α,ω-functionalized 2,4-dimethylpentane dyads and 2,4,6-trimethylheptane triads through asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.200603635

A match made in heaven: All the possible stereoisomers of α,ω-functionalized 2,4-dimethylpentane dyad and 2,4,6-tri- methylheptane triad chirons (see picture; A and B, respectively; FG = functional group, PG = protecting group) can be reached by using a c

Full text of DOI:10.1002/anie.200603635

Angewandte
Chemie
DOI: 10.1002/anie.200603635
Asymmetric Catalysis
a,w-Functionalized 2,4-Dimethylpentane Dyads and 2,4,6-
Trimethylheptane Triads through Asymmetric Hydrogenation**
Jianguang Zhou and Kevin Burgess*
In memory of Vorawit Banphavichit (Bee)
Chiral analogues of the Crabtree catalysts,[1] [Ir(cod)(py)-
(PR3)PF6] (that is, [M(N,P)*] systems; cod = cycloocta-l,5-
diene, py = pyridine) are excellent enantioselective catalysts
for hydrogenation reactions of trisubstituted alkenes,[2] and
have been used extensively to reduce alkenes that are largely
unfunctionalized insofar as they do not contain strongly
coordinating groups.[3,4] Consequently, asymmetric hydroge-
nations are potentially possible for a broad range of substrates
for which most other chiral catalysts are not effective.
(Scheme 1). These chirons are
found in a large family of natural
products: the deoxypolyketides.
Commercially available (S)-
methyl-3-hydroxyisobutyrate ((S)-
Roche ester) was converted into
several alcohol and ester deriva-
tives, including
2
(> 99% ee,
Scheme 2), which contains a very
Nearly all the substrates studied so far in hydrogenation
reactions mediated by chiral analogues of the Crabtree
catalyst give relatively simple products. To access more
sophisticated chirons we launched a program to study hydro-
genations of dienes and polyenes,[5–7] and Pfaltz and co-
workers recently described the reduction of a 1,5,9-triene to
give (R,R,R)-tocopherol.[8] This latter study stands out as the
most synthetically useful application of the chiral Crabtree
catalysts to date. Although formally a diastereoselective
synthesis, the preexisting chiral center in the substrate was too
far away from the nearest alkene to affect face selectivity. In
fact, none of the research on chiral analogues of the Crabtree
catalysts has systematically studied chiral substrates in which
the chiral center is close enough to influence the stereochem-
ical outcome. Herein we describe the first such study.
bulky silyl protecting group. Catalyst l-1 (BArFÀ = tetrakis-
(3,5-bis(trifluoromethyl)phenyl)borate) was derived from l-
Our goal was to use the carbene oxazoline complex 1[9,10]
to prepare the a,w-functionalized 2,4-dimethyl and 2,4,6-
trimethyl stereochemical dyads and triads
A and B
Scheme 1. a,w-Functionalized 2,4-dimethyl and 2,4,6-trimethyl
stereochemical dyads and triads.
[*] Dr. J. Zhou, Prof. K. Burgess
Department of Chemistry
TexasA & M University
Box 30012, College Station, TX 77841-3012 (USA)
Fax: (+1)979-845-8839
E-mail: burgess@tamu.edu
Scheme 2. a) Preparation of an anti type A chiron: 3 wasisolated in
90% yield with a 40:1 anti/syn ratio after one chromatographic
purification; b) model for substrate 2; c) a similar model for substrate
4; d) model for substrate 6; and, e) preparation of the syn type A
chiron: 7 wasisolated in 93% yield after one chromatographic
purification (syn/anti >120:1). Conversions were quantitative through-
out. All ratiosquoted were calculated from GC analysis. TBDPS =tert-
butyldiphenylsilyl, DIBALH=diisobutylaluminum hydride.
[**] We thank the late Dr. V. Banphavichit for preparing the catalyst and
Y. Zhu for performing some GC analyses. The National Science
Foundation (CHE-0456449) and The Robert A. Welch Foundation
are acknowledged for financial support.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 1129 –1131
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1129

Communications
aspartic acid, and d-1 from the corresponding enantiomer.
terminated before completion indicate that the rates of
reduction for the two double bonds are competitive.
Hydrogenation of substrate 2 using catalyst l-1 revealed that
the chirality of the substrate matched that of the l-catalyst[11]
and excellent diastereoselectivity was obtained. Interestingly,
catalyst d-1 gave an appreciable selectivity in the opposite
direction, which illustrated that catalyst control is operative in
this reaction. In fact, catalyst control applies in all the
examples reported here. However, the substrates also have an
intrinsic bias and, though less influential, it can be significant
for optimizing selectivities. For brevity, we refer to this
contribution as “the substrate vector”; this is different from
“substrate control”, which implies the overall stereoselectiv-
ity is governed by the substrate.
Other stereoisomers of the triad B were obtained by the
homologation of anti-3 and syn-7 (Scheme 2) into the
corresponding alkenes, and subsequent hydrogenation. The
anti,anti diastereomer was produced as depicted in
Scheme 3b. Again, this reaction is catalyst controlled, but a
high stereoselectivity was obtained by matching the catalyst
and substrate vectors. Our model for the substrate vector
(Scheme 3c) features a conformation that results from the
relief of 1,3-allylic strain and syn-pentane interactions[14]
which exposes one face of the alkene preferentially. Similarly,
A rationale for the substrate vector in the hydro-
genation of 2 is shown in Scheme 2b. This model
predicts that the preferred conformation minimizes
1,3-allylic strain;[12] thus hydrogenation is favored on
the alkene face which is least hindered. This subordi-
nate effect corresponds with the effect of l-1 to
enhance the catalyst vector. However, when d-1 is
used, the substrate and catalyst vectors are mis-
matched and, since the later is dominant, the stereo-
selectivity is reversed and also diminished.
Having shown that the reduction of ester 2 is a
good route to the anti isomer of chiron A, we then
focused on the syn epimer. The mismatched pair in the
reduction of 2 gave a 7.8:1 selectivity for the syn ester
3 (Scheme 2a). We sought to improve on this selec-
tivity by converting the substrate into the correspond-
ing allylic alcohol. We have previously found that the
catalyst approaches such a,b-unsaturated esters and
alcohols from opposite faces.[13] Thus, the substrate
vector for alcohol 4 matched with d-1, whereas the
corresponding ester 2 matched with l-1. Thus, for the
reduction of 4 to 5 (Scheme 2a), the (matched) d-1
catalyst favored the anti product, whereas syn selec-
tivity was only 3.6:1 when the (mismatched) l-1 was
used. However, favorable syn selectivity was obtained
by hydrogenation of the Z allylic alcohol 6 (> 99% ee)
using d-1 (Scheme 2e). The model shown in
Scheme 2d rationalizes this result.
Both antipodes of the Roche ester are commer-
cially available, so the two enantiomers of the syn and
anti chirons are accessible by using the methodology
outlined above. The first milestone in this study was
therefore reached, and attention was turned to chirons
B (Scheme 1).
A direct route to the chirons B is to hydrogenate
suitable diene substrates. We have been able to
Scheme 3. a) Preparation of an anti,syn type B chiron: 9 wasisolated in 83%
yield and with a 51:1 anti,syn/syn,syn ratio after one chromatographic purifica-
tion; b) preparation of an anti,anti type B chiron: 11 wasreduced (DIBALH) to
an isomer of alcohol 9 and wasisolated in 70% yield with a 120:1 anti,anti/
anti,syn ratio after chromatography; c) 1,3-allylic strain/syn-pentane model for
the hydrogenation of 10; d) similar model for 12; e) preparation of a syn,anti
type B chiron: 13 wasreduced to an isomer of alcohol 9 and wasisolated in
82% yield with a 89:1 syn,anti/syn,syn ratio after chromatography; f) prepara-
tion of syn,syn type B chiron: 15 wasisolated in 71% yield with >120:1 syn,syn/
syn,anti ratio after one chromatographic purification. Hydrogenation conditions
as in Scheme 2, although higher catalyst loadings (1 mol% versus 0.2 mol%)
were used because the scale of the reaction was smaller. nd=not detected.
achieve this transformation with high stereoselectivity
for one substrate, 8. This reaction (Scheme 3a) gives a
35:3.1 (that is ca. 11:1) selectivity in favor of the
anti,syn isomer relative to the other three isomers
combined. Furthermore, this diastereoisomer is sepa-
rable from the others through column chromatogra-
phy. This transformation is unique insofar as no
published method to deoxypolyketide chirons has
reported the simultaneous production of two chiral
centers. Experiments in which the reaction was
1130
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 1129 –1131

Angewandte
Chemie
700 rpm at 50 atm. After 4 h, the bomb was vented and the solvent
we believe that hydrogenation of substrate 12 gave a high
selectivity for the syn,anti isomer because the substrate vector
matches with l-1 (Scheme 3d and e). By analogy with the
reaction shown in Scheme 2d, the all-syn isomer 15 was
obtained from the Z allylic alcohol 14 as shown in Scheme 3 f.
Interchange of the functional groups at the termini of
chirons 9, 11, 13, and 15 would give the enantiomeric building
blocks for deoxypolyketide syntheses. Alternatively, these
enantiomers could be obtained from the (R)-Roche ester.
Thus, we had met the second objective of this study.
evaporated. The crude product was passed through a small plug of
silica gel (EtOAc/hexanes 3:7). The enantiomeric and diastereomeric
ratios of the crude material were then determined by capillary GC
analysis on a chiral b- or g-cyclodextrin (CD) stationary phase (carrier
gas: helium; column pressure: 29.71 psi; gas-flow rate: 2.1 mLminÀ1
;
gradient temperature: 58CminÀ1: starting temperature: 908C hold
time: 30 min, 2008C, 5 min, 908C.
Received: September 6, 2006
Revised: October 24, 2006
Published online: January 3, 2007
Routes to chirons A and B can be segregated into either
diastereoselective reactions involving chiral auxiliaries or
catalytic methods.[15] The former are the more tried and
tested, and we believe that, of these, the asymmetric
alkylation methodology reported by Myers et al. is the most
practical.[16] Nevertheless, catalytic approaches are gaining
importance. The carboalumination of alkenes by Negishi et
al.,[17] and the asymmetric cuprate Michael additions of
Feringa and co-workers[18] are exciting developments in this
field. However, the data collected herein show that routes to
deoxypolyketide fragments using asymmetric hydrogenation
can compete with the state-of-the-art methods in terms of
catalyst loading, stereoselectivities, and atom economy.[19]
The approach described herein is fundamentally different
from acyclic stereocontrol through directed hydrogenations
of chiral homoallylic alcohols.[20] These reactions have been
studied by using almost exclusively Rh or Ir catalysts of the
type where the metal is coordinated to a chelating chiral
bisphosphine (that is, not chiral Crabtree catalysts) and they
are almost invariably substrate controlled. Furthermore,
these systems are poor catalysts for the hydrogenation of
trisubstituted alkenes when the substrate does not contain a
homoallylic alcohol,[3,21] so they would not prove useful in the
reactions described here. However, other chiral analogues of
the Crabtree catalyst could be used, and some may give
higher stereoselectivities. The prospects for further refine-
ments to this method are therefore good, and the approach
may evolve into one that equals or supersedes the classical
directed approaches for acyclic stereocontrol through hydro-
genation.
Keywords: asymmetric catalysis · homogeneous catalysis ·
hydrogenation · iridium · polyketides
.
[1] R. H. Crabtree, Acc. Chem. Res. 1979, 12, 331.
[2] A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem. 1998, 110,
3047; Angew. Chem. Int. Ed. 1998, 37, 2897.
[3] X. Cui, K. Burgess, Chem. Rev. 2005, 105, 3272.
[4] R. Hoen, J. A. F. Boogers, H. Bernsmann, A. J. Minnaard, A.
Meetsma, T. D. Tiemersma-Wegman, A. H. M. de Vries, J. G.
de Vries, B. L. Feringa, Angew. Chem. 2005, 117, 4281; Angew.
Chem. Int. Ed. 2005, 44, 4209; .
[5] X. Cui, J. W. Ogle, K. Burgess, Chem. Commun. 2005, 672.
[6] X. Cui, Y. Fan, M. B. Hall, K. Burgess, Chem. Eur. J. 2005, 11,
6859.
[7] X. Cui, K. Burgess, J. Am. Chem. Soc. 2003, 125, 14212.
[8] S. Bell, B. Wustenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642.
[9] M. T. Powell, D.-R. Hou, M. C. Perry, X. Cui, K. Burgess, J. Am.
Chem. Soc. 2001, 123, 8878.
[10] M. C. Perry, X. Cui, M. T. Powell, D.-R. Hou, J. H. Reibenspies,
K. Burgess, J. Am. Chem. Soc. 2003, 125, 113.
[11] S. Masamune, W. Choy, J. S. Peterson, L. R. Sita, Angew. Chem.
1985, 97, 1; Angew. Chem. Int. Ed. Eng. 1985, 24, 1.
[12] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841.
[13] J. W. Ogle, Y. Fan, K. Burgess, unpublished results.
[14] R. W. Hoffmann, Angew. Chem. 2000, 112, 2134; Angew. Chem.
Int. Ed. 2000, 39, 2054.
[15] S. Hanessian, S. Giroux, V. Mascitti, Synthesis 2006, 7, 1057.
[16] A. G. Myers, B. H. Yang, H. Chen, D. J. Kopecky, Synlett 1997, 5,
457.
[17] E. Negishi, Z. Tan, B. Liang, T. Novak, Proc. Natl. Acad. Sci.
USA 2004, 101, 5782.
[18] R. D. Mazery, M. Pullez, F. Lopez, S. R. Harutyunyan, A. J.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 9966.
[19] B. M. Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed.
Eng. 1995, 34, 259.
[20] J. M. Brown, Angew. Chem. 1987, 99, 16 9;Angew. Chem. Int. Ed.
Engl. 1987, 26, 190.
Experimental Section
General catalytic hydrogenation conditions: The corresponding
alkene was dissolved in CH2Cl2 (1m solution) and the iridium catalyst
l-1 or d-1 (1.0 mol% for small-scale, 0.2 mol% for gram-scale
reactions, unless otherwise stated) was then added. The resulting
solution was degassed by three cycles of freeze–pump–thaw and then
transferred to a Parr bomb. The bomb was flushed with hydrogen for
1 min without stirring. The reaction mixture was then stirred at
[21] D. A. Evans, M. M. Morrissey, R. L. Dow, Tetrahedron Lett.
1985, 26, 6005.
Angew. Chem. Int. Ed. 2007, 46, 1129 –1131
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1131