Direct enantioselective organocatalytic hydroxymethylation of aldehydes catalyzed by α,α-diphenylprolinol trimethylsilyl ether

Article abstract of DOI:10.1021/ol9017479

The direct enantioselective hydroxymethylation of aldehydes utilizing α,α-diphenylprolinol trimethylsilyl ether as an organocatalyst is described. The intermediate α-substituted β-hydroxyaldehydes were not isolated but converted to the more readily isolab

Full text of DOI:10.1021/ol9017479

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4544-4547
Direct Enantioselective Organocatalytic
Hydroxymethylation of Aldehydes
Catalyzed by r,r-Diphenylprolinol
Trimethylsilyl Ether
Robert K. Boeckman, Jr.* and John R. Miller
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
rkb@rkbmac.chem.rochester.edu
Received July 30, 2009
ABSTRACT
The direct enantioselective hydroxymethylation of aldehydes utilizing r,r-diphenylprolinol trimethylsilyl ether as an organocatalyst is described.
The intermediate r-substituted ꢀ-hydroxyaldehydes were not isolated but converted to the more readily isolable derivatives. For example, the
derived hydroxy acids were isolated in up to 94% yield with excellent enantioselectivity.
R-Substituted ꢀ-hydroxy aldehydes and carboxylic acids are
very useful chiral building blocks.1 The need for an efficient,
enantioselective method for preparing these building blocks
can be seen from their widespread use in complex molecule
synthesis.1 To date, we are aware of only one report in the
literature describing enantioselective hydroxymethylation of
aldehydes utilizing organocatalysis.2 However, in our hands,
that literature protocol failed to reproduce the reported levels
of enantioselectivity (>99% reported, 70% ee observed). In
addition, that report suggested that the scope of substrates
may be rather limited and did not afford easily isolable chiral
building blocks useful for further transformations. Evans first
reported the preparation of these chiral building blocks
utilizing enolate chemistry and stoichiometric chiral auxil-
iaries to install the desired stereochemistry.3 Although use
of chiral auxiliary based methods affords excellent stereo-
selectivity, they require multiple operations and recycling
of the auxiliaries limiting their practicality on scale-up.
Thus, we sought to develop a practical and scalable method
for enantioselective hydroxymethylation of aldehydes. We
report herein the results of our studies that established that
efficient catalytic enantioselective hydroxymethylation can
be achieved. Employing biphasic mixtures of acceptable
organic solvents and suitably buffered formalin provided the
desired stable chiral building blocks in very good to excellent
yields. We first sought to establish an efficient catalytic cycle.
Subsequently, we envisioned use of R,R-diphenylprolinol
trimethylsilyl ether (1) as a chiral amine organocatalyst since
1 has found use as a relatively general organocatalyst for
R-functionalization of aldehydes.4,5
(4) For recent reviews, see: Palomo, C.; Mielgo, A. Asian J. Chem. 2008,
3, 922–948. Palomo, C.; Mielgo, A. Angew. Chem, Int. Ed. 2006, 45, 7876–
7880. Guillena, G.; Ramo´n, D. J. Tetrahedron: Asymmetry 2006, 17, 1465–
(1) For selected examples, see: Evans, D. A.; Dow, R. L.; Shih, T. L.;
Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290–5313.
Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 597–599.
Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899–10905.
Troy Lister, M. V. P. Angew. Chem., Int. Ed. 2006, 45, 2560–2564.
(2) Casas, J.; Sunde´n, H.; Co´rdova, A. Tetrahedron Lett. 2004, 45, 6117–
6119.
1492. Marigo, M.; Jorgensen, K. A. Chem. Commun. 2006, 2001–2011
.
(5) For examples, see: Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794–797. Hayashi, Y.;
Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–
4215
.
(6) Igarashi, M. T.; Masaru, J. Heterocycl. Chem. 1995, 32, 807–810.
Kimpe, N. D. V.; Roland, B. L. D.; Schamp, N. Chem. Ber. 1983, 116,
(3) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737–1739. Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.;
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215–8216.
3846–3857. Nagel, M.; Hansen, H.-J. Synlett 2002, 692–696
.
(7) Mori, K.; Ohki, M.; Matsui, M. Tetrahedron 1970, 26, 2821–2824
.
10.1021/ol9017479 CCC: $40.75
Published on Web 09/16/2009
 2009 American Chemical Society

A likely mechanism for catalytic hydroxymethylation of
aldehydes is outlined in Scheme 1. The enamine II, derived
mixture to 0.5 M completely suppressed formation of 5
arising from aldol dimerization of isovaleraldehyde and
provided acceptable reaction rates.10 The desired hydroxym-
ethylation reaction occurred in a variety of solvents; however,
significantly better yields were observed in nonpolar solvents
that were immiscible with formalin (i.e., toluene, hexane,
DCM, CHCl3). Under such biphasic reaction conditions, we
were pleased that the desired hydroxymethylation proceeded
using a catalytic amount (20-30 mol %) of pyrrolidine
affording 4 in good yield (after in situ reduction with NaBH4)
in ∼12 h at rt. A further decrease in catalyst loadings led to
unacceptably long reaction times.
Scheme 1
.
Plausible Mechanism for the Hydroxymethylation of
Aldehydes Catalyzed by 1
Having established the catalytic cycle for hydroxymethy-
lation, we then examined the asymmetric variant. Treatment
of isovaleraldehyde with 20-30 mol % of prolinol ether 1
in a biphasic mixture of toluene and ∼3.0 equiv of buffered
37% aq formaldehyde (commercial formalin) with efficient
mixing unexpectedly afforded principally the cyclic hemi-
acetal(s) 6 of the desired ꢀ-hydroxyaldehyde in which 2 equiv
of formaldehyde had been incorporated (Scheme 3). Since
from chiral amine 1 and the aldehyde, is postulated to react
with formaldehyde from the less hindered si face owing to
nonbonded interactions with the sterically demanding amine
R-substituent. Hydrolysis of the resulting iminium ion
completes the catalytic cycle.
Scheme 3. Derivitization of the Intermediate R-Substituted
, ,
ꢀ-Hydroxyaldehydesa b c
To demonstrate the required catalytic cycle in nonpolar
organic solvents, we began with the reaction of the preformed
pyrrolidine enamine 2 derived from isovaleraldeyde (Scheme
2).6 In preliminary experiments, we found that enamine 2
Scheme 2. Initial Experiment with Pyrroline Enamine 2
a Yields based on isolated yields after chromatography. b Enantiomeric
excess determined by chiral GC analysis. c Absolute configuration assigned
by comparison of the sign of optical rotation to known 8a.
upon reaction with ∼3.0 equiv of 37% aq fomaldehyde in a
variety of solvents afforded principally allylic alcohol 37 after
reduction with NaBH4 accompanied by minor amounts of
the desired diol 4.2 Upon further investigation, we determined
that the undesired elimination was promoted by formic acid.
A similar result had been reported by Pihko during develop-
ment of a process R-methylenation of aldehydes.8 The sample
of formalin solution we employed was found to have pH
∼5 owing to accumulation of HCO2H over time resulting
from air oxidation of HCHO.9
Upon the basis of that observation, we buffered the
formaldehyde solution with NaOAc and/or the reaction
medium with a commerical pH 7 phosphate buffer which
was found to surpress the undesired formation of 3.
Formalin proved to be the optimal source of formaldehyde.
We also found that adjusting the concentration of the reaction
6 and the derived ꢀ-hydroxyaldehyde were difficult to handle
and purify owing to their proclivity for oligomerization, we
expected that TBS protection or Pinnick oxidation of 6 would
provide more readily isolable materials suitable for further
transformation.11,12 The structure of 6, which was unstable
to isolation/purification, was inferred from the formation of
silyl ether 7 (90% yield, >99% ee) upon treatment of crude
6 with TBSCl/imidazole. As noted previously, aldehyde 7
and congeners proved sensitive to racemization upon chro-
(10) Joshi, L. D.; Srivastava, A. C.; Dutta, B. K. Fert. Technol. 1976,
13, 128–30.
(11) For a review, see: Raach, A.; Reiser, O. J. Prakt. Chem. 2000,
342, 605–608
.
(8) Kallianos, A. G.; Warfield, A. H.; Simpson, M. I. U.S. Patent 3,
704, 714, December 5, 1972.
(12) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348–6359. Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-
(9) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.
I. J. Org. Chem. 1995, 60, 6159–6167.
Org. Lett., Vol. 11, No. 20, 2009
4545

matographic purification; however, these materials were
obtained sufficiently pure for further use.12
Table 2. Effect of Carbon Branching for the
Hydroxymethylation of Aldehydes
Formation of 6 was surprising and potentially fortuitous
since the stability of 6 may be responsible for the high degree
of enantioselectivity observed by preserving the chirality at
the newly generated R chiral center given the ease of
racemization of such aldehydes.12
Alternatively, Pinnick oxidation (NaClO2, NaH2PO4, 2-meth-
yl-2-butene) of 6 afforded (R)-2-(hydroxymethyl)-3-methyl-
butanoic acid 8a in excellent yield (94%) and enantiospec-
ificity (98% ee) as also shown in Scheme 3.
Since the reaction performed well in biphasic media, we
set out to investigate whether the nature of the organic solvent
affected the observed enantioselectivity. Indeed, employing
more polar solvents such as CH2Cl2 (71% ee) and CHCl3
(79% ee) degraded the enantioselectivity ∼20% relative to
that observed in the most nonpolar solvents hexane (93%
ee) and toluene (98% ee). It is noteworthy that the decrease
in % ee is correlated with the solubility of water in the
organic phase (Table 1).
a Yields based on isolated yields after chromatography. b Enantiomeric
excess determined by chiral GC analysis of methyl esters (see Supporting
Information).
Table 1. Effect of Solvent on the Enantioselectivity
groups. As seen from Table 3, the results for a variety of
substrates are uniformly very good to excellent. The precur-
sor aldehydes afforded the corresponding ꢀ-hydroxy acids
entry
solvent
time (h)
ee (%)a
1
2
3
4
DCM
15
15
15
15
71
79
93
98
Table 3. Functional Group Tolerance for the
Hydroxymethylation of Aldehydes
CHCl3
hexane
toluene
a Enantiomeric excess determined by chiral GC analysis of methyl ester.
Having determined optimal reaction conditions, we set out
to examine structurally diverse aldehydes including those
bearing substituents and branched side chains. We found that
most aldehyde branching patterns are tolerated (Table 2).
Reaction of three linear and ꢀ-branched aliphatic aldehydes
afforded the desired ꢀ-hydroxy acids 8a-c in 71-94% yield
and 92-99% ee. It is especially noteworthy that R branching
is also tolerated providing hydroxy acid 8d bearing a fully
substituted chiral center in >99% ee but somewhat lower
yield (50%) possibly owing to the slower reaction rate. The
absolute configuration of all the products 8a-j were assigned
by comparison or analogy to known hydroxy acids
8a,c,j.13-15
Further investigation of the scope has shown that the
method tolerates a wide array of functional groups, including
esters, alkynes, and protected nitrogen and oxygen functional
(13) Jin, Y. Synlett 1998, 1189–1190
(14) Takacs, J. M.; Jaber, M. R.; Vellekoop, A. S. J. Org. Chem. 1998,
63, 2742–2748
.
a Yields based on isolated yields after chromatography. b Enantiomeric
excess determined by chiral GC analysis of methyl esters (see Supporting
Information).
.
(15) Monteil, T.; Danvy, D.; Plaquevent, J.-C.; Duhamel, L.; Duhamel,
P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. Synth. Commun. 2001, 31,
211–218
.
4546
Org. Lett., Vol. 11, No. 20, 2009

8e-j in 60-93% yields in 90-99% ee. Noteworthy chemose-
lectivity is observed for R-hydroxymethylation of an alde-
hyde in the presence of a methyl ketone in the formation of
acid 8i.16 No interaction of the intermediate enamine with
the electrophilic functional groups was noted in formation
of acids 8e and 8h,i.
Scheme 5
.
Application of the Hydroxymethylation of Aldehydes
to the Synthesis of (-)-Rasfonin
However, limitations in subtrate scope were encountered.
Aldehydes of the general structures 9-11 failed to undergo
hydroxymethylation using the standard conditions outlined
above. For 9, the low reactivity may result from formation
of an unusually stable enamine upon reaction with amine 1.
Such aldehydes have been employed in organocatalytic
reactions but normally require higher reaction temperatures
and the presence of acid to catalyze reaction.17 In our case,
use of harsher conditions would surely lead to elimination
and/or erosion of enantiocontrol. As are the aldehydes 10
and 11 bearing R heteroatoms, the resulting enamines are
notoriously unstable decomposing under our reaction condi-
tions. Aldehydes such as 10 and 11 have also been employed
successfully in organocatalytic reactions, but different catalyst
frameworks and nonaqueous reaction conditions are re-
quired.18 Furthermore, substrates where a carbonyl func-
tionality is present five atoms removed from the enamine,
afforded only R-methylenated products presumably owing
to assisted elimination by interaction with the terminal
functional group.
hydroxymethylation of aldehyde 14,20 followed by TBS
protection of the resulting alcohol and Wittig reaction with
ylide 15, provided the ester 16 (98% ee) in 74% yield over
three steps without purification of any intermediates. Ester
16 was transformed through the related aldehyde 17 via
Wittig olefination to acid 12 which was coupled to pyrone
alcohol 18 using a Yamaguchi coupling.19,21 Desilylation
gave (-)-Rasfonin 13 identical to a sample of synthetic (-)-
Rasfonin.19,21
In summary, we have disclosed a practical method for the
R-hydroxymethylation of aldehydes affording, after deriva-
tization, bench stable and in some cases crystalline solid
materials which can be utilized as chiral building blocks in
total synthesis. Further studies to expand the scope of
enamine catalysis to a variety of aldehyde functionalization
reactions are currently underway.
The hydroxymethylation is readily scalable. Catalyst
loadings can be decreased to 5 mol % without loss of % ee
or significant increase in reaction time as shown for prepara-
tion of 8j (Scheme 4). On scale, the exothermic Pinnick
oxidation step must be conducted at 0 °C.
Acknowledgment. We are grateful for support of these
studies by Novartis Pharma AG and Novartis Pharmaceu-
ticals Corp.
Scheme 4. Large-Scale Example of Hydroxymethylation
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9017479
(17) Sulzer-Mosse´, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A.
Synthesis 2007, 1729–1732
.
(18) Ian Storer, R.; MacMillan, D. W. C. Tetrahedron 2004, 60, 7705–
Our methodology was applied to a shortened synthesis of
the acid side chain (-)-12 of (-)-Rasfonin 13 prepared
previously by our group (Scheme 5).19 Organocatalytic
7714
.
(19) Boeckman, R. K., Jr.; Pero, J. E.; Boehmler, D. J. J. Am. Chem.
Soc. 2006, 128, 11032–11033
(20) Barrett, A. G. M.; Flygare, J. A.; Spilling, C. D. J. Org. Chem.
1989, 54, 4723–4726
(21) Akiyama, K.; Yamamoto, S.; Fujimoto, H.; Ishibashi, M. Tetra-
hedron 2005, 61, 1827–1833
.
.
(16) When an equimolar amount of 1 and acetone were mixed in an
NMR tube, no detectable enamine formation was observed at rt.
.
Org. Lett., Vol. 11, No. 20, 2009
4547