Elongation of 1,3-polyols via iterative catalyst-directed carbonyl allylation from the alcohol oxidation level

Article abstract of DOI:10.1021/ol901136w

Iterative enantioselective carbonyl allylation from the alcohol oxidation level under the conditions of iridium catalyzed transfer hydrogenation enables chain elongation of 1,3-polyols. High levels of catalyst-directed enantioselectivity and diastereosele

Full text of DOI:10.1021/ol901136w

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3112-3115
Elongation of 1,3-Polyols via Iterative
Catalyst-Directed Carbonyl Allylation
from the Alcohol Oxidation Level
Abbas Hassan, Yu Lu, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received May 22, 2009
ABSTRACT
Iterative enantioselective carbonyl allylation from the alcohol oxidation level under the conditions of iridium catalyzed transfer hydrogenation
enables chain elongation of 1,3-polyols. High levels of catalyst-directed enantioselectivity and diastereoselectivity are observed.
In the course of exploring C-C bond forming hydrogena-
tions beyond hydroformylation,1 we recently found that
iridium catalyzed transfer hydrogenation of allylic acetates
or allenes in the presence of aldehydes results in highly
enantioselective carbonyl allylation.2-5 Whereas reactions
from the aldehyde oxidation level employ isopropanol as
reductant, alcohols may serve dually as hydrogen donor and
(4) For selected reviews of carbonyl allylation based on the reductive
coupling of metallo-π-allyls derived from allylic alcohols, ethers, or
carboxylates, see: (a) MasuyamaY. Palladium-Catalyzed Carbonyl Allylation
Via π-Allylpalladium Complexes. In AdVances in Metal-Organic Chemistry;
Liebeskind, L. S. Ed.; JAI Press: Greenwich, 1994; Vol. 3, pp 255-303.
(b) TamaruY. Palladium-Catalyzed Reactions of Allyl and Related Deriva-
tives with Organoelectrophiles. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, Ei.-i.; de Meijere, A., Eds.; Wiley: New
York, 2002; Vol. 2, pp 1917-1943. (c) TamaruY. Novel Catalytic Reactions
involving π-Allylpalladium and -Nickel as the Key Intermediates: Umpolung
and ꢀ-Decarbopalladation of π-Allylpalladium and Nickel-Catalyzed Ho-
moallylation of Carbonyl Compounds with 1,3-Dienes. In PerspectiVes in
Organopalladium Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier:
Amsterdam, 1999; pp 215-231. (d) Kondo, T.; Mitsudo, T.-a. Curr. Org.
Chem. 2002, 6, 1163. (e) Tamaru, Y. Eur. J. Org. Chem. 2005, 13, 2647.
(f) Zanoni, G.; Pontiroli, A.; Marchetti, A.; Vidari, G. Eur. J. Org. Chem.
2007, 22, 3599.
(1) For selected reviews on C-C bond forming hydrogenation and transfer
hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische, M. J. J. Org.
Chem. 2007, 72, 1063. (b) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische,
M. J. Acc. Chem. Res. 2007, 40, 1394. (c) Shibahara, F.; Krische, M. J.
Chem. Lett. 2008, 37, 1102. (d) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34.
(2) For enantioselective carbonyl allylation, crotylation and reverse
prenylation Via iridium catalyzed transfer hydrogenation, see: (a) Kim, I. S.;
Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340. (b) Kim,
I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14891. (c)
Kim, I. S.; Han, S.-B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514.
(d) Han, S. B.; Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009,
131, 6916. (e) Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische,
M. J. Angew. Chem., Int. Ed. 2009, 48, 5018.
(3) For reviews on enantioselective carbonyl allylation, see: (a) Yama-
moto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (b) Ramachandran, P. V.
Aldrichim. Acta 2002, 35, 23. (c) Kennedy, J. W. J.; Hall, D. G. Angew.
Chem., Int. Ed. 2003, 42, 4732. (d) Denmark, S. E.; Fu, J. Chem. ReV.
2003, 103, 2763. (e) Yu, C.-M.; Youn, J.; Jung, H.-K. Bull. Korean Chem.
Soc. 2006, 27, 463. (f) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683.
(g) Hall, D. G. Synlett 2007, 1644.
(5) For selected examples of carbonyl allylation via catalytic Nozaki-
Hiyama-Kishi coupling of allylic halides, see: (a) Fu¨rstner, A.; Shi, N. J. Am.
Chem. Soc. 1996, 118, 2533. (b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi,
A. Polyhedron 2000, 19, 537. (c) McManus, H. A.; Cozzi, P. G.; Guiry,
P. J. AdV. Synth. Catal. 2006, 348, 551. (d) Hargaden, G. C.; Mu¨ller-Bunz,
H.; Guiry, P. J. Eur. J. Org. Chem. 2007, 4235. (e) Hargaden, G. C.;
O’Sullivan, T. P.; Guiry, P. J. Org. Biomol. Chem. 2008, 6, 562.
10.1021/ol901136w CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

aldehyde precursor, enabling asymmetric carbonyl allyl-
ation,2a,b,e crotylation,2c and reverse prenylation2d directly
from the alcohol oxidation level in the absence of any
stoichiometric organometallic reagents.
Table 1. Asymmetric Transfer Hydrogenative Carbonyl
Allylation of O-Benzyl 1,3-Propylene Glycol 1aa
In addition to the step economy associated with bypassing
discrete alcohol oxidation and the preactivation attending
stoichiometric use of chiral allylmetal reagents, the ability
to perform carbonyl allylation directly from the alcohol
oxidation level enables allylations that are not easily achieved
using aldehyde electrophiles. For example, whereas double
asymmetric allylation of 1,3-diols delivers C2-symmetric
adducts with exceptional levels of optical enrichment,2e
corresponding allyl additions employing malondialdehydes
are unknown. On the basis of this unique capability, an
iterative two-directional elongation of 1,3-diols to furnish
1,3-polyols was achieved.2e,6,7 Here, we report related one-
directional chain elongations employing monoprotected 1,3-
diols as starting materials. In all cases, high levels of catalyst-
directed enantioselectivity and diastereoselectivity are
observed.8 This protocol, which involves iterative allylation
from the alcohol oxidation level, avoids ꢀ-alkoxy aldehyde
intermediates, which are often unstable with respect to
elimination.
Our initial studies focused on the asymmetric allylation
of O-benzyl 1,3-propylene glycol 1a. Under previously
reported conditions employing the cyclometalated catalyst
generated in situ from [Ir(cod)Cl]2, (S)-Cl,MeO-BIPHEP, and
3-nitrobenzoic acid,2b the coupling of allyl acetate (1000 mol
%) to 1a at 120 °C delivers the homoallyl alcohol 2a in 82%
isolated yield and 94% enantiomeric excess (Table 1, entry
1). Lowering the reaction temperature to 100 °C slightly
enhanced the degree of optical enrichment, but decreased
the isolated yield of 2a (Table 1, entry 2). At 120 °C, a
decrease in the loading of allyl acetate from 10 to 5
equivalents diminished the isolated yield of 2a by only 8%
(Table 1, entries 1 and 3). However, upon a further decrease
in the loading of allyl acetate from 5 to 2 equivalents, the
isolated yield was unchanged (Table 1, entries 3 and 4).
Finally, using the iridium C,O-benzoate generated in situ
from [Ir(cod)Cl]2, (S)-Cl,MeO-BIPHEP and 4-chloro-3-
nitrobenzoic acid, the homoallyl alcohol 2a is obtained in
88% isolated yield and 95% enantiomeric excess (Table 1,
entry 5). As decreased reaction temperature (100 °C) or
extended reaction time (40 h) did not improve this result
(Table 1, entries 6 and 7), the latter conditions employing
temp yield
entry
acid additive
allyl acetate
°C
(%) ee (%)
1
2
3
4
3-NO2-BzOH
3-NO2-BzOH
3-NO2-BzOH
3-NO2-BzOH
1000 (mol %) 120
1000 (mol %) 100
82
76
74
74
94 (S)
96 (S)
94 (S)
95 (S)
500 (mol %)
200 (mol %)
120
120
5
6
4-Cl-3-NO2-BzOH 200 (mol %) 120
88 95 (S)
4-Cl-3-NO2-BzOH 200 (mol %)
4-Cl-3-NO2-BzOH 200 (mol %)
100
45
95 (S)
95 (S)
7b
100
79
a All reactions were performed in 13 × 100 mm pressure tubes. The
cited yields are of material isolated by silica gel chromatography and
represent the average of two runs. Enantiomeric excess was determined by
chiral stationary phase HPLC analysis. See Supporting Information for
experimental details. b The reaction was allowed to proceed for 40 h.
the catalyst modified by 4-chloro-nitrobenzoic acid at 120
°C were selected for iterative homologation of 2a to form
higher 1,3-polyols (Table 1, entry 5).
The iterative synthesis of higher 1,3-polyols requires
exceptional levels of catalyst-directed diastereoselectivity.
To explore this prospect, homoallyl alcohol 2a was converted
to the corresponding tert-butyldimethylsilyl ether 2b and
subjected to ozonolysis in methanol solvent employing a
small quantity of Sudan III as indicator (3-5 drops of a 1.5
mM solution in methanol).9 Upon complete consumption of
2b, as revealed through the change from a pink to a colorless
solution, the reaction mixture was treated with sodium
borohydride to deliver the alcohol 2c in 92% isolated yield.
Upon exposure of 2c to the allylation conditions optimized
for compound 1a (Table 1) employing the catalyst modified
by (S)-Cl,MeO-BIPHEP at 120 °C, the product of carbonyl
allylation (R,S)-3a was obtained in 55% isolated yield as a
15:1 ratio of diastereomers. By lowering the reaction
temperature to 100 °C and extending the reaction time to
40 h under otherwise identical conditions, (R,S)-3a was
obtained in 79% isolated yield as a 17:1 ratio of diastereo-
mers. Under these same conditions, but using the catalyst
modified by (R)-Cl,MeO-BIPHEP, the diastereomeric adduct
(R,R)-3a was obtained in 71% isolated yield as a 15:1 ratio
of diastereomers. Upon use of the achiral iridium catalyst
ligated by BIPHEP, (R,S)-3a and (R,R)-3a are produced in
an equimolar ratio (Scheme 1).
(6) For a review on two-directional chain elongation in target-oriented
synthesis, see: Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9
.
(7) For selected reviews of the synthesis of 1,3-diol substructures, see:
(a) Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15, 47. (b) Oishi, T.;
Nakata, T. Synthesis 1990, 635. (c) Schneider, C. Angew. Chem., Int. Ed.
1998, 37, 1375. (d) Bode, S. E.; Wohlberg, M.; Mu¨ller, M. Synthesis 2006,
With compounds (R,S)-3a and (R,R)-3a in hand, the
stereoselective synthesis of higher homologues was under-
taken. Exposure of (R,S)-3a or (R,R)-3a to methanol in the
presence of p-toluenesulfonic acid (10 mol %) with subse-
quent introduction of 2,2-dimethoxypropane delivers the
diastereomeric acetonides (R,S)-3b and (R,R)-3b, respec-
tively, which are isolated as single diastereomers. Ozonolysis
557
.
(8) For selected examples of catalyst directed diastereoselectivity, see:
(a) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 1109.
(b) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A., III; Sharpless,
K. B.; Walker, F. J. Science 1983, 949. (c) Kobayashi, S.; Ohtsubo, A.;
Mukaiyama, T. Chem. Lett. 1991, 831. (d) Hammadi, A.; Nuzillard, J. M.;
Poulin, J. C.; Kagan, H. B. Tetrahedron: Asymmetry 1992, 3, 1247. (e)
Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J. Am. Chem. Soc. 1996, 118,
8837. (f) Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano, J. Tetrahedron
Lett. 1998, 39, 1713. (g) Balskus, E. P.; Jacobsen, E. N. Science 2007,
317, 1736. (h) Han, S. B.; Kong, J. R.; Krische, M. J. Org. Lett. 2008, 10,
4133.
(9) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807.
Org. Lett., Vol. 11, No. 14, 2009
3113

Scheme 1
.
Catalyst-Directed Diastereoselectivity in the Transfer Hydrogenative Carbonyl Allylation of 2c and Synthesis of Higher
Homologues 4aa
a See Supporting Information for experimental details.
of (R,S)-3b and (R,R)-3b followed by NaBH4 reduction in
accordance with the aforementioned procedure9 provides
(R,S)-3c and (R,R)-3c. Transfer hydrogenative carbonyl
allylation of (R,S)-3c or (R,R)-3c employing the catalyst
modified by (S)-Cl,MeO-BIPHEP at 100 °C delivers the
products of carbonyl allylation (R,S,S)-4a and (R,R,S)-4a,
respectively. Using the enantiomeric catalyst modified by
(R)-Cl,MeO-BIPHEP, (R,S)-3c or (R,R)-3c are transformed
to homoallylic alcohols (R,S,R)-4a and (R,R,R)-4a, respec-
tively. In each case, the minor diastereomer could not be
yield and 95% enantiomeric excess. Conversion of 6a to the
tert-butyldimethylsilyl ether 6b, followed by removal of the
p-methoxybenzyl ether delivers the primary neopentyl al-
cohol 6c. Transfer hydrogenative carbonyl allylation of 6c
employing the catalyst modified by (R)-Cl,MeO-BIPHEP at
120 °C provides the homoallyl alcohol (R,R)-7a in 78%
isolated yield in a 12:1 diastereomeric ratio. Using the
catalyst modified by (S)-Cl,MeO-BIPHEP at 120 °C, 6c is
converted to the homoallyl alcohol (S,R)-7a in 82% isolated
yield in an 11:1 diastereomeric ratio. Using the achiral
iridium catalyst modified by BIPHEP, (R,R)-7a and (S,R)-
7a are formed in roughly equal proportion. Thus, catalyst-
directed chain elongation may be conducted sequentially
from either terminus of the precursor (Scheme 2).
1
detected by H NMR analysis. Upon use of the achiral
iridium catalyst ligated by BIPHEP, (R,S)-3c and (R,R)-3c
are converted to equimolar quantities of (R,S,S)-4a, (R,S,R)-
4a and (R,R,S)-4a, (R,R,R)-4a, respectively (Scheme 1).
To illustrate the utility of this methodology in a related
context, O-p-methoxybenzyl neopentyl glycol 5a was sub-
jected to transfer hydrogenative carbonyl allylation employ-
ing the catalyst modified by (R)-Cl,MeO-BIPHEP at 120 °C.
The homoallylic alcohol 6a was produced in 80% isolated
In summary, under the conditions of transfer hydrogenative
carbonyl allylation, the stereochemical bias of enantiomeric
iridium catalysts modified by (R)-or (S)-Cl,MeO-BIPHEP is
found to override the intrinsic diastereofacial bias of transient
ꢀ-chiral aldehydes. Based on this finding, a concise enantio-
3114
Org. Lett., Vol. 11, No. 14, 2009

Scheme 2.
Transfer Hydrogenative Chain Elongation from Both Termini of Neopentyl Glycol 5aa
a See Supporting Information for experimental details.
and diastereoselective synthesis of 1,3-polyols was achieved
via iterative chain elongation. The utility of this approach
stems from the ability to circumvent use of chirally modified
allylmetal reagents, which require multistep preparation, and
the ability to perform chain elongation directly from the
alcohol oxidation level, which avoids discrete generation of
ꢀ-alkoxy aldehydes that are often unstable. Future studies
will focus on the development of related C-C bond forming
transfer hydrogenations, including imine additions from the
amine oxidation level.10,11
Acknowledgment. We acknowledge the Robert A. Welch
Foundation, the American Chemical Society Green Chem-
istry Institute Pharmaceutical Roundtable, and the NIH-
NIGMS (RO1-GM069445) for partial support of this re-
search. The Higher Education Commission, Pakistan is
acknowledged for generous fellowship support (A.H.). Dr.
Oliver Briel of Umicore is thanked for the generous donation
of [Ir(cod)Cl]2.
(10) The collective alcohol-unsaturate C-C couplings we describe (refs
1c,d) may be viewed as hydrohydroxyalkylations. For related amine-
unsaturate C-C couplings, or hydroaminoalkylations, see: (a) Maspero, F.;
Clerici, M. G. Synthesis 1980, 305. (b) Nugent, W. A.; Ovenall, D. W.;
Homes, S. J. Organometallics 1983, 2, 161. (c) Herzon, S. B.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 6690. (d) Herzon, S. B.; Hartwig, J. F.
J. Am. Chem. Soc. 2008, 130, 14940. (e) Kubiak, R.; Prochnow, I.; Doye,
S. Angew. Chem., Int. Ed. 2009, 48, 1153. (f) Bexrud, J. A.; Eisenberger,
P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. J. Am. Chem. Soc. 2009,
131, 2116.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) For a synthesis of the Bryostatin A-ring, using such transfer
hydrogenations, see: Lu, Y.; Krische, M. J. Org. Lett. 2009, 11, DOI:
(10.1021/ol901096d).
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