A protecting group-free synthesis of (-)-hortonones A-C from the Inhoffen-Lythgoe diol

Article abstract of DOI:10.1039/c6ob01738j

A synthesis of hortonones A-C has been accomplished from vitamin D₂via the Inhoffen-Lythgoe diol without the use of protective groups. Key steps in the syntheses include a TMS-diazomethane mediated regioselective homologation of the cyclohexano

Full text of DOI:10.1039/c6ob01738j

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DOI: 10.1039/C6OB01738J
Organic and Biomolecular Chemistry
ARTICLE
A Protecting Group-Free Synthesis of (-)-Hortonones A-C from the
Inhoffen-Lythgoe Diol
Hovsep Stambulyana and Thomas G. Minehana*
Received 00th January 20xx,
Accepted 00th January 20xx
A synthesis of hortonones A-C has been accomplished from Vitamin D2 via the Inhoffen-Lythgoe diol without the use of
protective groups. Key steps in the syntheses include a TMS-diazomethane mediated regioselective homologation of the
cyclohexanone ring to a cycloheptanone moiety and a sodium naphthalenide-mediated allylic alcohol transposition. It has
been found that the absolute configuration of the natural hortonones is opposite that of the synthetic material prepared
from Vitamin D2.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
The hexahydroazulenones hortonones A-C (Figure 1) are a
series of rearranged sequiterpenoids isolated by Andersen et
al. in 2011 from the leaves of Sri Lankan Hortonia.1
Importantly, hortonone C showed in vitro cytotoxicity against
human breast cancer MCF-7 cells at 5 µg/mL. A short synthetic
route to these compounds would facilitate further
investigation of their biological properties and allow for the
preparation of derivatives with enhanced antitumor activities.
In addition, total synthesis would allow a confirmation of the
relative and absolute stereostructure of these natural
products.
Figure 1. Hortonones A-C
We envisioned that the Inhoffen-Lythgoe diol,2 a trans-
fused 6,5 ring system possessing an array of contiguous
stereocenters readily available either from ergocalciferol
(vitamin D2) by exhaustive oxidative cleavage3 or by
asymmetric synthesis,18 was an ideal synthetic precursor of the
hortonones. Acid- or base-mediated isomerization of the easily
derived ketone 5 would give the cis ring fusion present in the
hortonones. Subsequent ring homologation, dehydrogenation,
and 1,3-enone transposition would give hortonone C;
hortonones A and B then could be derived from hortonone C
by organometallic 1,2-addition followed by 1,3- oxidative
transposition (Figure 2).
Figure 2. Retrosynthetic analysis of hortonones A-C.
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with FeCl3 were unfruitful.7 Furthermore, reduVcietwioAnrticolefOntlhinee
ketone to the corresponding alcohol and attempted
Results and Discussion
DOI: 10.1039/C6OB01738J
elimination of the alcohol with Burgess reagent17 led to an
inseparable mixture of alkene regioisomers. However, it was
discovered that exposure of 6 to TMSCHN2 and BF3•OEt2 in
DCM at -40 °C followed by warming to room temperature
provided the expanded ketone 7 in 74% yield with high
regioselectivity (10:1 7:8).8 It is likely that approach of
TMSCHN2 to the activated carbonyl of 6 preferentially takes
place in such a way as to minimize steric interactions between
the bulky trimethylsilyl group and the cyclopentane ring of 6.
As a result, the favoured addition conformer (Scheme 2) places
the alpha carbon atom “b” anti to the nitrogen leaving group,
giving rise to cycloheptanone 7 as the major product upon
rearrangement. Dehydrogenation of 7 was then accomplished
by the Saegusa protocol (TBSOTf, Et3N, CH2Cl2, 0° C, 2h; 50 mol
% Pd(OAc)2, CH3CN, rt, overnight),9 affording enone 9 in 94%
yield.
Oxidative cleavage of ergocalciferol with ozone (1:1 CH2Cl2/CH3OH)
followed by reductive workup with NaBH4 afforded low overall
yields (~40%) of the Inhoffen-Lythgoe diol in our hands.3 However,
subjecting the crude ozonolysis product mixture to catalytic
dihydroxylation (1 mol % OsO4, NMO, acetone/H2O),4 oxidative
cleavage (KIO4, dioxane/H2O) and reduction (NaBH4/MeOH) gave
the desired diol 4 in 75% overall yield (Scheme 1). Transformation
to the intermediate ketone 5 was then achieved in 85% yield by a
three-step sequence involving selective tosylation of the primary
alcohol, reduction of the tosylate with LiAlH4, and oxidation of the
secondary alcohol with Dess-Martin Periodinane.5
Scheme 1. Synthesis of intermediate 5. Reagents and
conditions: (a) O3, CH2Cl2, MeOH, -78 °C; (b) NaBH4, MeOH, rt,
20 min; (c) 1 mol% OsO4, NMO, acetone, H2O, rt, 5h; (d) KIO4,
1:1 dioxane/H2O, rt, 3h; (e) TsCl, Et3N, DMAP, CH2Cl2, rt, 1h;
(f) LiAlH4, THF, rt, 5h; (g) Dess-Martin Periodinane, CH2Cl2, rt,
1h.
Scheme 2. Synthesis of cis-enone 9. Reagents and conditions: (a)
NaH, THF, reflux, 4h; (b) TMSCHN2, BF3•OEt2, CH2Cl2, -40 °C – rt;
(c) TBSOTf, Et3N, CH2Cl2, rt, 2h; (d) 50 mol% Pd(OAc)2, CH3CN, rt,
12h.
The trans-fused ketone 5 was then subjected to isomerization
under basic conditions (NaH, THF, reflux, 4 h)6 to provide the
corresponding cis ketone 6 in 72% yield after chromatography
(Scheme 2). Initial attempts at homologation of this ketone to
the 7-5 ring system of the hortonones by cyclopropanation of
the kinetic trimethylsilyl enol ether of 6 and oxidative cleavage
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Conversion of cycloheptenone 9 into hortonone C required a
1,3-enone transposition,19-21 the most utilized method for
which is the protocol of Wharton.10 However, all attempts to
transpose the enone of 9 by Wharton reaction of the
corresponding epoxy ketone failed. Nonetheless, hortonone C
could be secured by a sequence involving an allylic alcohol 1,3-
transposition (Scheme 3).22 Reduction of 9 with DIBAH
followed by stereoselective epoxidation and mesylation of the
secondary alcohol afforded a 78% overall yield of 10, the
relative stereochemistry of which was confirmed by two-
dimensional NMR (NOESY) experiments (See Scheme 3 and
Supporting Information). Compound 10 was then reduced with
a solution of sodium naphthalenide in THF (3M) at -10 °C to
the corresponding allylic alcohol,11 which was then oxidized
with the Dess-Martin reagent5 to provide hortonone C in 88%
yield. Spectroscopic data (1H NMR, 13C NMR, MS, UV) for
synthetic hortonone C were fully consistent with those
reported for the natural sample by Anderson et al.1 However,
the specific rotation for our sample (-116.0) was in the
opposite sense of that reported for natural hortonone C (+74).
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DOI: 10.1039/C6OB01738J
Scheme 4. Preparation of hortonones A and B. Reagents and
conditions: (a) MeLi, THF, -78 °C; (b) PCC, 4Å sieves, CH2Cl2,
1.5 h, rt; (c) TBSOTf, diisopropylethylamine, CH2Cl2, -78 °C, 1h;
(d) MCPBA, CH2Cl2, NaHCO3, -20 °C, 1h; aq. Na2S2O3.
Figure 3. Proposed structures of natural hortonones A-C.
71% yield by methyllithium addition (ether, -78 °C) followed by
oxidative transposition of the tertiary allylic alcohol with PCC
(4Å sieves, CH2Cl2).14 Oxidation of hortonone A to hortonone B
was accomplished in 69% yield by enolization (TBSOTf, DIPEA,
-78 °C),15 regioselective epoxidation (1.1 equiv MCPBA, CH2Cl2,
NaHCO3, -20 °C) and aqueous hydrolysis (Scheme 4).16
Selective attack of the peracid at the less crowded exocyclic
olefin of the dienolsilane intermediate appears to be favoured
at lower temperatures. Again, all spectrocopic data for
synthetic hortonones A and B closely matched those reported
for the natural products, with the exception of the specific
rotations (synthetic hortonone A: [α]D -31.7; natural
hortonone A: [α]D +24.0; synthetic hortonone B: [α]D -37.5;
natural hortonone B: [α]D +24.0).
Scheme 3. Preparation of hortonone C. Reagents and
conditions: (a) DIBAH, CH2Cl2, -78 °C; (b) MCPBA, CH2Cl2,
NaHCO3, 2h, rt; (c) MsCl, Et3N, CH2Cl2, rt, 1h; (d) Na0,
naphthalene, THF, -10 °C, 30 min; (e) Dess-Martin
periodinane, CH2Cl2, 1h, rt.
Initial attempts to prepare hortonone A by conjugate addition
of organocuprates (CH3MgBr/CuI12; Me2CuLi/TMSCl13) to
enone 9 and oxidation of the resulting ketone afforded
complex product mixtures and low overall yields. However,
hortonone A could be easily prepared from hortonone C in
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17 (a) G. M. Atkins and E. M. Burgess J. Am. Chem. Soc. 1968,
Conclusions
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90, 4744; (b) E. M. Burgess, H. R. RenDtoOnI: 1a0n.1d03E9./AC6. OTBa0y1lo73r8JJ.
Org. Chem. 1973, 38, 26.
The synthesis presented here allows the preparation of all
three hortonones in 12-15 steps from the readily available
Inhoffen-Lythgoe diol. This study has revealed that the
absolute configuration of the hortonones is opposite that
originally proposed by Andersen at al. (Figure 3),1 and thus
vitamin D2 is not a likely biosynthetic precursor of this family
of natural products. A synthetic route to (+)-hortonones A-C
from an alternate starting material is currently being
investigated and our findings will be reported in due course.
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Acknowledgements
This communication is dedicated to Professor Peter B. Dervan
on the occasion of his 70th birthday. The authors thank Jason
Lee for his preparation of compound 4. We acknowledge the
National Science Foundation (CHE-1508070), the National
Institutes of Health (SC3 GM 096899-01) and the donors of the
American Chemical Society Petroleum Research Fund (53693-
URI) for their generous support of this research.
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