Synthesis of the Privileged 8-Arylmenthol Class by Radical Arylation of Isopulegol

Article abstract of DOI:10.1021/acs.orglett.6b01047

Hydrogen atom transfer (HAT) circumvents a disfavored Friedel-Crafts reaction in the derivatization of the inexpensive monoterpene isopulegol. A variety of readily prepared aryl and heteroaryl sulfonates undergo a formal hydroarylation to form 8-arylmenthols, privileged scaffolds for asymmetric synthesis, as typified by 8-phenylmenthol. High stereoselectivity is observed in related systems. This use of HAT significantly extends the chiral pool from the inexpensive monoterpene isopulegol.

Full text of DOI:10.1021/acs.orglett.6b01047

Letter
pubs.acs.org/OrgLett
Synthesis of the Privileged 8‑Arylmenthol Class by Radical Arylation
of Isopulegol
Steven W. M. Crossley,† Ruben M. Martinez,† Sebastian Guevara-Zuluaga, and Ryan A. Shenvi*
́
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Hydrogen atom transfer (HAT) circumvents a
disfavored Friedel−Crafts reaction in the derivatization of the
inexpensive monoterpene isopulegol. A variety of readily prepared
aryl and heteroaryl sulfonates undergo a formal hydroarylation to
form 8-arylmenthols, privileged scaffolds for asymmetric synthesis, as
typified by 8-phenylmenthol. High stereoselectivity is observed in
related systems. This use of HAT significantly extends the chiral
pool from the inexpensive monoterpene isopulegol.
documented substantial variations in diastereocontrol achieved
due to variations in the identity of the aryl group,7,9b,c,e−i but
short routes to these aryl analogs are not available.
ew chemical reactions to modify abundant terpenes find
Napplication in polymer science, medicine, and chemistry,
as well as the flavor and fragrance industry.1 Chiral catalysts,
reagents, and auxiliaries, for example, can be sourced from
cyclic monoterpenes,2 which are usually inexpensive, abundant,
and easily removed from reaction mixtures. During recent
studies of the isocyanoterpene (ICT) class,3 we required access
to aryl derivatives of the broadly applicable chiral controller, 8-
phenylmenthol (1).4 The parent alcohol (−)-1 or (+)-1 can be
appended to carboxylic acids to effect highly stereoselective
reactions, as shown in Figure 1a,b.5,6 Many reports have also
Although either enantiomer of 1 is commercially available,
the high cost [(−)-1: 340 $/g; (+)-1: 840 $/g] and low supply
of these molecules impedes direct functionalization7 and
probably reflects the cost of their five- or six-step syntheses
from (+)- or (−)-pulegone (3.4 $/g at 97% purity and 206 $/g,
respectively; prices from Sigma; see Figure 1c).4 Desymmet-
rization of ( )-trans-2-cumyl-cyclohexanol using a lipase can be
an effective alternative to 1,8 but yields range from 31% to 48%
over two resolution cycles and commercial costs are high (214
$/g for (−)-2-cumylcyclohexanol; (+)-isomer discontinued).
Analogs of 1 have been synthesized by Corey’s route,9 but are
not widely available, and we could find no examples in the
literature of heteroaryl analogs.10
Here we report a radical method that provides rapid access to
(+)- and (−)-8-phenylmenthol and numerous chiral arylated
menthol derivatives. Combination of hydrogen atom transfer
(HAT) radical generation11,12 with a radical Smiles−Truce
rearrangement13,14 allows homoallylic alcohols to be formally
hydroarylated using arylsulfonyl halides. Electron-deficient,
-neutral, and -rich arenes may be engaged, as well as
electron-rich sites on heterocycles, orthogonal to the Minisci
reaction.
The obvious precursor to (−)-8-phenylmenthol is (−)-iso-
pulegol [(−)-2], whose low cost of 0.10 $/g reflects its
intermediacy in the multikiloton industrial synthesis of
(−)-menthol itself (Figure 2).15 However, direct Brønsted
acid mediated Friedel−Crafts phenylation of isopulegol results
in complex mixtures due to selective ionization of the alcohol
functionality. Therefore, we turned away from a cationic
mechanism to investigate radical arylation.
Received: April 11, 2016
Figure 1. Uses and synthesis of 8-phenylmenthol (1).
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01047
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Organic Letters
Letter
Figure 2. Aryl transfer strategy and execution.
We previously reported that carbon-centered radicals
generated under Mukaiyama-type conditions16,17 are suffi-
ciently persistent to engage proximal arenes.11f,18,19 Frequently,
the chemoselectivity of these conditions is orthogonal to
Brønsted acid mediation. To effect aryl transfer to the
isopulegol alkene, we imagined appending an arene to the
proximal alcohol with a single-electron nucleofuge (Figure 2).14
However, benzoates (entries 1−4) or (phenyl)silyl20 ethers
(entries 5−6) led only to hydrogenation products B or
recovered starting materials A, even if strong electron-
withdrawing groups were appended. The sulfonate linker
alone (3, entry 7) was competent to produce aryl transfer
product (−)-1, which is the targeted auxiliary. Radical Smiles−
Truce rearrangements reported by Motherwell, Studer, Tada,
and Stephenson also utilize a sulfonate radical nucleofuge,13,14
which appears to provide both Thorpe−Ingold acceleration and
an inductive electron-withdrawing effect. A range of metal
complexes could affect this transformation in the absence of O2,
but stoichiometric metal reagents were required consistently,
presumably due to metal sequestration via irreversible binding
of sulfite radical (ROSO2·) or liberated sulfur dioxide (SO2).21
Despite extensive efforts, attempts to effect metal turnover were
unsuccessful, although addition of TBHP accelerated the
reaction.22
Figure 3. Survey of aryl sulfonate transfer using (−)-isopulegol.
competently generate the arylated products, which are easy to
separate from hydrogenation byproducts. Naphthyl groups
transfer efficiently (7−8), and the 1-naphthyl derivative (8)
shows restricted bond rotation (see SI), illustrating the steric
clash this rearrangement will tolerate. Even a 1-pyrenyl
substituent can be transferred: 9 may be of some utility for
enantioselective catalysis.23 Pyridyl groups are very efficient in
accepting alkyl radicals, as observed by Minisci in intermo-
lecular settings,24 and we accordingly observed efficient 2-
pyridyl transfer (10). However, in this case, electron-poor (11)
or -rich (12) 3-pyridyl groups can be selectively engaged,
whereas the 3-position is generally unreactive in intermolecular
Minisci coupling. These nitrogen heterocycles appended to the
menthyl skeleton may be appealing chiral Lewis bases to
investigate for enantioselective catalysis. Other heteroaro-
matics−quinolines, furans, thiophenes, thiazoles, and benzo-
thiazoles (13−17) all transfer efficiently. The benzofurazan will
transfer (18), albeit in very modest yield. In this case, we
attempted to improve the yield by varying the metal complex,
As shown in Figure 3, we found that a diverse set of aryl
sulfonates function well in this chemistry. Most of the
arylsulfonyl chloride/fluoride precursors are commercially
available, and all are accessible in short sequences (see
Supporting Information [SI]). Notably, anisole can be
appended at its more electron-rich ortho- (4a) and para-
(4b) positions. As expected, electron-rich tolyl groups (5a−c)
do not engage the electron-rich tert-alkyl radical as efficiently as
electron-deficient halogenated aromatics (6a−c), but still
B
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but found instead that Fe(acac)3 caused double N−O bond
cleavage,25 and only trace aryl transfer product was observed.
Although use of stoichiometric Mn(dpm)3 is not cost-
prohibitive, we discovered that its partial replacement with the
inexpensive salt Mn(OAc)3·2H2O could effectively lower its
loading to 5 mol %, albeit with longer reaction times. The
presence of Mn(OAc)3·2H2O in solution presumably allows
the active Mn(dpm)n complex to reform in situ. Indeed,
addition of 20 mol % of ligand (Hdpm) with 1 equiv of
Mn(OAc)3·2H2O behaves identically to 5 mol % Mn(dpm)3.
At 1/20 the price ($1.1 vs $24/mmol, Sigma) and a much
reduced formula weight, we found this to be convenient and
scalable.
crystallography; see SI). These results suggest that such a
transformation may find utility beyond the intended application
of aryl menthol synthesis.
In summary, we demonstrate an inexpensive, two-step route
for the synthesis of arylated menthols from the simple building
blocks isopulegol and arene sulfonyl halides. This strategy
leverages HAT to generate quaternary sp3−sp2 carbon−carbon
bonds with exclusive Markovnikov selectivity and is sufficiently
mild to tolerate a wide array of electronically, sterically, and
functionally differentiated arenes and heteroarenes. More
importantly, this HAT strategy for terpene functionalization
significantly expands the reach of the monoterpene chiral pool,
especially to chiral Lewis bases such as pyridine 10, quinoline
13, thiazole 16, and their derivatives. We anticipate this
expansion will prove valuable for the development of new chiral
catalysts and reagents.
These optimized conditions were successfully applied to the
scaled synthesis of both isomers of 1 (Figure 4), with (+)-1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01047.
X-ray crystallography data (CIF, CIF)
Detailed experimental procedures, spectral data, and
chromatograms (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rshenvi@scripps.edu.
Author Contributions
†S.W.M.C. and R.M.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the NIH
(GM105766 and F31 GM111050 to R.M.) and NSERC (PGS-
D3 fellowship to S.C.). Additional support was provided by Eli
Lilly, Novartis, Bristol-Myers Squibb, Amgen, Boehringer-
Ingelheim, the Sloan Foundation, and the Baxter Foundation.
We thank Dr. Milan Gembicky, Dr. Curtis Moore, and
Professor Arnold L. Rheingold (University of California, San
Diego) for X-ray crystallographic analysis.
Figure 4. Further applications for HAT-initiated aryl transfer.
originating from (−)-citronellal; (+)-isopulegol is more
expensive than (−)-2. Cyclization of 19 occurred in high
yield and high diastereoselectivity to deliver (+)-isopulegol, as
precedented.26 Sulfonylation and aryl transfer proceeded
smoothly to yield 1.3 g of (+)-1 (96% ee) in 41% overall
yield from commercial materials.
We were curious to see whether radicals derived from
prochiral alkenes or linear aryl sulfonates were competent to
undergo stereoselective aryl transfer. As shown in Figure 4c,
simple linear sulfonate 20a undergoes radical aryl transfer to
give γ-phenyl alcohol 19b in both good yield (73%) and high
stereoselectivity (16:1 dr). Identical selectivity is observed in
reactions involving classically generated radicals.14b,e The
terminal alkene is key to obtaining high yields because the
initial HAT reaction is not regioselective in sterically and
electronically equivalent alkenes, e.g. 1,2-disubstituted alkenes.
In a similar manner, the substrate 21a undergoes clean
rearrangement with very high stereoselectivity (>20:1) to give
the stereochemically dense alcohol 21b (assigned by X-ray
DEDICATION
Dedicated to E. J. Corey.
■
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