Stereochemical control in the reduction of 2-chromanols

Article abstract of DOI:10.1021/ol061727g

(Chemical Equation Presented) Reduction of C5-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane reductants and 2,4-trans-chromans using the smaller silane PhSiH₃. The stereochemical outcome has been rational

Full text of DOI:10.1021/ol061727g

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4711-4714
Stereochemical Control in the Reduction
of 2-Chromanols
Kelin Li,†,‡ Kumar Vanka,† Ward H. Thompson,† and Jon A. Tunge*,†,‡
Department of Chemistry, 1251 Wescoe Hall DriVe, 2010 Malott Hall,
UniVersity of Kansas, Lawrence, Kansas 66045-7582, and
KU Chemical Methodologies and Library DeVelopment Center of Excellence,
UniVersity of Kansas, 1501 Wakarusa DriVe, Lawrence, Kansas 66047
tunge@ku.edu
Received July 13, 2006
ABSTRACT
Reduction of C5-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane reductants and 2,4-trans-chromans
using the smaller silane PhSiH3. The stereochemical outcome has been rationalized on the basis of a Curtin Hammett kinetic situation arising
−
from hydride delivery to two different conformations of an intermediate oxocarbenium ion. This method provides a powerful way to control
the relative stereochemistry of these substructures which are prevalent in bioactive natural products.
Substituted chromans are a class of compounds that are found
widely in bioactive natural products. The broad range of
bioactivities exhibited by molecules containing this core
element has led to their description as “privileged struc-
tures”.1 Given that the key scaffold in these compounds
remains constant, one can attribute their biological selectivity
to the nature, pattern, and stereochemistry of substitutents
that adorn the chroman core.
For example, the stereochemistry of the myristinin fla-
vanoids has been shown to affect their bioactivities, with
myristinin A being a more potent polymerase â-inhibitor and
the atropisomeric myristinins B/C being more potent COX-2
inhibitors (Figure 1).2 Thus, control of stereochemistry in
Figure 1.
the formation of natural and synthetic flavanoids is of
considerable interest.
Herein we report a stereoselective reduction of 2-chroman-
ols to provide molecules that contain the core structure of
the myristinins.3 In some cases, the choice of reductant allows
selective synthesis of either the cis-2,4 or trans-2,4 diaster-
eomers.
To begin, we were interested in examining the stereo-
chemistry of reduction of oxocarbenium ions derived from
2-chromanols using silane reductants (Scheme 1).3 It was
expected that the desired 2-chromanols would be accessible
via the addition of organometallic reagents to dihydrocou-
† Department of Chemistry.
‡ KU Chemical Methodologies and Library Development Center of
Excellence.
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893-930.
(2) (a) Deng, J.-Z.; Starck, S. R.; Li, S.; Hecht, S. M. J. Nat. Prod. 2005,
68, 1625-1628. (b) Maloney, D. J.; Deng, J.-Z.; Starck, S. R.; Gao, Z.;
Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 4140-4141. (c) Sawadjoon,
S.; Kittakoop, P.; Kirtikara, K.; Vichai, V.; Tanticharoen, M.; Thebtaranonth,
Y. J. Org. Chem. 2002, 67, 5470-5475.
10.1021/ol061727g CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/23/2006

Scheme 1
Scheme 3
marins. We have recently reported a simple, atom-economical
procedure for the synthesis of dihydrocoumarins based on
acid-catalyzed hydroarylation of cinnamic acids.4 While
treatment of dihydrocoumarins with PhMgBr did not lead
to any addition product,5 their reaction with 0.9 equiv of
PhLi selectively provided mixtures of the two possible
monoaddition products in good yields (Scheme 2).6,7 The
diastereomers (Scheme 3). In an attempt to improve this ratio,
i-Pr3SiH was used as the reductant which indeed provided
the cis product in 20:1 dr as determined by 1H NMR
spectroscopy. Interestingly, use of PhSiH3 as the reductant
afforded the trans product selectively (1:11 cis/trans). It is
important to note that the cis- and trans-chromans are both
configurationally stable under the reaction conditions.
The observed products could possibly arise from one of
two mechanisms. First, hydrosilylation of the ketone followed
by intramolecular substitution could produce the chroman.5
Alternatively, formation of an oxocarbenium ion from the
lactol followed by addition of hydride is a possibility
(Scheme 1).8 Since the observed stereochemical dependence
on the nature of the silane is inconsistent with an intramo-
lecular SN1 reaction, we favor the latter mechanism.
Given the silane-dependent reversal of stereochemical
outcome, experiments aimed at determining the origin of
stereoselectivity were conducted. To begin, a variety of
lactol/chalcone mixtures that differ only in the substitution
of the arene ring of the chroman were prepared. These
substrates were subjected to reductions with i-Pr3SiH, Et3-
SiH, or PhSiH3. While PhSiH3 always gave more trans
product than Et3SiH or i-Pr3SiH did, it is clear from the data
in Table 2 that a substituent in the 5-position is required for
high trans selectivity.
Scheme 2
lactol (2)/ketone (3) ratio of the product proved to be highly
variable (Table 1). While we do not have a definitive
Table 1. PhLi Additions to Dihydrocoumarins (Scheme 3)
reactant
R5
R6
R7
R8 yield (%) lactol/ketone
The stereochemical outcome of the reduction can be
explained if one considers the delivery of hydride to the
hypothetical oxocarbenium ion intermediate. Geometry
1a
1b
1c
1d
1e
1f
1g
1h
1i
OMe
H
H
Me
Me
H
H
Me
OMe OMe
Me
H
OMe
H
H
H
H
H
i-Pr
H
H
H
H
75a
97
74
95
60a
81
0.54:1
0.69:1
0.64:1
6.4:1
18.5:1
0.48:1
0.47:1
2.4:1
t-Bu
OCH2O
Cl
H
OMe
H
Me
H
H
OMe
Me
OMe
H
(3) For related lactol reductions, see: (a) Coghlan, M. J.; Kym, P. R.;
Elmore, S. W.; Wang, A. X.; Luly, J. R.; Wilcox, D.; Stashko, M.; Lin,
C.-W.; Miner, J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane, B. C. J. Med.
Chem. 2001, 44, 2879-2885. (b) Kraus, G. A.; Frazier, K. A.; Roth, B.
D.; Taschner, M. J.; Neuenschwander, K. J. Org. Chem. 1981, 46, 2417-
2419. (c) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Org. Chem. 1987,
52, 1273-1276.
95
H
73a
61a
82a
62a
0.52:1
13.5:1
15.7:1
1j
1k
H
H
Me
Me
(4) Li, K.; Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881-
2883.
i-Pr
H
(5) Over-addition occurs at higher temperatures: Geissman, T. A. J. Am.
Chem. Soc. 1940, 62, 1363-1367. Overreduction was also observed with
PhLi in THF.
a The mass balance is recovered starting material.
(6) Czernecki, S.; Perlat, M. C. J. Org. Chem. 1991, 56, 6289-6292.
(7) Heating the product mixtures did not change the ratio of products,
so we assume that thermodynamic product ratios are obtained.
(8) (a) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem.
Soc. 2005, 127, 5322-5323. (b) Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2000, 122, 168-169.
explanation for the variability, it appears that R5-alkyl
substitution favors lactol (2) formation and R5 + R8 alkyl
substitution provides the highest ratios of lactol.
Treatment of the lactol/ketone mixture 2a/3a with BF3‚Et2O
and Et3SiH at -78 °C for 1 h resulted in complete conversion
to the product chroman 4a as a 1.7:1 cis/trans mixture of
(9) Frisch, M. J. et al. Gaussian 98, reVision A.6; Gaussian, Inc.:
Pittsburgh, PA, 1998.
(10) This is consistent with the known steric interaction between these
two aryl groups in the atropisomeric myristinins B and C.
4712
Org. Lett., Vol. 8, No. 21, 2006

Hammett kinetic situation, the cis/trans ratio equals the
product of Keq and the ratio of rate constants for hydride
delivery (Scheme 4).
Table 2. Selective Reductions of Lactol/Chalcone Mixtures
product
R5
R6
R7
R8
X-H
yield (%) (dr)a
4a
OMe
H
OMe
H
i-Pr3Si
Et3Si
PhH2Si
Et3Si
PhH2Si
Et3Si
PhH2Si
i-Pr3Si
PhH2Si
56 (20:1)
65 (1.7:1)
94 (1:11)
90 (>20:1)
72 (2.7:1)
82 (>20:1)
50 (7.3:1)
76 (11:1)
99 (1:10)
99 (9.1:1)
99 (1.6:1)
99 (1:17)
89 (14:1)
49 (2.6:1)
68 (>20:1)
63 (5:1)
Scheme 4
4b
4c
4d
4e
H
t-Bu
OCH2O
Cl
H
H
H
H
H
Me
Me
Me
H
H
i-Pr i-Pr3Si
Et3Si
PhH2Si
Et3Si
PhH2Si
Et3Si
PhH2Si
i-Pr3Si
PhH2Si
i-Pr3Si
PhH2Si
4f
H
OMe
H
H
H
H
H
H
4g
4h
4i
H
OMe
Me
OMe
H
Me
H
56 (11:1)
95 (1:12)
62 (13:1)
82 (1:4)
OMe OMe
With large hydride sources such as i-Pr3SiH, axial delivery
of the hydride is expected to occur preferentially on the
equatorial conformer so as to minimize the incipient 1,3-
diaxial interaction (kcis . ktrans).3c,12 In this case, the reaction
product is primarily controlled by the rates of hydride
delivery (kcis/ktrans . Keq); thus, the cis product is favored
regardless of the conformational equilibrium.
4j
Me
H
H
Me i-Pr3Si
PhH2Si
Me i-Pr3Si
PhH2Si
55 (4:1)
96 (1:14)
86 (14:1)
99 (1:11)
4k
i-Pr
H
a Yield and cis/trans ratio of isolated product.
optimizations at the B3LYP/6-31G* level of theory, using
the Gaussian program,9 show that a simple 2,4-diphenyl-
substituted oxocarbenium ion intermediate adopts a half-chair
structure where the 4-aryl group can occupy either a
pseudoaxial or a pseudoequatorial position. When R5 ) H,
the calculations show that the C4-phenyl group prefers to
occupy the equatorial position by 0.4 kcal/mol (Figure 2).
If the hydride source is small (i.e., PhSiH3), then hydride
can be delivered axially to either conformer (kcis ∼ ktrans). In
this case, the product ratio will have a large dependence on
population of conformers as given by Keq.13 Thus, when R5
) H and there is a small preference for the equatorial
conformer, PhSiH3 provides low cis selectivity. However,
the trans-chroman is selectively produced from substrates
where R5 * H and the axial conformer is preferred.
Scheme 5
Figure 2. Most stable conformations of oxocarbenium ions.
However, if R5) Me, then the C4-phenyl group prefers the
axial position by 3.2 kcal/mol.10
Further calculations show that the barrier for interconver-
sion of the axial and equatorial conformers is 3.8 kcal/mol
for R5 ) H and 4.8 kcal/mol for R5 ) Me. Therefore, the
conformational equilibrium is rapidly maintained at -78 °C,
and reduction of the oxocarbenium is expected to follow
Curtin-Hammett kinetics.11 In the case of a Curtin-
In summary, we have developed a convenient, stereose-
lective procedure for the reduction of 2-chromanols. The
reduction is the key step in a convenient three-step procedure
Org. Lett., Vol. 8, No. 21, 2006
4713

for the formation of diarylchromans from phenols and
cinnamic acids (Scheme 5). Furthermore, the stereochemistry
of the reduction can be predicted on the basis of a simple
Curtin-Hammett kinetic model for hydride delivery to an
intermediate oxocarbenium ion. Finally, the ability to
selectively access either cis- or trans-chromans is expected
to facilitate production of stereochemically diverse chemical
libraries.
(11) (a) Seeman, J. I. Chem. ReV. 1983, 83, 83-134. (b) Eliel, E. L.;
Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley and
Sons: New York, 1994; pp 648-655. (c) Carey, F. A.; Sundberg, R. J.
Advanced Organic Chemistry, 3rd ed.; Plenum: New York, 1990; pp 215-
216.
(12) Axial addition to oxocarbenium ions is favored: (a) Stevens, R.
V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032-7035. (b)
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Perga-
mon: New York, 1983; pp 209-221.
(13) At 20 °C, the rate of conformational interconversion is calculated
to be ca. 109 s-1, while those for hydride delivery to an oxocarbenium ion
are estimated to be 102 s-1 for PhSiH3 and 104 for Et3SiH. (a) Mayr, H.;
Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos,
R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001,
123, 9500-9512. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res.
2003, 36, 66-77.
Acknowledgment. We acknowledge support of this work
by the National Institutes of Health (KU Chemical Meth-
odologies and Library Development Center of Excellence,
P50 GM069663).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all compounds. Cartesian
coordinates of the DFT-optimized structures. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061727G
4714
Org. Lett., Vol. 8, No. 21, 2006