Trans-2-tritylcyclohexanol as a chiral auxiliary in permanganate-mediated oxidative cyclization of 2-methylenehept-5-enoates: Application to the synthesis of trans-(+)-linalool oxide

Article abstract of DOI:10.1021/ol502454r

The permanganate-mediated oxidative cyclization of a series of 2-methylenehept-5-eneoates bearing different chiral auxiliaries was investigated, leading to the discovery of trans-2-tritylcyclohexanol (TTC) as a highly effective chiral controller for the f

Full text of DOI:10.1021/ol502454r

Letter
pubs.acs.org/OrgLett
trans-2-Tritylcyclohexanol as a Chiral Auxiliary in Permanganate-
Mediated Oxidative Cyclization of 2‑Methylenehept-5-enoates:
Application to the Synthesis of trans-(+)-Linalool Oxide
Ali M. Al Hazmi,† Nadeem S. Sheikh,†,∥ Carole J. R. Bataille,† Azzam A. M. Al-Hadedi,†,⊥ Sam V. Watkin,†
Tim J. Luker,‡ Nicholas P. Camp,§ and Richard C. D. Brown*,†
†Department of Chemistry, The University of Southampton, Highfield, Southampton SO17 1BJ, U.K.
‡AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, U.K.
§Eli Lilly Research Centre U.K., Erl Wood Manor, Windlesham GU20 6PH, U.K.
S
* Supporting Information
ABSTRACT: The permanganate-mediated oxidative cyclization of a series of 2-methylenehept-5-eneoates bearing different
chiral auxiliaries was investigated, leading to the discovery of trans-2-tritylcyclohexanol (TTC) as a highly effective chiral
controller for the formation of the 2,5-substituted THF diol product with high diastereoselectivity (dr ∼97:3). Chiral resolution
of ( )-TTC, prepared in one step from cyclohexene oxide, afforded (−)-(1S,2R)-TTC (er >99:1), which was applied to the
synthesis of (+)-trans-(2S,5S)-linalool oxide.
hiral auxiliaries based on substituted cyclohexanols
originates from an initial reaction of permanganate ion with the
more electron-poor enoate alkene, followed by cyclization.5−7
In the pursuit of enhanced diastereoselectivity for oxidative
cyclizations of structurally related diene systems, some simple
modifications to the cyclohexyl auxiliary were considered. Here
we report the synthesis and chiral resolution of trans-2-
(trityl)cyclohexanol (TTC)8 and compare its efficacy with
several other cyclohexyl derivatives in the context of oxidative
cyclization. We also describe a stereoselective synthesis of the
trans-THF-containing alcohol (+)-trans-(2S,5S)-linalool oxide
(furanoid form),9 a monoterpenoid present in essential oils,
foods, and beverages and used in perfumery.10
To examine the stereodirecting influence of the 2-cyclo-
hexanol substituent on oxidative cyclization of 6-methyl-2-
methylenehept-5-eneoates 7a−d, a number of racemic trans-2-
substituted cyclohexanols were synthesized by addition of
organomagnesium or organolithium reagents to cyclohexene
oxide (Scheme 2).11 Subsequent reaction with either 6-methyl-
2-methylenehept-5-eneoyl chloride (6a) or PFP ester 6b led to
the corresponding substituted cyclohexyl esters 7a−d.12 For
comparative purposes, (1R,2S)-(−)-TCC and camphor sultam
derivatives 7e and (−)-8, respectively, were similarly
synthesized.
C
continue to find applications in asymmetric synthesis.1
Since the introduction of 8-phenylmenthol by Corey,2
researchers have sought cyclohexanol derivates that offer
improved levels of diastereocontrol and/or can be more readily
accessed in enantiomerically pure form.3 We recently applied
the (+)-(1S,2R)-trans-2-cumylcyclohexanol ((+)-TCC) auxil-
iary to the synthesis of the trans-THF-containing fragment of
the terpenoid natural product eurylene using a selective
oxidative monocyclization of a trienoate.4 In this context, the
TCC auxiliary returned an acceptable level of diastereoinduc-
tion, giving rise to an inseparable mixture of diastereoisomeric
oxidative cyclization products 2 and 3 (Scheme 1). The
diastereoisomers were separated following conversion to their
bis-trimethylsilyl ethers. The regio- and diastereoselectivity
Scheme 1. Stereoselective Oxidative Monocyclization of
(1S,2R)-TCC Trienoate 14
The 2-substituted cyclohexyl compounds displayed typical
NMR spectroscopic data, with the exception of trans-2-
tritylcyclohexanol (( )-5d) and its derivatives, which exhibited
Received: August 19, 2014
Published: September 16, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Synthesis of 6-Methyl-2-methylenehept-5-eneoic
Acid Cyclohexyl Esters 7a−e
Scheme 3. Oxidative Cyclization of 6-Methyl-2-
methylenehept-5-eneoic Acid Derivatives 7a−e, (−)-8, and 9
yields in the range 57−99%, but with markedly different levels
of diastereoinduction; only the (−)-TCC and ( )-TTC
auxiliaries conferred significant levels of stereocontrol upon
1
significant broadening of signals in the H and 13C NMR
spectra corresponding to the trityl group, highlighting the
increased steric congestion of this system.13 Furthermore, the
vinylic β proton signals of the enoate 7d displayed upfield shifts
(δ 5.14 and 5.20) relative to cyclohexyl esters 7a−c (δ 5.30−
5.48 and 5.86−6.12), while the chemical shifts for TCC ester
(−)-7e lay in between (δ 5.30 and 5.69) (Table 1). Shielding of
1
the cyclization (dr 4.2:1 by H NMR and 97:3 by HPLC,
respectively), and only TTC showed very high levels of
induction. Assignment of the major diastereoisomers ( )-12d
and 12e was ultimately accomplished through the synthesis of
trans-(2S,5S)-linalool oxide (19) described below.
In view of the high level of diastereocontrol achieved in the
oxidative cylization of ( )-7d bearing the racemic TTC
auxiliary, we wished to develop a chiral resolution of TTC
and illustrate its application in a synthesis of the terpenoid
natural product (+)-(2S,5S)-linalool oxide (19). Synthesis of
(+)-linalool oxide (19) would also allow stereochemical
determination of the major diastereoisomer 12d from the
oxidative cyclization. Chiral resolution of ( )-TTC was realized
on a 95 mmol scale through formation of mixed oxalate esters
with (−)-menthol (Scheme 4);15,16 the mixture of diastereo-
meric derivatives was heated in MeOH followed by hot
filtration of the sparingly soluble diester (+)-14 with 35%
recovery (dr >99:1, HPLC). Hydrolysis of the mixed oxalate
ester (+)-14 afforded (−)-5d (24 mmol), which was assigned as
the (1S,2R)-enantiomer using the advanced Mosher ester
method.17 In addition, the (S)-Mosher ester derivative proved
Table 1. Oxidative Cyclization of Cyclohexyl Dienoates 7a−e
a
yield (12 + 13)
entry
diene
)-7a
R
(%)
dr (12:13)
b
c
1
2
3
4
5
(
(
(
(
4-MeC6H4
Bn
57
1:1
b
d
d
,
e
e
)-7b
)-7c
82
1.3:1
1.8:1
b
,
CHPh2
99
b
e
,
f
)-7d, ( )-TTC CPh3
62
32.3:1
g
c
,
h
(−)-7e, (−)-TCC
CMe2Ph
94
4.2:1
a
Isolated unoptimized yields of purified compounds are quoted.
b
c
Racemic products were obtained. Ratio of diastereoisomers
d
estimated from the 1H NMR spectrum. Major diastereoisomers
e
12b and 12c are tentatively assigned by analogy with 12d. Ratio of
f
diastereoisomers determined using HPLC. The relative stereo-
chemistry of the major diastereoisomer 12d was assigned by
conversion of (−)-7d to trans-(2S,5S)-linalool oxide (19) described
g
h
below. 97% ee. The assignment of the major diastereoisomer is
described in the Supporting Information.
Scheme 4. Chiral Resolution of (−)-(1S,2R)-TTC through
Diastereomeric Oxalate Ester formation
the β-enoate substituents in a series of 8-arylmenthol
crotonates has been cited as support for a favored “stacked”
s-trans ground-state conformation, which correlated qualita-
tively with enhanced stereoselectivity.3e
Oxidative cyclization studies commenced with exposure of
the methyl ester 9 to permanganate/AcOH, resulting in highly
efficient formation of the racemic THF diol 10 in 92% yield
(Scheme 3). By contrast, the yield for the oxidative cyclization
of the dienoyl (2R)-camphorsultam 8 was low (38%), although
the product was obtained as a single diastereoisomer (−)-11.14
Oxidation of cyclohexyl esters 7a−e using KMnO4 gave
diastereoisomeric THF diols 12 and 13 with unoptimized
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amenable to X-ray structural determination, thereby confirming
the absolute stereochemistry of (−)-TTC to be (1S,2R).18
Overall, this resolution process provides a simple and
convenient access to the TTC auxiliary in either enantiomeric
form on a multigram scale without the need for chromato-
graphic purification.19
An improved three-step synthesis of the diene (−)-7d was
developed starting from reaction of (−)-TTC with ethyl
chlorooxoacetate (Scheme 5), followed by selective Grignard
Scheme 5. Synthesis of trans-(2S,5S)-Linalool Oxide (19)
Figure 1. Model for the diastereofacial selectivity observed in the
oxidative cyclization of 6-methyl-2-methylenehept-5-eneoates.
hexanol (TTC), is reported. It was shown to confer higher
levels of diastereofacial selectivity in comparison to other
cyclohexyl derivatives studied for the oxidative cyclization of 2-
methylenehept-5-eneoates and was applied to a stereoselective
synthesis of trans-(+)-linalool oxide furanoid form. Notably, the
reported synthesis illustrates the potential application of
permangate-mediated oxidative cyclization (formally produces
2,5-cis-THF-diols) to the synthesis of trans-THF systems.
Furthermore, TTC may find utility in other auxiliary-controlled
diastereoselective processes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, chromatograms, X-
1
ray structures, and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rcb1@soton.ac.uk.
Present Addresses
addition to the less hindered ester group and methylenation of
the resulting α-ketoester 15.20 Oxidative cyclization of dienoate
(−)-7d on a ∼14 mmol scale afforded the THF-diol (−)-12d
in 73% yield as a 97:3 mixture of diastereoisomers (HPLC),
which underwent selective deoxygenation of the primary
carbinol group by treatment of the mono thionocarbamate 16
with TTMSS/AIBN in hot toluene.21 Although direct
reduction of TTC ester 17 to the aldehyde 18 was possible
using DIBAL-H, the volatility of the resulting aldehyde
complicated its isolation from the reaction mixture. Instead, a
two-step reduction-Dess−Martin oxidation protocol was
preferred. Pure (−)-TTC was recovered (84%) following the
reductive cleavage and chromatographic separation, demon-
strating the potential to recycle the auxiliary. The synthesis was
completed by methylenation of the aldehyde 18 to afford 120
mg of (+)-linalool oxide in 64% isolated yield. The synthetic
(+)-linalool oxide (er 97:3, chiral GC) displayed physical and
spectroscopic data consistent with reported values for the
(+)-(2S,5S)-enantiomer of linalool oxide (furanoid form).22
The stereochemical outcome of the reaction may be
accounted for by preferential reaction of permanganate ion
with the si-face of the enoate alkene (Figure 1), with the trityl
derivative functioning as a comparatively superior chiral
controller to the cumyl group. The observed shielding and
significant upfield shift of the alkene protons are also consistent
with the depicted ground-state solution conformation.
∥Department of Chemistry, Faculty of Science, King Faisal
University, P.O. Box 380, Al-Ahsa 31982, Saudi Arabia.
⊥On leave from the Department of Chemistry, College of
Science, University of Mosul 41002, Iraq.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge The University of Southampton (N.S.S.),
AstraZeneca (C.J.R.B.), The Higher Committee for Education
Development in Iraq (A.A.M.A.-H.), Eli Lilly (S.V.W.), and
EPSRC for studentship support. The European Regional
Development Fund (ERDF, ISCE-Chem & INTERREG IVa
program 4061) is also gratefully acknowledged.
REFERENCES
■
(1) For a review, see: (a) Whitesell, J. K. Chem. Rev. 1992, 92, 953−
964. For some recent examples, see: (b) Garcia-Mera, X.; Alves, M. J.;
Goth, A.; do Vale, M. L.; Rodriguez-Borges, J. E. Tetrahedron 2013, 69,
2909−2919. (c) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J.
E.; Yin, J. D. Tetrahedron 2011, 67, 6382−6403. (d) Wolfe, B. H.;
Libby, A. H.; Al-awar, R. S.; Foti, C. J.; Comins, D. L. J. Org. Chem.
2010, 75, 8564−8570. (e) Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi,
Y. Org. Lett. 2009, 11, 1833−1836. (f) Pettersson, M.; Knueppel, D.;
Martin, S. F. Org. Lett. 2007, 9, 4623−4626. (g) Tayama, E.; Kimura,
In conclusion, one-step synthesis and chiral resolution of a
sterically encumbered cyclohexyl auxiliary, trans-2-tritylcyclo-
5106
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Letter
H. Angew. Chem., Int. Ed. 2007, 46, 8869−8871. (h) Miller, A. K.;
Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.; Trauner, D. J. Am.
Chem. Soc. 2006, 128, 17057−17062. (i) Comins, D. L.; Schilling, S.;
Zhang, Y. C. Org. Lett. 2005, 7, 95−98. (j) Shu, C.; Liebeskind, L. S. J.
Am. Chem. Soc. 2003, 125, 2878−2879.
(18) Bataille, C. J. R.; Brown, R. C.D.; Horton, P. N.; Huth, S. L.
Private communication to the Cambridge Structural Database,
deposition no. CCDC 1014228, 2014.
(19) (+)-(1R,2S)-TTC can be obtained from recrystallization of the
concentrated filtrate and is described in the Supporting Information.
(20) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahedron
1996, 52, 13513−13520.
(2) (a) Ensley, H. E.; Parnell, C. A.; Corey, E. J. J. Org. Chem. 1978,
43, 1610−1612. (b) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975,
97, 6908−6909.
(21) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1988, 53,
3641−3642.
(3) (a) Inhulsen, I.; Akiyama, N.; Tsutsumi, K.; Nishiyama, Y.;
̈
(22) [α]D = +7.6 (c 0.6, CHCl3, 22 °C) [lit.9c +8.33 (c 0.6, CHCl3, 20
°C). For (2R,5R) lit.9d −7.45 (c 2.54, CHCl3, 20 °C)].
Kakiuchi, K. Tetrahedron 2013, 69, 782−790. (b) Yang, D.; Xu, M.;
Bian, M. Y. Org. Lett. 2001, 3, 111−114. (c) do Vale, M. L. C.;
Rodriguez-Borges, J. E.; Caamano, O.; Fernandez, F.; Garcia-Mera, X.
Tetrahedron 2006, 62, 9475−9482. (d) Sarakinos, G.; Corey, E. J. Org.
Lett. 1999, 1, 1741−1744. (e) Dumas, F.; Mezrhab, B.; d’Angelo, J.;
Riche, C.; Chiaroni, A. J. Org. Chem. 1996, 61, 2293−2304.
(f) Basavaiah, D.; Krishna, P. R. Tetrahedron 1995, 51, 12169−
12178. (g) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58,
4656−4661. (h) Whitesell, J. K.; Chen, H. H.; Lawrence, R. M. J. Org.
Chem. 1985, 50, 4663−4664.
(4) Sheikh, N. S.; Bataille, C. J.; Luker, T. J.; Brown, R. C. D. Org.
Lett. 2010, 12, 2468−2471. In the original work, the major and minor
diastereoisomers were incorrectly assigned. The original assignment
was based on comparison of specific rotation data of a derivative with a
known compound. The corrected assignment is shown in Scheme 1.
(5) (a) Walba, D. M.; Przybyla, C. A.; Walker, C. B. J. Am. Chem. Soc.
1990, 112, 5624−5625. (b) Lee, D. G.; Brown, K. C. J. Am. Chem. Soc.
1982, 104, 5076−5081. Mechanism: (c) Baldwin, J. E.; Crossley, M.
J.; Lehtonen, E. M. M. J. Chem. Soc., Chem. Commun. 1979, 918−920.
(d) Poethig, A.; Strassner, T. Collect. Czech. Chem. Commun. 2007, 72,
715−727.
(6) For regioselective permanganate oxidative cyclization of
trienoates, see: (a) Brown, R. C. D.; Hughes, R. M.; Keily, J.;
Kenney, A. Chem. Commun. 2000, 1735−1736. (b) Brown, R. C. D.;
Bataille, C. J.; Hughes, R. M.; Kenney, A.; Luker, T. J. J. Org. Chem.
2002, 67, 8079−8085.
(7) For auxiliary-controlled selective permanganate oxidative
monocyclizations of trienes, see ref 4, ref 6, and: (a) Morris, C. L.;
Hu, Y. L.; Head, G. D.; Brown, L. J.; Whittingham, W. G.; Brown, R.
C. D. J. Org. Chem. 2009, 74, 981−988.
(8) Although ( )-trans-2-tritylcyclohexanol (TTC) has been
reported, we are not aware of its application as a chiral auxiliary.
Peddle, G. J. D. J. Organomet. Chem. 1968, 14, 115−121.
(9) For examples of diastereocontrolled syntheses of trans-linalool
oxide (furanoid form), see: (a) Wan, K. K.; Litz, J. P.; Vosburg, D. A.
Tetrahedron: Asymmetry 2010, 21, 2425−2428. (b) Liu, B.; Duan, S.
Q.; Sutterer, A. C.; Moeller, K. D. J. Am. Chem. Soc. 2002, 124,
10101−10111. (c) Duan, S. Q.; Moeller, K. D. Org. Lett. 2001, 3,
2685−2688. (d) Mischitz, M.; Faber, K. Synlett 1996, 978−980.
(e) Garcia, M. A.; Meou, A.; Brun, P. Synlett 1994, 911−912.
́
(f) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963−3964.
(10) Surburg, H.; Panten, J. Common Fragrance and Flavor Materials:
Preparation, Properties and Uses, 5th ed.; Wiley-VCH: Weinheim, 2006.
(11) (a) Schwartz, A.; Madan, P.; Whitesell, J. K.; Lawrence, R. M.
Org. Synth. 1990, 69, 1−9. (b) Peddle, G. J. D. J. Organomet. Chem.
1968, 14, 115−121.
(12) The syntheses of 6-methyl-2-methylenehept-5-eneoyl chloride
(6a), PFP ester 6b, dieneoyl camphorsultam 8, and methyl ester 9 are
described in the Supporting Information
(13) Copies of 1H and 13C NMR spectra can be found in the
Supporting Information
(14) For details of stereochemical determination by X-ray
crystallography, see the Supporting Information.
(15) Shen, R. C.; Corey, E. J. Org. Lett. 2007, 9, 1057−1059.
(16) (−)-Menthol (ee ≥ 99%).
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092−4096.
5107
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