfide 21b. The 1H and 13C NMR spectra of synthetic 1c were
identical with natural product 1. Moreover, synthetic 1c and
authentic natural product 1 exhibited identical behavior on TLC,
confirming the absolute configuration as drawn.26
Table 1. IC50 Values of Synthetic Stereoisomers of Laurenditerpenol
isomer
hypoxia (16 h) pHRE3-TK-luca
1c
1d
ent-1g
0.82 µM
3.4 µM
>30 µM
a Values were obtained from the T47D cell-based reporter assay.
penol 1c. Inversion of configuration at C1, C6, and C7
essentially deactivated ent-1g.
In summary, the goal of assigning the absolute configuration
of laurenditerpenol has been accomplished from eight plausible
stereoisomers by its first asymmetric total synthesis in a highly
convergent manner. The flexibility of the current strategy to
deliver either configuration at each stereocenter allows construc-
tion of all stereoisomers of this valuable natural product for
further biological evaluation. An asymmetric variant of the
current total synthesis and the structure–activity relationships
of all the isomers and the rational design of other novel HIF-1
analogues for chemical biology studies are in progress and the
results will be reported in due course.
Acknowledgment. We thank Dr. Blake E. Watkins for his
technical help. This investigation was conducted in a facility
constructed with support from research facilities improvement
program Grant No. C06 Rr-14503-01 from the National Center
for Research Resources, National Institutes of Health. Support
provided by NIH-NCI CA98787 (DGN).
The synthetically produced isomers of laurenditerpenol were
evaluated for their ability to inhibit hypoxia-induced HIF-1
activation in T47D breast tumor cells.27 Synthetic laurenditer-
penol 1c is very similar in potency (IC50 0.82 µM) to the original
compound isolated from L. intricata (Table 1).28 At concentra-
tions as high as 30 µM, compound 1c neither inhibited luciferase
expression from the pGL3-control reporter, nor inhibited T47D
cell proliferation/viability under assay conditions. Therefore, the
inhibition of hypoxia-induced HIF-1 activation (pHRE3-TK-
luc) by 1c was selective and independent of any effect on T47D
cell viability. Inversion of configuration at C7 1d was associated
with a 76% drop in potency, relative to synthetic laurenditer-
Supporting Information Available: Spectral characterization
data of selected compounds (1H, 13C NMR, HRMS). This material
is available free of charge via Internet at http://pubs.acs.org.
References
(1) Tatum, J. L.; Kelloff, G. J.; Gillies, R. J.; Arbeit, J. M.; Brown, J. M.;
Chao, K. S. C.; Chapman, J. D.; Eckelman, W. C.; Fyles, A. W.;
Giaccia, A. J.; Hill, R. P.; Koch, C. J.; Krishna, M. C.; Krohn, K. A.;
Lewis, J. S.; Mason, R. P.; Melillo, G.; Padhani, A. R.; Powis, G.;
Rajendran, J. G.; Reba, R.; Robinson, S. P.; Semenza, G. L.; Swartz,
H. M.; Vaupel, P.; Yang, D.; Croft, B.; Hoffman, J.; Liu, G.; Stone,
H.; Sullivan, D. Hypoxia: Importance in tumor biology, noninvasive
measurement by imaging, and value of its measurement in the

6302 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Letters
management of cancer therapy. Int. J. Radiat. Biol. 2006, 82, 699–
757.
(2) (a) Giaccia, A.; Siim, B. G.; Johnson, R. S. HIF-1 as a target for drug
development. Nat. ReV. Drug DiscoVery 2003, 2, 803–811. (b)
Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. ReV. Cancer
2003, 3, 721–732.
vinigrol, an architecturally novel diterpenoid with potent platelet
aggregation inhibitory and antihypertensive properties. 1. Application
of anionic sigmatropy to construction of the cctalin substructure. J.
Org. Chem. 2003, 68, 6096–6107.
(16) (a) Chanu, A.; Safir, I.; Basak, R.; Chiaroni, A.; Arseniyadis, S.
Enantioselective total synthesis of 1-epi-pathylactone A. Org. Lett.
2007, 9, 1351–1354. (b) Lipshutz, B. H.; Pollart, D.; Monforte, J.;
Kotsuki, H. Palladium(II)-catalyzed acetal/ketal hydrolysis/exchange
reactions. Tetrahedron Lett. 1985, 26, 705–708.
(17) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; p 473. (b) Omura, K.
Iodine oxidation of a-tocopherol and its model compound in alkaline
methanol: unexpected isomerization of the product quinone mono-
ketals. J. Org. Chem. 1989, 54, 1987–1990.
(18) CCDC 656779 contains the supplementary crystallographic data for
compound 2. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(19) Dabby, R. E.; Kenyon, J.; Mason, R. F. The basic reductive fission of
sulfones. J. Chem. Soc. 1952, 4881–4882.
(20) Ketone 16 was separated from traces of epimerized diastereomers by
column chromatography. To confirm the configuration of 16 at the
C6 stereocenter, a diastereomeric mixture of selenides were separated
by silica gel flash column chromatography to afford the 2,3-anti-isomer
17a and the 2,3-syn-isomer 17b in 2:3 ratio. Observation of NOESY
correlations between H2 and H6 in the 2,3-anti-isomer 17a confirmed
its 6S configuration.
(3) (a) Maxwell, P. H.; Dach, G. U.; Gleadle, J. M.; Nicholls, L. G.; Harris,
A. L.; Stratford, I. J.; Hankinson, O.; Puch, C. W.; Ratcliffe, P. J.
Hypoxia-inducible factor-1 modulates gene expression in solid tumors
and influences both angiogenesis and tumor growth. Proc. Natl. Acad.
Sci. U.S.A. 1997, 94, 8104–8109. (b) Moeller, B. J.; Dreher, M. R.;
Rabbani, Z. N.; Schroeder, T.; Cao, Y.; Li, C. Y.; Dewhirst, M. W.
Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer
Cell 2005, 8, 99–110. (c) Ryan, H. E.; Lo, J.; Johnson, R. S. HIF-1a
is required for solid tumor formation and embryonic vascularization.
EMBO J. 1998, 17, 3005–3015. (d) Ryan, H. E.; Poloni, M.; McNulty,
W.; Elson, D.; Gassmann, M.; Arbeit, J. M.; Johnson, R. S. Hypoxia-
inducible factor-1a is a positive factor in solid tumor growth. Cancer
Res. 2000, 60, 4010–4015. (e) Unruh, A.; Ressel, A.; Mohamed, H. G.;
Johnson, R. S.; Nadrowitz, R.; Richter, E.; Katschinski, D. M.; Wenger,
R. H. The hypoxia-inducible factor-1a is a negative factor for tumor
therapy. Oncogene 2003, 22, 3213–3220.
(4) (a) Melillo, G. Targeting hypoxia cell signaling for cancer therapy.
Cancer Metastasis ReV. 2007, 26, 341–352. (b) Semenza, G. L.
Development of novel therapeutic strategies that target HIF-1. Expert
Opin. Ther. Targets 2006, 10, 267–280.
(5) Mohammed, K. A.; Hossain, C. F.; Zhang, L.; Bruick, R. K.; Zhou,
Y.-D.; Nagle, D. G. Laurenditerpenol, a new diterpene from the tropical
marine alga Laurencia intricata that potently inhibits HIF-1-mediated
hypoxic signaling in breast tumor cells. J. Nat. Prod. 2004, 67, 2002–
2007.
(6) (a) Caine, D.; Collison, R. F. Reactions of the lithium dienolate of
2,5-dimethyl-3(2H)-furanone with unsaturated compounds. Synlett
1995, 503–504. (b) Caine, D. S.; Paige, M. A. Reactions of a 3(2H)-
furanone lithium enolate with 4-halocrotonates. Synlett 1999, 1391–
1394. (c) Lipshutz, B. H. Five-membered heteroaromatic rings as
intermediates in organic synthesis. Chem. ReV. 1986, 86, 795–820.
(7) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. Asymmetric Diels-Alder
cycloaddition reactions with chiral R,ꢀ-unsaturated N-acyloxazoli-
dinones. J. Am. Chem. Soc. 1988, 110, 1238–1256. (b) Liao, L.-a.;
Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M. An efficient and general
method for resolving cyclopropene carboxylic acids. Tetrahedron 2004,
60, 1803–1816.
(8) CCDC 656780 contains the supplementary crystallographic data for
compound (-)-10. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(9) Lange, G. L.; Corelli, N. Synthesis of the sesquiterpenoid lactarane
skeleton by a radical cyclobutylcarbinyl/cyclopropylcarbinyl fragmen-
tation sequence. Tetrahedron Lett. 2007, 48, 1963–1965.
(10) Miller, D.; Bilodeau, F.; Burnell, R. H. Stereoselective syntheses of
isomers of 3,7-dimethylnonadecane, a sex pheromone of the alfalfa
blotch leafminer (Agromyza frontella (Rondani)). Can. J. Chem. 1991,
69, 1100–1106.
(11) Yamanaka, M.; Arisawa, M.; Nishida, A.; Nakagawa, M. An intriguing
effect of Yb(OTf)3-TMSCl in the halogenation of 1,1-disubstituted
alkenes by NXS: Selective synthesis of allyl halides. Tetrahedron Lett.
2002, 43, 2403–2406.
(12) Hydrogenation with Pd/C-EtOAc, MeOH, or EtOH at H2 atm or 80
psi for 16 h did not furnish any required product. Hydrogenation with
Wilkinsons catalyst was also found to be unfavorable.
(13) (a) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. Sodium perborate:
A mild and convenient reagent for efficiently oxidizing organoboranes.
J. Org. Chem. 1989, 54, 5930–5933. (b) Stephan, E.; Brossat, M.;
Lecomte, V.; Bouit, P.-A. Synthesis of the 11b-hydroxymethyl-androst-
4-en-3,17-dione. Tetrahedron 2006, 62, 3052–3055.
(14) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. Staggered models
for asymmetric induction: attack trajectories and conformations of
allylic bonds from ab initio transition structures of addition reactions.
J. Am. Chem. Soc. 1982, 104, 7162–7166.
(21) Kim, J. H.; Lim, H. J.; Cheon, S. H. A facile synthesis of (6S,1′S)-
(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin. Tetrahedron 2003,
59, 7501–7507.
(22) (a) Luche, J. L. Lanthanides in organic chemistry. 1. Selective 1,2-
reductions of conjugated ketones. J. Am. Chem. Soc. 1978, 100, 2226–
2227. (b) Luche, J. L.; Gemal, A. L. Lanthanoids in organic synthesis.
5. Selective reductions of ketones in the presence of aldehydes. J. Am.
Chem. Soc. 1979, 101, 5848–5849. (c) Luche, J. L.; Rodriguez-Hahn,
L.; Crabbe, P. Reduction of natural enones in the presence of cerium
trichloride. J. Chem. Soc., Chem. Commun. 1978, 601–602.
(23) (a) Serra, S.; Brenna, E.; Fuganti, C.; Maggioni, F. Lipase-catalyzed
resolution of p-menthan-3-ol monoterpenes: preparation of the enan-
tiomer-enriched forms of menthol, isopulegol, trans- and cis-piperitol,
and cis-isopiperitenol. Tetrahedron: Asymmetry 2003, 14, 3313–3319.
(b) Takao, K.; Tsujita, T.; Hara, M.; Tadano, K. Asymmetric total
syntheses of (+)-cheimonophyllon E and (+)-cheimonophyllal. J. Org.
Chem. 2002, 67, 6690–6698.
(24) Spectroscopic analysis and mechanistic implications of these kind of
systems are under progress, and the detailed results will be explored
elsewhere in the future.
(25) To improve the epimerized product yield, several basic conditions were
attempted. Either similar yield or decomposed product(s) especially
with metal hydrides in aprotic solvents was obtained. It was determined
at this stage to use this quick and processible reaction, albeit to provide
the material for exploration.
(26) See Supporting Information for a complete set of spectral data.
Regarding the rotation value, variation in rotation value from reported
1 and synthesized 1c may be due to nonidentical experimental
conditions. When we recorded the rotation of our authentic sample
and synthetic sample under identical experimental conditions, the
rotation value is identical.
(27) For experimental details, see Supporting Information.
(28) It is critical to note that due to the poor solubility of laurenditerpenol
in the formulation for biological evaluation, the original IC50 values
varied between separate concentration-response studies, and the
average IC50 value (0.4 µM) from a series of independent experiments
was ultimately reported. This variation in potency is within the range
of values observed in the original studies.
(15) (a) Mitsunobu, O. The use of diethyl azodicarboxylate and triphenyl-
phosphine in synthesis and transformation of natural products.
Synthesis 1981, 1–28. (b) Paquette, L. A.; Guevel, R.; Sakamoto, S.;
Kim, I. H.; Crawford, J. Convergent enantioselective synthesis of
JM7011062