Synthesis, stereostructure, and conformations of novel Bi- and trifunctional (+)-isomenthone derivatives

Article abstract of DOI:10.1021/ol027434e

(Matrix presented) Following protection, keto alcohols 4 [from (+)-isomenthone] undergo reduction to 1,3-diol 6 (S configuration at the new stereocenter). Organometallic C-nucleophiles add to the carbonyl with the same facial selectivity as hydride, provi

Full text of DOI:10.1021/ol027434e

ORGANIC
LETTERS
2003
Vol. 5, No. 4
467-470
Synthesis, Stereostructure, and
Conformations of Novel Bi- and
Trifunctional (+)-Isomenthone
Derivatives
,†
John M. Gardiner,* Philip D. Crewe,† Gillian E. Smith,‡,§ Kenneth T. Veal,‡
Robin G. Pritchard,† and John E. Warren†
Department of Chemistry, UMIST, SackVille Street, Manchester M60 1QD, U.K., and
GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, U.K.
john.gardiner@umist.ac.uk
Received December 9, 2002
ABSTRACT
Following protection, keto alcohols 4 [from (+)-isomenthone] undergo reduction to 1,3-diol 6 (S configuration at the new stereocenter).
Organometallic C-nucleophiles add to the carbonyl with the same facial selectivity as hydride, providing multifunctional derivatives, e.g., 8
and 9, with five contiguous stereocenters. The side chain hydroxyl of 4 is elaborated into amino and amide derivatives (e.g., 12). Structural
analysis shows that 6, 8, 9, and the precursor to 12 (10) all adopt triaxial solid-state conformations.
A considerable number of terpenoid derivatives are useful
chiral controllers in asymmetric synthesis,1 including some
very effective chiral reagents (e.g., allylboron reagents), chiral
auxiliaries (e.g., 8-phenylmenthol), and chiral catalysts.
While menthone has provided the chiral information in many
systems, applications of isomenthone derivatives are es-
sentially unknown. Carbon-carbon bond formation to the
kinetic enolate of menthone (at C6) is generally not diaste-
reospecific, and most elaborations from menthone have thus
been at the carbonyl group. We have previously shown that
aldol reactions of (+)-isomenthone (1) with a wide range of
aldehydes are all completely diastereospecific in C-C
formation to C6 with the same sense of diastereocontrol at
the new C6 center (to 2 and/or 3) (Scheme 1).2 This offers
the potential of elaborating isomenthone into bi- and tri-
functional ligands by elaboration at both the terpene carbonyl
and at the R methylene, without complications from generat-
ing mixtures of ring diastereomers.
Scheme 1
† UMIST.
‡ GlaxoSmithKline.
While the new C6 stereocenter is introduced with complete
control, Re or Si selectivity for addition to the carbonyl group
§ Current address: GlaxoSmithKline, Old Powder Mills, Leigh, Nr.
Tonbridge, Kent, TN11 9AN, UK.
10.1021/ol027434e CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/24/2003

of either alkyl or aryl aldehydes is in most cases not specific,
providing threo/erythro mixtures, though in some cases, a
single (threo) diastereomer is obtained. The diastereoselec-
tivity can be affected by modifying conditions; separation
of diastereomers, if desired, is achievable through chroma-
tography or crystallization.2
acetal 7a, facilitating NMR proof of absolute stereochemistry
of reduction in the case of 6a.
Scheme 2
While (+)-isomenthone itself has been shown to exist in
solution mainly as the diastereomer with isopropyl group
axial,3 all aldol derivatives we have prepared adopt the
conformation shown in Scheme 1 (at least in the solid state)
with the isopropyl equatorial and the hydroxylated side chain
disposed axial (even when this hydroxylated group is
aromatic or branched).2 Recently, an extensive study of solid
state and solution conformations and aggregation states of
cycloalkanone-derived aldols (without R,R′-disubstitution)
has appeared.4 We will describe more extensive structural
analyses (by X-ray crystallography and NMR) of isomen-
thone-derived aldols elsewhere.2b
We have sought to utilize this homologation to provide a
versatile entry to new derivatives, which, through elaboration
of the ring carbonyl and/or side chain hydroxyl, could
provide novel bi- and trifunctional systems containing five
contiguous chiral centers. We report here the conversion of
(+)-isomenthone to examples of novel diols, of amino
alcohols and derivatives, and of thioalcohols. This establishes
the viability of using isomenthone as a starting material for
diverse new ligand candidate synthesis via ring diastereospe-
cific aldol homologation intermediates.
The stereostructure of 6b obtained from reduction of 4b
with LAH (then THP removal) was established directly
through X-ray structure analysis (Figure 1). This then allowed
We previously established that reduction of the keto
alcohol 2 (R1 ) Et) and its silyl ether derivative 4a
introduced the new secondary alcohol center with S config-
uration with high selectivity.5 To assess whether other keto
alcohols 2 and derivatives were reduced with comparable
diastereocontrol, both THP ether derivative 4b, and SEM
ether derivative 4c, of the isopropyl system 2 (R1
)
isopropyl) were prepared and reduced using LAH. This
afforded almost exclusively one configuration at the new
chiral center giving (after deprotections) 6a/b from 5a/b
(Scheme 2).5 Reaction of diol 6 with diiodomethane gave
the (conformationally locked) methylene acetal product 7b.
Attempted removal of the SEM ether of 5c with TFA did
not provide diol (6b), but instead directly afforded the same
methylene acetal 7b. This proved that reduction of both
SEM- and THP-protected systems (4) proceed with the same
sense of diastereocontrol. Similarly, 6a forms isopropylidene
Figure 1. X-ray structure of 6b.
assignment of the structure of acetal 7b as the trans-decalin
system shown. These results indicate that reduction of
unprotected or SEM-, TBDMS-, or THP-protected aldols,
with either of two different hydride sources5 and applied to
two different aldol substrates, proceeds with a common sense
of diastereoselectivity in creation of the new alcohol-bearing
stereocenter in all cases. It is likely that reductions of other
related keto alcohol derivatives would proceed with good
diastereocontrol in this same sense.
(1) (a) Blaser, H.-U. Chem. ReV. 1992, 92, 935-952. (b) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000. (c)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999.
(2) (a) Chughtai, J. H.; Gardiner, J. M.; Harris, S. G.; Parsons, S.; Rankin,
D. W. H.; Schwalbe, C. H. Tetrahedron Lett. 1997, 38, 9043-9046. (b)
Gardiner, J. M.; Chughtai, J. H.; Crewe, P. D.; Smith. G. E.; Veal, K. T.;
Warrren, J. E.; Pritchard, R. G.; Harris, S. G.; Parsons, S.; Rankin, D. W.
H.; Schwalbe, C. H. Unpublished work.
(3) Smith, W. B.; Amezcua, C. Magn. Reson. Chem. 1998, 36, S3-
S10.
(4) Kitamura, M.; Nakano, K.; Miki, T.; Okada, M.; Noyori, R. J. Am.
Chem. Soc. 2001, 123, 8939-8950.
(5) Gardiner, J. M.; Chughtai, J. H.; Sadler, I. H. Tetrahedron: Asymmetry
1998, 9, 599-606. Both NaBH4 and LiAlH4 gave the same sense of
diasterecontrol.
The X-ray structure shows that diol 6 adopts the conformer
shown placing three ring substituents axial, with only the
ring isopropyl group equatorial. Crystal forces may be
468
Org. Lett., Vol. 5, No. 4, 2003

responsible for this triaxial conformational preference in the
solid state, since the diol forms asymmetric dimers held
together by H-bonding between the two oxygens of one
molecule and the two hydroxyl protons of the other molecule.
However, 1H NMR of both 6 and its diacetate show that the
proton on the ring hydroxyl-bearing carbon (C2) does not
have any diaxial coupling. Thus, the same conformation with
three groups disposed axially is adopted both in solution and
in the solid state.
With reduction routes available to convert different keto
alcohols to chiral 1,3-diols and monoprotected derivatives
whose absolute structures are now defined, this chemistry
should allow ready provision of further diol analogues as
well as to 1,3-diol derivatives (e.g., phosphinites) as novel
chiral ligand candidates. We have adapted this chemistry to
the synthesis of diol libraries of this type showing that a
range of funtionalized aldols can be prepared, reduced, and
screened as ligands in parallel to identify new enantioselec-
tive chiral ligands.6 There is one related example of a
menthone-derived 1,3-diol of this sort, an aluminum complex
of which catalyzes a Diels-Alder reaction with up to 82%
ee.7
derived system without the side chain attached.8 This
illustrates that this chemistry provides a route into new
families of more functionalized chiral ligand candidates.
We also wished to differentiate the two functional groups
of the keto alcohols to demonstrate entry to various other
new bifunctional and also trifunctional ligand types. Our
route for introduction of nitrogen was via preparation of the
azide derivative of (+)-isomenthone-derived aldol products.
Attempts to introduce the azido group into 4b, 4c, or 2/3
(R1 ) Ph) through mesylation, tosylation, or triflation were
unsuccessful due to competing side reactions. The azide was
successfully introduced through a Mitsunobu-type reaction,
using 2,4,4,6-tetrabromo-2,5-cyclohexadienone, triphenylphos-
pine, and the diazobis(pyridine) zinc.9 Thus, keto alcohol 2
[R1 ) Ph] was converted into azido ketone 10 in good yield
(Scheme 4). Replacement of OH by the azido group excludes
Scheme 4
Our second target was the addition of nonhydride nucleo-
philes to the ring carbonyl to introduce a new C-C bond
and adding new functionality along with a new hydroxylated
quaternary center.
Two illustrative examples are presented here of reactions
of protected aldol 4b with Grignard and organolithium
reagent. Allylmagnesium bromide reacts with 4b to give a
single diastereomeric product 8, while 2-lithiopyridine
reacted with 4b also giving, after deprotection, a single
diastereomeric product 9 (Scheme 3). In both cases, the
effects of H-bonding by the hydroxyl in driving conforma-
tional preference in the crystal structure (for the axial side
chain). However, an X-ray structure of azide 10 shows the
same ring conformation as in all keto alcohols, so that
H-bonding from the aldol hydroxyl does not appear to be
determining in conformational preferences in the solid state
for (+)-isomenthone derivatives. The same azidation chem-
istry was successfully applied to 3 [R1 ) CHdCHPh].
This entry to 1,3-azidoketones provides a valuable hub,
since both the azide and carbonyl groups could be elaborated
to other functionality. There are recent examples of terpenoid-
derived amino alcohols acting as effective catalysts.10 In this
context, we reduced the azide to an amino ketone by
hydrogenation (unoptimized) to provide 11, and this was then
further elaborated to the amido phosphine 12 (Scheme 4).
The combination of P, N, O functionality, frequently
including an amide, is heterofunctionality common to several
recently reported chiral ligands catalyzing various pro-
cesses.11
Scheme 3
nucleophile has added with the same facial sense as with
hydride additions. This strongly suggests a general preference
for any additions to this carbonyl of this substrate type. This
predictivity is valuable for synthesis of further defined
diastereomeric targets from various aldol intermediates. The
pyridyl system 9 has an interesting trifunctional ligand
architecture. The most related prior example is a menthyl-
(8) Herrmann, W. A.; Haider, J. J.; Fridgen, J.; Lobmaier, G. M.; Spiegler,
M. J. Organomet. Chem. 2000, 603, 69-79.
(9) (a) Saito, A.; Saito, K.; Tanaka, A.; Oritani, T. Tetrahedron Lett.
1997, 38, 3955. (b) Viaud, M. C.; Rollin, P. Synthesis, 1990, 130.
(10) (a) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc.
1998, 120, 9800-9809. (b) Panev, S.; Linden, A.; Dimitrov, V. Tetrahedron:
Asymmetry 2001, 12, 1313-1321. (c) Dimitrov, V.; Dobrikov, G.; Genov,
M. Tetrahedron: Asymmetry 2001, 12, 1323-1329.
(6) Gardiner, J. M.; Crewe, P. D.; Smith, G. E.; Veal, K. T. Unpublished
results, 2002. Ligands identified with up to 90% ee.
(7) Naraku, G.; Hori, K.; Ito, Y. N.; Katsuki., T. Tetrahedron Lett. 1997,
38, 8231-8232.
Org. Lett., Vol. 5, No. 4, 2003
469

We also sought to convert diols of type 6 into bisphos-
phines (by double substitution of bistriflates or tosylates) or
bisphosphinites from the diol by phosphinylation. Attempts
at generating bisphosphines were unsuccessful. However,
reaction of diol 6 [R1 ) i-Pr] with bisphenylphosphoryl
chloride led to formation of (oxidized) monophosphorylated
13 (Scheme 5).
Scheme 6
Scheme 5
array of different ligand architectures and functionalities
containing two or three heteroatoms. This chemistry can now
be exploited to construct ranges of new bi- and trifunctional
ligands for evaluation in other target systems.
To introduce a thiol function, the tosylate derivative of
keto alcohol 2 [R1 ) Ph] was reacted with lithium thiophen-
oxide. Two thioether products 14 and 15 were formed, the
minor (15) being that from concomitant substitution and C6
epimerization (Scheme 6). This is the only example where
we have ever seen any epimerization chemistry and may be
accounted for by the basicity of lithium thiophenoxide.
In conclusion, this work has shown that diastereospecific
aldol elaborations of (+)-isomenthone allows entry to an
Acknowledgment. We thank GlaxoSmithKline and
EPSRC for a CASE award (supporting P.D.C.) and EPSRC
for instrumentation grants GR/L52246 (NMR), GR/M30135
(IR), and GR/L84391 (HPLC). The EPSRC Mass Spectrom-
etry Service are thanked for analyses of some of the new
compounds described.
Supporting Information Available: 1H, 13C/DEPT,
COSY, and HMBC spectra are available for compounds 6,
8, 9-11, 13, and 15. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) (a) Mino, T.; Kashihara, K.; Yamashita, M. Tetrahedron: Asymmetry
2001, 12, 287-291. (b) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M.
J. Org. Chem. 2000, 65, 7033. (c) Uozumi, Y.; Mizutani, K.; Nagai, S.-I.
Tetrahedron Lett. 2001, 42, 407. (d) Uozumi, Y.; Yasoshima, K.; Miyachi,
T.; Nagai, S.-I. Tetrahedron Lett. 2001, 42, 411. (e) Hou, D. R.; Burgess,
K. Org. Lett. 1999, 1, 1745-1747. (f) Gilbertson, S. R.; Lan, P. Org. Lett.
2001, 3, 2237-2240.
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