Anti-selective aldol reactions with titanium enolates of N-glycolyloxazolidinethiones

Article abstract of DOI:10.1021/ol034001i

(Matrix presented). A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an N-glycolyloxazolidinethione with titanium (IV) chloride and (-)-sparteine followed by addition of an aldehyde activated with additional TiCl₄ resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.

Full text of DOI:10.1021/ol034001i

ORGANIC
LETTERS
2003
Vol. 5, No. 4
591-594
Anti-Selective Aldol Reactions with
Titanium Enolates of
N-Glycolyloxazolidinethiones
Michael T. Crimmins* and Patrick J. McDougall
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received January 2, 2003
ABSTRACT
A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an
N-glycolyloxazolidinethione with titanium (IV) chloride and (−)-sparteine followed by addition of an aldehyde activated with additional TiCl4
resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest
levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.
The stereoselective glycolate aldol addition is a useful
carbon-carbon bond-forming process, giving rise to differ-
entially protected 1,2-diols. Methods for producing the syn
diastereomers include the Evans boron enolate aldol addi-
tion1 using N-glycolyloxazolidinones, which has proven to
be very successful with a wide variety of aldehydes and
protecting groups.2 Additionally, the titanium enolates of
N-glycolyloxazolidinones and N-glycolyloxazolidinethiones
have demonstrated high syn selectivities with good yields.3
Masamune’s norephedrine esters have also been used to
generate the syn adducts.4 Effective methods for obtaining
the anti aldol adducts from glycolate enolates, however, are
less prevalent. Moderately selective anti aldol reactions of
tin(II) enolates of N-acylthiazolidinethiones and N-acyl-
oxazolidinones have been observed by Mukaiyama5 and
Evans,6 respectively. Alternative auxiliary-based approaches
include the use of oxapyrone boron enolates7 or selone auxil-
iaries.8 Chiral tin(II) Lewis acids9 have also been moderately
successful. Here we report a general method for anti-selective
glycolate aldol additions using a variety of substrates and
aldehydes through a simple and inexpensive procedure,
mediated by the 4-benzyl-oxazolidine-2-thione auxiliary.
Our initial investigation of the glycolate anti aldol addition
revealed that the thiazolidinethione auxiliary10 1 (Figure 1)
(1) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
Figure 1. Chiral auxiliary variants.
(2) Selected examples: Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills,
S. G. J. Am. Chem. Soc. 1990, 112, 2998-3017. Keck, G. E.; Palani, A.;
McHardy, S. F. J. Org. Chem. 1994, 59, 3113-3122. Crimmins, M. T.;
Choy, A. L. J. Org. Chem. 1997, 62, 7548-7549.
gave excellent anti selectivity; however, up to 20 mol % of
the free auxiliary was detected in the product. This competing
deacylation during the course of the reaction resulted in low
(3) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-
5476. Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A. L. J. Org.
Chem. 2000, 65, 8499-8509.
(4) Andrus, M. B.; Sekhar, B. B. V. S.; Turner, T. M.; Meredith, E. L.
Tetrahedron Lett. 2001, 42, 7197-7201.
(5) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753-756.
(6) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961-1963.
10.1021/ol034001i CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003

yields. Fortunately, switching to the oxazolidinethione
auxiliary 2 alleviated this problem, providing similar levels
of asymmetric induction accompanied by only trace amounts
of deacylation. In contrast, the oxazolidinone auxiliary 3
(R ) allyl) produced both anti diastereomers (ca. 1.2:1)
accompanied by approximately 10% of the syn isomers.
Several oxazolidinethiones were studied, with 4-benzyl-
oxazolidine-2-thione 2 showing the highest level of asym-
metric induction.
The effect of the glycolate ether group was explored in
an effort to optimize the selectivity and expand the scope of
the reaction. The O-allyl- (4) and O-benzyl-protected (5)
glycolates (Figure 2) were chosen on the basis of their ability
a
Table 1. Variation of Precomplexing TiCl4
a Substrate ) 4. Performed with method A. b Ratios indicate major
diastereomer with respect to all other diastereomers. Ratios were determined
1
by 400 MHz H NMR of the unpurified material.
precomplexation of the aldehyde can occur in situ. After the
enolate was formed by exposure of the N-glycolyloxa-
zolidinethione to TiCl4 and (-)-sparteine at -78 °C, the
remainder of the TiCl4 was added directly to the enolate
solution followed immediately by addition of the aldehyde
(method A).11 Alternatively, the aldehyde could be treated
with the additional Lewis acid in a separate flask followed
by cannula transfer to the enolate (method B).12 Both
methods provided the anti adducts with similar selectivities
and yields.
The results for various aldehydes are presented in Table
2. The O-allyl glycolate 4 provided the anti adducts of
Figure 2. Substrates for anti aldol additions.
Table 2. Anti Aldol Additionsa
to withstand the Lewis acidic reaction conditions while
providing easy removal of the protecting group. The O-
methyl glycolate 6 was also examined. All three substrates
provided good anti selection; however, the O-allyl glycolate
proved to be the most diastereoselective and delivered the
anti adducts in the highest yields for all aldehydes tested.
Aldol additions utilizing these substrates began with the
generation of their respective titanium enolates under condi-
tions previously developed in our laboratory employing
titanium(IV) chloride and (-)-sparteine.10 As expected,
addition of an aldehyde directly to the enolate selectively
provided the Evans syn diastereomer. However, treatment
of the same aldehyde with additional TiCl4, prior to addition
of the aldehyde to the enolate, led to selective formation of
one anti isomer. In most instances, the syn diastereomers
were not observed. The degree of anti selection was highly
dependent on the amount of TiCl4 used to activate the
aldehyde. The results, depending on the aldehyde, can be
generalized as follows: saturated aldehydes gaVe higher
selectiVities using >2 equiV of TiCl4 to each equiValent of
aldehyde, while R,â-unsaturated aldehydes required >3
equiV of TiCl4 for optimum results. Examples illustrating this
effect are shown in Table 1.
A general one-pot procedure for the anti aldol addition
was ultimately developed on the basis of the observation that
a All additions were performed using method A. b Aldehydes were freshly
distilled over Ca2SO4 prior to use. c Isomeric ratios were determined by
(7) Andrus, M. B.; Sekhar, B. B. V. S.; Meredith, E. L.; Dalley, N. K.
Org. Lett. 2000, 2, 3035-3037.
1
400 MHz H NMR analysis of the unpurified material. d Yields of major
diastereomer. Determined by combined chromatographic separation and
NMR analysis. e Adducts 7a-d, 8a, and 9b were performed using 2.3 equiv
of TiCl4:aldehyde. Adducts 7e-g, 8b, and 9a,c were performed using 3.1
equiv of TiCl4:aldehyde.
(8) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks,
L. A., III. J. Am. Chem. Soc. 2000, 122, 386-387.
(9) Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 3329-3332.
(10) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894-902.
592
Org. Lett., Vol. 5, No. 4, 2003

aliphatic aldehydes in consistently high selectivities and good
yields, without significant formation of the syn isomers
(typically <3%). Isomeric ratios up to 97:3 for the two anti
products, A1 and A2, were observed for unhindered aldehydes
(adducts 7a-c); however, isobutyraldehyde gave a slightly
lower selectivity of 87:13, possibly due to the steric demands
of the isopropyl group (7d). The anti selectivities for R,â-
unsaturated and aromatic aldehydes with 4 were less
consistent, ranging from 95:5 with acrolein (7e) to 73:23(:4
syn) with crotonaldehyde (7f). Benzaldehyde gave the
poorest selectivity (7g). The O-benzyl 5 and O-methyl 6
substrates also performed well with aliphatic aldehydes,
although the selectivities and yields were significantly lower
than with 4 (8a and 9a,b). These substrates also gave varying
results with acrolein, providing the aldol adducts in a 74:26
ratio for 5 (8b) and 88:12 for 6 (9c). The relative and absolute
configuration of aldol adduct 9a was confirmed by X-ray
analysis. The stereochemistry of adduct 7a was confirmed
by chemical conversion of 9a to 7a.13 The stereochemistry
of the remaining aldol adducts was inferred by comparison
of NMR data.
Figure 3. Proposed syn transition state.
to previously demonstrated examples using propionate
substrates.10
Proposed transition states for both the syn and anti aldol
additions are shown in Figures 3 and 4. For the syn
As mentioned previously, selective formation of the Evans
syn diastereomer occurred upon addition of the free aldehyde
to the preformed enolate without prior activation. Select
examples using substrate 4 are shown in Table 3. Notably,
Table 3. Syn Aldol Additions10
Figure 4. Proposed anti transition state.
diastereomer, the reaction has previously been proposed to
proceed via a six-member chairlike transition state as
shown.10 On the basis of the observation that precomplexing
the aldehyde with a Lewis acid leads to the anti isomer, we
believe that addition to the enolate occurs via an open
transition state, as suggested by Heathcock to explain
propionate anti aldol additions using N-acyloxazolidinones.15
In addition, the glycolate oxygen may coordinate to the TiCl4
that serves to activate to the aldehyde as shown. Positioning
the aldehyde substituent away from the auxiliary leads to
the observed anti product. The involvement of the glycolyl
oxygen in coordination to the metal bound to the aldehyde
is supported by the observation that the N-propionyl oxa-
zolidinethione produces the non-Evans syn diastereomer
under the same conditions.
a (-)-Sparteine (1 equiv). b (-)-Sparteine (1 equiv) + N-methylpyrroli-
dinone (1 equiv). c Determined by 400 MHz 1H NMR analysis of the
unpurified material. d Based on chromatographic isolation of the major
diastereomer.
adding 1 equiv of N-methylpyrrolidinone to the enolization
procedure14 resulted in a significant increase in yields, similar
Synthetic manipulation of the aldol adducts can be readily
accomplished via cleavage of the oxazolidinethione auxiliary
and differentiation of the 1,2-diol. Removal of the auxiliary
to multiple functional groups, including the versatile Weinreb
(11) Method A. The N-glycolyloxazolidinethione glycolate (0.172 mmol)
and 5 mL of dichloromethane were added to a dry round-bottom flask under
argon. After the mixture was cooled to -78 °C, titanium(IV) chloride (0.023
mL, 0.206 mmol) was added dropwise and the solution was allowed to stir
for 10 min. A freshly prepared solution of (-)-sparteine (0.103 mL, 0.206
mmol; 2 M in dichloromethane) was added dropwise to the mixture, and
the solution was allowed to stir for 40 min. TiCl4 (0.057 mL, 0.516 mmol
or 0.075 mL, 0.688 mmol if the aldehyde was R,â-unsaturated) was added
directly to the enolate solution. After the mixture was stirred for 1 min,
freshly distilled aldehyde (0.224 mmol) was added dropwise to the reaction.
The reaction was allowed to stir for 15 min and quenched with half-saturated
ammonium chloride. The organic layer was separated and the aqueous layer
extracted twice with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The crude mixture was analyzed by 1H
NMR followed by column chromatography purification.
(12) Method B. See enolate formation in method A. To a separate dry
flask was added 5 mL of CH2Cl2 and TiCl4 (0.057 mL, 0.516 mmol or
0.075 mL, 0.688 mmol if the aldehyde was R,â-unsaturated), and the mixture
was cooled to -78 °C. Freshly distilled aldehyde (0.224 mmol) was added
to the TiCl4 solution. The resulting mixture was transferred via cold cannula
to the enolate after 10 s. The reaction was allowed to stir for 15 min followed
by workup as in method A.
(13) See Supporting Information.
(14) --Sparteine (1 equiv) + N-methylpyrrolidinone (1 equiv).
(15) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-
5750.
Org. Lett., Vol. 5, No. 4, 2003
593

amide, can be performed under mild conditions.10 Further-
more, deprotection of the benzyl and allyl ethers16 allows
for further manipulation of glycolyl hydroxyl.
Acknowledgment. We thank the National Institutes
of Health (NIGMS, GM60567) for generous financial
support.
In summary, a new anti aldol process has been developed
utilizing the titanium enolate of various N-glycolyloxazoli-
dinethiones and a titanium(IV) chloride activated aldehyde.
O-Methyl, O-benzyl, and O-allyl glycolyloxazolidinethiones
provided the anti adducts in high selectivities and yields using
a simple one-pot procedure.
Supporting Information Available: Experimental pro-
cedures for oxazolidinethione substrates, spectral data of all
new compounds, and correlation studies of aldol adducts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224.
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