Catalytic asymmetric synthesis of hydroxy enol ethers: Approach to a two-carbon homologation of aldehydes

Article abstract of DOI:10.1021/ol050255n

(Chemical Equation Presented) Hydroboration of ethoxy acetylene, transmetalation to zinc, and addition to aldehydes in the presence of a chiral amino alcohol ligand (MIB) affords hydroxy enol ethers with high ee. The resultant enantiomerically enriched hydroxy enol ethers were converted to protected hydroxy aldehydes, a useful synthetic building block for the construction of a variety of polyoxygenated natural products. In addition, diastereoselective formation of syn- and anti-1,3-diols was studied.

Full text of DOI:10.1021/ol050255n

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1729-1732
Catalytic Asymmetric Synthesis of
Hydroxy Enol Ethers: Approach to a
Two-Carbon Homologation of Aldehydes
Sang-Jin Jeon, Young K. Chen, and Patrick J. Walsh*
Department of Chemistry, P. Roy and Diana T. Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
pwalsh@sas.upenn.edu
Received February 7, 2005
ABSTRACT
Hydroboration of ethoxy acetylene, transmetalation to zinc, and addition to aldehydes in the presence of a chiral amino alcohol ligand (MIB)
affords hydroxy enol ethers with high ee. The resultant enantiomerically enriched hydroxy enol ethers were converted to protected hydroxy
aldehydes, a useful synthetic building block for the construction of a variety of polyoxygenated natural products. In addition, diastereoselective
formation of syn- and anti-1,3-diols was studied.
â-Hydroxy carbonyls, 1,3-diols, and related polyols are
common structural motifs in natural products. As such, much
attention has been devoted to development of methods for
the synthesis of these â-oxygenated systems. Significant
effort has been focused on the asymmetric aldol reaction,
which is particularly powerful for the generation of polypro-
pionate backbone.1-7 In contrast, the asymmetric acetate aldol
reaction that leads directly to an aldehyde functionality has
proven to be a more challenging problem.8,9
The difficulties associated with acetate aldol reactions have
prompted investigations into alternative methods to generate
â-hydroxy aldehydes. One of the most popular non-aldol
entries into â-hydroxy aldehydes involves the catalytic
asymmetric allylation of aldehydes followed by oxidative
cleavage of the allyl group (Scheme 1, A). It is limited,
however, to substrates that do not contain additional func-
tional groups that are sensitive toward the oxidative cleavage
Scheme 1. Non-Aldol Approach to â-Hydroxy Aldehydes
(1) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004, 33,
65-75.
(2) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200.
(3) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
(4) Mahrwald, R. Chem. ReV. 1999, 99, 1095-1120.
(5) Machajewski, T. D.; Wong, C.-H.; Lerner, R. A. Angew. Chem., Int.
Ed. 2000, 39, 1352-1374.
(6) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 10, 1595-
1601.
(7) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(8) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798-6799.
(9) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752-
1755.
10.1021/ol050255n CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/24/2005

conditions.10,11 A less common approach entails a one-carbon
homologation of an R-hydroxy aldehyde with a Wittig
reagent and subsequent hydrolysis of the resultant hydroxy
enol ether12-16 (Scheme 1, reaction B).
In this letter, we report a new non-aldol approach to the
enantioenriched â-hydroxy aldehydes involving catalytic
asymmetric addition of a vinyl ether to an aldehyde and
hydrolysis of the newly formed enol ether (Scheme 1,
reaction C).
We recently reported17-20 a catalytic asymmetric alkenyl-
zinc addition to aldehydes using Nugent’s â-amino alcohol
(MIB) as a chiral ligand (Scheme 2).21 Alkenylzinc reagents
enantioenriched hydroxy enol ethers, which in turn could
be transformed into â-hydroxy aldehydes. Notably, the
subsequent hydrolysis of the protected hydroxy enol ether
can be performed selectively in the presence of other
sensitive functionality. This sequence amounts to an asym-
metric two-carbon homologation of aldehydes to â-hydroxy
aldehydes.
In our initial investigations, we applied the conditions
employed in Scheme 2 using ethoxy acetylene as the terminal
alkyne and diethylzinc as a transmetalating reagent. It is
known that ethoxy acetylene undergoes hydroboration with
high regioselectivity to provide the trans-alkenylborane.27
We initially employed catalyst loading of 4 mol % to achieve
modest to good levels of enantioselectivity with benzalde-
hyde (Table 1, entries 1-3). Increasing ligand loading to
Scheme 2. Enantioselective Synthesis of Allylic Alcohols
Table 1. Optimization of Reaction Conditions
were generated in situ following Oppolzer’s procedure.22,23
Thus, hydroboration of a terminal alkyne was followed by
transmetalation to zinc. Upon introduction of 2 mol % (-)-
MIB and aldehyde substrate, vinylation proceeds smoothly
to afford a variety of allylic alcohols with high levels of
enantioselectivity and yields. We have successfully employed
this procedure in the synthesis of enantioenriched R-amino
acids,18 γ-unsaturated â-amino acids,19 and epoxy alcohols
containing up to three contiguous stereocenters.17,20 Other
groups have also studied the asymmetric vinylation of
aldehydes.24-26
We envisioned that asymmetric vinylation of aldehydes
employing ethoxy acetylene might allow access to highly
a R2BH:ethoxy acetylene:R′2Zn:aldehyde ) 1.2:1.2:1.4:1. b Syringe pump
addition of substrate solution (1 M in toluene) for 30 min.
(10) Bailey, P. S. Ozonization in Organic Chemistry; Academic Press:
New York, 1978; Vol. 1.
(11) Pappo, R.; Allen, D. S. J.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478-479.
(12) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-
5476.
10 mol % did not improve enantioselectivity and reducing
the catalyst loading to 1.5 mol % resulted in product of only
65% ee. Decreasing the reaction temperature to -20 °C had
no beneficial effect. A further decrease to -50 °C resulted
in a reduction in the enantioselectivity (entries 4 and 5).
Similar results were obtained with 4-chlorobenzaldehyde
under the same conditions (entry 6).
(13) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002,
58, 1817-1834.
(14) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J.
Am. Chem. Soc. 1988, 110, 10770-10771.
(15) Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122, 11090-11097.
(16) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521-10532.
(17) Lurain, A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70,
1262-1268.
We next examined alternative methods to generate the
vinyl zinc reagent. No effect was observed on use of
dimethylzinc in place of diethylzinc (entries 7 and 8). To
minimize the background reaction between the reactive vinyl
reagent and the aldehyde, we added the substrate to the
preformed vinylzinc reagent dropwise. In principle, the slow
(18) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225-12231.
(19) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677-
10683.
(20) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J.
J. Am. Chem. Soc. 2004, 126, 13608-13609.
(21) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369-1370.
(22) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-
173.
(23) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org. Chem. 2001,
66, 4766-4770.
(24) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778-1784.
(25) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem.
2003, 68, 1589-1590.
(26) Bra¨se, S.; Dahmen, S.; Ho¨fener, S.; Lauterwasser, F.; Kreis, M.;
Ziegert, R. E. Synlett 2004, 2647-2669.
(27) Miyaura, N.; Maeda, K.; Suginome, H. J. Org. Chem. 1982, 47,
2117-2120.
1730
Org. Lett., Vol. 7, No. 9, 2005

addition allows more of the reaction to proceed through the
ligand-accelerated pathway.28
derwent smooth vinylation to afford the desired hydroxy enol
ethers with high enantioselectivities (92-94%) and yields
between 82% and 97% (entries 5-7).
As illustrated in entries 6 and 7, changing the hydro-
boration reagent from Cy2BH to Et2BH resulted in a small
increase in enantioselectivity. This led us to examine the use
of an alternative vinyl ether borane, namely tris(vinyl ether)
borane prepared by hydroboration of ethoxyacetylene with
BH3‚SMe2.27 Fortunately, employing 0.4 equiv of this reagent
in the asymmetric vinylation reaction with 4 mol % (-)-
MIB and slow addition of the aldehyde at -10 °C, followed
by warming to 0 °C furnished the hydroxy enol ether with
excellent enantioselectivities.
In contrast to aldehydes with R-branching, substrates
bearing â-branching or devoid of branching afforded products
with moderate enantioselectivities. As shown in Table 2
(entries 8 and 9), isovaleraldehyde and 3-(naphthalene-2-
ylmethoxy)propionaldehyde were converted to the enol ether
products in 73% and 78% enantioselectivities with yields
>95%. Aldehydes containing protected R-hydroxy groups
likewise exhibited low enantioselectivities (entries 10 and
11).
With the hydroxy enol ethers in hand, we next turned our
attention to their hydrolysis. As illustrated in Scheme 3, the
As illustrated in Table 2, enantioselectivities and yields
in the vinylation of benzaldehyde and related derivatives
Scheme 3. Synthesis of Masked â-Hydroxy Aldehydes
Table 2. Modified Synthesis of Hydroxy Enol Ethers
two-step procedure for hydrolysis of the hydroxy enol ethers
began with protection of the hydroxyl group as the TBS or
benzyl ether. Subsequent treatment with Hg(OAc)2 in wet
THF followed by KI induced elimination led to the clean
formation of the protected â-hydroxy aldehydes in high
yields. As depicted in Scheme 3, asymmetric vinylation of
isobutyraldehyde, followed by TBS protection led to the
corresponding enol ether in 88% yield. Hydrolysis and
workup with saturated KI afforded the desired â-oxygenated
aldehyde in 71% yield. Likewise, the benzyl protected
â-hydroxy aldehyde was obtained by an analogous sequence
in 80% for the addition and protection and 71% yield in the
hydrolysis step. The enol ether derived from cyclohexyl
aldehyde was transformed to the corresponding â-hydroxy
aldehyde by applying the same protocol (85% and 71%,
respectively). Other metal salts are known to catalyze the
hydrolysis of enol ethers.29 Unfortunately, due to the
increased sensitivity of the hydroxy enol ethers toward Lewis
acid-catalyzed eliminations, other metals led to formation
of elimination products.
We proceeded next to the construction of 1,3-diol moieties,
which are ubiquitous structural motifs in biologically active
compounds. We envisioned that 1,3-diols could be assembled
by diastereoselective vinyl ether addition to enantioenriched
â-hydroxy aldehydes. To our knowledge, there are few
investigations of catalyst controlled diastereoselective addi-
tions of organozinc reagents to chiral aldehydes.30-32 In the
a All reactions employed 4 mol % of (-)-MIB and slow substrate
addition.
provided the hydroxy enol ethers with enantioselectivities
ranging from 89% to 95% and yields >93% (entries 1-4).
Aliphatic aldehydes containing R-branching, such as cyclo-
hexane carboxaldehyde, isobutanal, and pivalaldehyde, un-
(29) Aoyama, H.; Tokunaga, M.; Hiraiwa, S.; Shirogane, Y.; Obora, Y.;
Tsuji, Y. Org. Lett. 2004, 6, 509-512.
(30) Niwa, S.; Hatanaka, T.; Soai, K. J. Chem. Soc., Perkin. Trans. 1
1991, 2025-2027.
(31) Soai, K.; Shimada, C.; Takeuchi, M.; Itabashi, M. J. Chem. Soc.,
Chem. Commun. 1994, 1994, 567-578.
(28) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 3250-3251.
Org. Lett., Vol. 7, No. 9, 2005
1731

absence of catalyst, the sense of asymmetric induction of
â-hydroxy aldehydes is enforced by either â-chelation or
Felkin control depending on protection groups. Both control-
ling elements result in the same preferential anti-diol
product.33
We studied the effect of the chiral ligand (MIB) on the
diastereoselective addition of vinyl ethers to chiral â-hydroxy
aldehydes as shown in Table 3. Examination of the mis-
benzyl protected substrate to 3.8:1. Combination of the
protected (S)-â-hydroxy aldehydes with (+)-MIB resulted
in dr values of 1:7.8-8.0 for the TBS derivatives and 1:9.3
for the benzyl analogue, favoring the anti-diol. Both the
matched and mismatched combinations proceeded with
excellent yields. The resulting â-hydroxy enol ethers could,
in principle, be protected and hydrolyzed to prepare 1,3-
polyols. Configurational assignment of diastereomers was
done by inspection of the 13C chemical shifts of the
corresponding acetonides.34
In conclusion, we have developed a non-aldol method to
prepare acetate aldol products. Our procedure involves an
efficient and enantioselective addition of vinyl enol ether to
an aldehyde to furnish hydroxy enol ethers with high levels
of enantioselectivity. Protection of the hydroxyl group
followed by hydrolysis provides the desired protected â-
hydroxy aldehydes in good yields. We have also demon-
strated that this cycle can be repeated to afford 1,3-
oxygenated products with moderate to good control over
diastereoselectivity. The advantage of this method over the
asymmetric aldehyde allylation/ozonolysis protocol is that
our method can be applied to substrates containing additional
C-C double bonds.
Table 3. Diastereoselective Additions to Masked â-Hydroxy
Aldehydes
entry
R
P
ligand
yield (%)
syn:anti
1
2
3
4
5
6
c-hexyl
TBS
(-)-MIB
(+)-MIB
(-)-MIB
(+)-MIB
(-)-MIB
(+)-MIB
93
95
96
95
97
96
2.3:1
1:7.8
2.4:1
1:8
3.8:1
1:9.3
isopropyl
isopropyl
TBS
Bn
Acknowledgment. This work was supported by the NSF
(CHE-0315913). We are also grateful to Akzo Chemical for
the gift of alkyl zinc reagents. S.J.J. thanks Eli Lily and
Y.K.C. thanks Atofina for fellowships.
matched and matched catalyst-substrate combinations in-
dicated that moderate to good control over diastereoselec-
tivity can be achieved. When the (S)-enantiomer of the TBS
protected â-hydroxy aldehydes were used, (-)-MIB was the
mismatched catalyst, giving diastereomeric ratios of 2.3:1
favoring the syn-diol products. The dr increased with the
Supporting Information Available: Experimental details
and full characterizations of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050255N
(32) Marshall, A. J.; Eidam, P. Org. Lett. 2004, 6, 445-448.
(33) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840-10852.
(34) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 9-17.
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