Development of a new family of chiral auxiliaries

Article abstract of DOI:10.1021/acs.orglett.5b00278

A new family of chiral auxiliaries designed on a conformationally restricted version of (-)-8-phenylmenthol has been developed. Both enantiomers are available from an inexpensive synthesis conducted on multigram scale. A first application has showed compa

Full text of DOI:10.1021/acs.orglett.5b00278

Letter
pubs.acs.org/OrgLett
Development of a New Family of Chiral Auxiliaries
Fabien Gelat, Vincent Richard, Olivier Berger, and Jean-Luc Montchamp*
Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129, United States
*
S Supporting Information
ABSTRACT: A new family of chiral auxiliaries designed on a
conformationally restricted version of (−)-8-phenylmenthol has
been developed. Both enantiomers are available from an
inexpensive synthesis conducted on multigram scale. A first
application has showed comparable diastereoselectivity between
the novel auxiliary and (−)-8-phenylmenthol.
tilization of chiral auxiliaries is one of the main strategies
Scheme 1. Synthesis of Racemic Auxiliary from Tetralone
1
U
for the synthesis of enantiopure compounds. Trans-
formations tend to be versatile, proceed with a predictable
sense of asymmetric induction, and lead to products in
enantiomerically enriched form. A successful and popular
example is the (−)-8-phenylmenthol auxiliary. It was first
introduced by Corey for the realization of highly asymmetric
2
Lewis acid catalyzed Diels−Alder reactions. Since then, it has
been used to afford good diastereoselectivity in numerous
organic transformations. However, (−)-8-phenylmenthol is
expensive, its synthesis is not straightforward, and it is also not
afforded 8-phenyltetralone 3 in 87% yield. Reduction using
sodium borohydride in methanol at 0 °C gave 2.26 g of the
desired 8-phenyltetralol 1 in a quantitative yield.
3
very modular since each modification on the substituent
However, the first step of the above sequence using the
ruthenium complex, the boronic ester, and an unusual solvent is
too expensive for large-scale work. For this reason, we decided
to find an alternative for the preparation of 3 (Scheme 2).
requires a separate set of reactions starting from (R)-
4
(
+)-pulegone. Furthermore, access to its enantiomer, (+)-8-
phenylmenthol, is problematic since (S)-(−)-pulegone is not
5
,6
accessible from the “chiral pool”.
8
Following the literature, we obtained 21.3 g of the 8-iodo-1-
Herein, we are introducing a new family of chiral auxiliaries
synthesized in both enantiomeric form on multigram scale and
from cheap starting materials. Our design (Figure 1) is based
tetralone 8 in 46% yield over 4 steps, starting from
commercially available 5,6,7,8-tetrahydro-1-naphthylamine 4.
The four steps are simple and only require one purification
by column chromatography at the end of the process: (i)
acetylation, to 5, (ii) oxidation 6, (iii) deprotection to 7, and
(
iv) Sandmeyer reaction to 8. Compound 8 was thus obtained
from 25 g of amine 4 in 46% overall yield. Subsequent Suzuki
Scheme 2. Alternative Synthesis for 8-Phenyltetralone 3
Figure 1. Design of chiral auxiliary based on a restricted conformation
of (−)-8-phenylmenthol.
on a conformationally restricted version of (−)-8-phenyl-
menthol using 1-tetralone as the platform. Auxiliary 1 shares
most of his backbone with (−)-8-phenylmenthol, but the
phenyl substituent is generally perpendicular to the tetralol ring
system.
Strategically, to have access to both enantiomers, we decided
to resolve the racemic auxiliary instead of using asymmetric
synthesis. Racemic alcohol 1 was synthesized via two different
pathways. The first one is a two steps synthesis from 1-tetralone
7
(
Scheme 1). Following a known procedure, the reaction
between tetralone 2 and phenylboronic acid neopentylglycol
ester using a ruthenium catalysis in pinacolone at reflux
Received: January 28, 2015
Published: April 3, 2015
©
2015 American Chemical Society
1819
DOI: 10.1021/acs.orglett.5b00278
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Organic Letters
Letter
coupling between 8 and phenylboronic acid afforded 11.6 g of
the desired 8-phenyltetralone 3 in 74% yield.
Reduction of 8-iodo-1-tetralone 8 with sodium borohydride
in methanol at 0 °C for 15 h afforded the iodo-tetralol 10 in
99% yield. Then esterification using (R)-O-acetylmandelic acid
chloride followed by deacetylation and column chromatography
gave both diastereoisomers 11a and 11b in a 35% yield each in
diastereopure form. At this stage, substitution on the aromatic
ring (bulky or substituted aromatic or heteroaromatic) could be
accomplished. This was illustrated for the synthesis of auxiliary
1. Acetylation of diastereoisomer 11a followed by Suzuki
coupling using phenylboronic acid and PdCl /PPh , then
The resolution of racemic alcohol 1 was achieved by
formation of a mandelate ester followed by the chromato-
graphic separation of both diastereoisomers. This approach has
9
already been used successfully with various alcohol. Ester-
ification of 1 with enantiopure (R)-O-acetylmandelic acid
1
0
chloride and pyridine in dichloromethane at 0 °C, followed
by deacetylation using K CO in an acetone/MeOH mixture at
2
3
room temperature afforded a mixture of both diastereoisomers
in 79% yield (Scheme 3). At this point, the two
2
3
9
hydrolysis afforded the chiral auxiliary (S)-1 in 83% yield
Scheme 5).
(
Scheme 3. Resolution of the Chiral Auxiliary
Scheme 5. Synthesis of 1 via the Iodo Key Intermediate 6
The absolute configuration was determined by comparison of
the sign of the specific rotation of 1 thereby allowing the
configurations of both diastereoisomers of 11 to be established.
To validate the concept of our new chiral auxiliary, we
decided to compare the induction of diastereoselectivity
between the novel chiral auxiliary and (−)-8-phenylmenthol
through a known reaction: addition of a Grignard on a pyruvate
diastereoisomers 9 were separated by column chromatography
on silica gel, to afford 6 g of each diastereoisomerically pure
compound as a crystalline white solid 9a and 9b. The
configuration was determined by single X-ray crystallography
of 9b. Hydrolysis of both diastereoisomers by sodium
hydroxide in acetone/water at room temperature afforded 3.5
g each of enantiopure auxiliaries 1 in a quantitative yield. A
control experiment to establish the integrity of the alcohol
stereocenter was conducted. Esterification of enantiopure
alcohol (S)-1 by (R)-O-acetylmandelic acid chloride gave a
single diastereoisomer showing that no racemization occurred.
Because a good auxiliary should be modular, the possibility to
have a common enantiopure intermediate before functionaliza-
tion was also investigated. 8-Iodo-1,2,3,4-tetrahydro-naphtalen-
11
ester. Enantiopure chiral alcohol (S)-1 was converted to the
corresponding pyruvate 12 in 67% yield, by reaction with
pyruvic acid, 4-dimethylaminopyridine, triethylamine, and
dichloromethyl methyl ether in dichloromethane (Scheme 6).
Scheme 6. Addition of Phenylmagnesium Bromide to
Pyruvate 12
1
-ol 10 appeared to be an excellent candidate for this purpose.
Compound 10 was easily synthesized by reduction of ketone 8.
Fortunately, the same strategy used for the resolution of the
chiral alcohol 1 (Scheme 3) was also successful with iodo-
alcohol 10 (Scheme 4).
Scheme 4. Resolution of the Key Iodide Intermediate 10
Addition of phenylmagnesium bromide in ether at -78 °C in
diethyl ether for 6 h led to a high level of induction. Compound
1
3 was obtained with a diastereoisomeric excess of 96% in 74%
yield. For comparison, (−)-8-phenylmenthol results in 92%
de. Interestingly, 2-epi,ent-8-phenylmenthol, generally used
to induce the opposite sense of chirality, led only to 68% de.
11a
11b
The absolute configuration of ester 13 was determined by
hydrolysis using sodium hydroxide in acetone/water at reflux
overnight, and comparison of the sign of the specific rotation of
1
2
the resulting acid 14 gives [α] = −36.3 (c 0.8, CHCl ) [lit.
3
[
α] = −36.8 (c 0.4, EtOH) for ee >95%].
The stereochemistry of this addition reaction can be
rationalized by the addition of the nucleophile to the sterically
1
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DOI: 10.1021/acs.orglett.5b00278
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Organic Letters
Letter
accessible re face of 12 with a syn-orientation of the carbonyl
group (Figure 2).
(6) However, (S)-(−)-pulegone can be prepared by PCC oxidation
of (−)-citronellol: Corey, E. J.; Ensley, H. E.; Suggs, J. W. J. Org. Chem.
13
1
976, 41, 380−381.
(
7) Kitazawa, K.; Kochi, T.; Kakiuchi, F. Org. Synth. 2010, 87, 209−
17.
8) Nguyen, P.; Corpus, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M.
2
(
E. J. Org. Chem. 2003, 68, 10195−10198.
(
(
9) Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548−3551.
10) (R)-O-Acetylmandelic acid chloride should be freshly
synthesized or stored at 0 °C and used within one month to avoid
racemization: Cahiez, G.; Metais, E. Terahedron. Lett. 1995, 36, 6449−
Figure 2. Rationalization of the stereochemistry.
6
452.
(11) (a) Whitesell, J. K.; Deyo, D.; Bhattaharya, A. J. Chem. Soc.,
Chem. Commun. 1983, 802. (b) Whitesell, J. K.; Liu, C.-L.; Buchanan,
M. C.; Chen, H.-H.; Minton, M. A. J. Org. Chem. 1986, 51, 551−553.
In conclusion, we have introduced a new chiral auxiliary
platform. Both enantiomers of 1 are available on a multigram
scale relatively inexpensively from commercial starting materials
and through simple reactions. The resolution of key
intermediate 10 allows the facile and divergent functionaliza-
tion on a diastereopure compound at the end of the synthesis.
The first application showed that auxiliary 1 displayed a level of
diastereocontrol slightly superior to that of (−)-8-phenyl-
menthol. The modular elaboration of the iodide intermediate
with various substituents and extension of the platform will be
investigated in future work. Efforts to simplify the resolution
procedure will also be made.
(
12) Pez
́
ez-Estrada, S.; Lagunas-Rivera, S.; Vargas-Días, M. E.;
Velaz
́
quez-Ponce, P.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron:
Asymmetry 2005, 16, 1837−1843.
(13) Whitesell, J. K.; Bhattacharya, A.; Henke, K. J. Chem. Soc., Chem.
Commun. 1982, 988−989.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Detailed experimental procedures, compound characterization
data, and HPLC chromatograms. Crystallographic data have
been deposited to the Cambridge Crystallographic Data Centre
as a CIF file with file number CCDC 1040079 and is also
included in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: j.montchamp@tcu.edu. Phone: (817) 257 6201.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation under Grant No. 0953368 and 1262254.
We also acknowledge TCU professor Kayla Green for her help
with X-ray crystallography. We also thank the referees for
helpful comments.
REFERENCES
■
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DOI: 10.1021/acs.orglett.5b00278
Org. Lett. 2015, 17, 1819−1821