Inverse temperature dependence in the diastereoselective addition of grignard reagents to a tetrahydrofurfural

Article abstract of DOI:10.1021/ol900324s

A remarkable example of inverse-temperature-dependent diastereoselectivity was uncovered while investigating the addition of Grignard reagents to a 3-hydroxytetrahydrofurfural. The free hydroxyl group in the tetrahydrofurfural was found to play a key role

Full text of DOI:10.1021/ol900324s

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2057-2060
Inverse Temperature Dependence in the
Diastereoselective Addition of Grignard
Reagents to a Tetrahydrofurfural
Jeffrey Mowat,† Baldip Kang,† Branden Fonovic,‡ Travis Dudding,*,‡ and
Robert Britton*,†
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe,
Burnaby, BC, Canada V5S 1S6, and Department of Chemistry, Brock UniVersity,
500 Glenridge AVenue, St. Catharines, ON, Canada L2S 3A1
rbritton@sfu.ca; tdudding@brocku.ca
Received February 13, 2009
ABSTRACT
A remarkable example of inverse-temperature-dependent diastereoselectivity was uncovered while investigating the addition of Grignard reagents
to a 3-hydroxytetrahydrofurfural. The free hydroxyl group in the tetrahydrofurfural was found to play a key role in these processes, a result
corroborated through a series of DFT calculations that also highlighted an entropic preference for the formation of one diastereomer.
A number of biologically active compounds possess the
2-(1-hydroxyethyl)-tetrahydrofuran subunit, and synthetic
approaches to these substances often involve the diastereo-
selective addition of organometallic reagents to tetrahydrofur-
furals. For example, annonaceous acetogenins,1 many natural2
and unnatural3 carbohydrates, and the structurally related marine
oxylipids 24and 45 (Figure 1) have all been accessed via
synthetic routes that incorporate this strategic coupling reaction.
The diastereochemical outcome of these addition reactions are
often rationalized by cyclic chelate models (e.g., 6) similar to
that originally proposed by Wolfrom and Hanessian6 for the
addition of methyl magnesium iodide to the protected dialdose
5. In this case, it was reasoned6 that coordination between the
Grignard reagent and both the carbonyl and tetrahydrofuran ring
oxygen directs nucleophilic attack to the less hindered si face
of the aldehyde to provide 7 selectively. However, there are a
number of exceptions to this model, and as a result, a thorough
screen of both solvents2c,e and organometallic reagents7 is
often required to optimize the diastereoselectivity of these
processes.3c The addition of organometallic reagents to
oxygenated tetrahydrofurfurals (e.g., 5) is further complicated
by additional coordination sites, and consequently both the
relative configuration2d and choice of protecting group1b for
the oxygen substituents on the tetrahydrofuran ring play key
roles in determining the degree and direction of stereose-
lection. Previously, we reported the development of a general
synthetic strategy that provides access to all configurational
isomers of the 3-hydroxytetrahydrofuran scaffold from a
† Simon Fraser University.
‡ Brock University.
(1) (a) Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed.
2000, 39, 3622. (b) Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739.
(c) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 723.
(2) (a) Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.;
Singh, G.; Yang, Y.; Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett.
2003, 13, 3345. (b) Suzuki, T.; Chida, N. Chem. Lett. 2003, 32, 190. (c)
Takahashi, S.; Kuzuhara, H. J. Chem. Soc., Perkin Trans. 1 1997, 607. (d)
Giuliano, R. M.; Villani, F. J. J. Org. Chem. 1995, 60, 202. (e) Takahashi,
S.; Kuzuhara, H. Chem. Lett. 1992, 21.
(3) (a) Kim, K. S.; Ahn, Y. H.; Park, S. B.; Cho, I. H.; Joo, Y. H.;
Youn, B. H. J. Carbohydr. Chem. 1991, 10, 911. (b) Amouroux, R.; Ejjiyar,
S.; Chastrette, M. Tetrahedron Lett. 1986, 27, 1035. (c) Danishefsky, S. J.;
DeNinno, M. P.; Phillips, G. B.; Zelle, R. E.; Lartey, P. A. Tetrahedron
1986, 42, 2809. (d) Yoshimura, J.; Ohgo, Y.; Ajisaka, K.; Konda, Y. Bull.
Chem. Soc. Jpn. 1972, 45, 916. (e) Horton, D.; Hughes, J.; Thomson, J. J.
Org. Chem. 1968, 33, 728.
(5) (a) Mori, Y.; Sawada, T.; Furukawa, H. Tetrahedron Lett. 1999, 40,
731. (b) Wang, Z.-M.; Shen, M. J. Org. Chem. 1998, 63, 1414. (c)
Chikashita, H.; Nakamura, Y.; Uemura, H.; Itoh, K. Chem. Lett. 1993, 477.
(d) Williams, D. R.; Harigaya, Y.; Moore, J. L.; D’sa, A. J. Am. Chem.
Soc. 1984, 106, 2641. (e) Hatakeyama, S.; Sakurai, K.; Saijo, K.; Takano,
S. Tetrahedron Lett. 1985, 26, 1333.
(6) Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800.
(7) For the optimization of diastereoselectivity through screening of
organometallic reagents and additives see refs 1b, 2c, 2d, and 2e.
(4) (a) Gadikota, R. R.; Callam, C. S.; Lowary, T. L. J. Org. Chem.
2001, 66, 9046.
10.1021/ol900324s CCC: $40.75
Published on Web 03/27/2009
 2009 American Chemical Society

Table 1. Addition of Grignard Reagents to Aldehyde 1
entry
R9,17
solvent temp (°C) products (ratio)a % yieldb
1
2
3
4
5
6
7
8
ethyl
THF
-78 to 20
10a:10b (1:1)
10a:10b (2:1)
10a:10b (3.3:1)
10a:10b (1.3:1)
10a:10b (2:1)
10a:10b (5:1)
10a:10b (5:1)
10a:10b (1:1)
10a:10b (5:1)
10a:10b (5.1:1)
10a:10b (5.8:1)
10a:10b (8:1)
11a:11b (3.6:1)
11a:11b (8:1)
2:12 (5.5:1)
57
62
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
n-hexyl
n-hexyl
PhCH3 -78 to 20
CH2Cl2 -78 to 20
CH2Cl2 -40
CH2Cl2 -35
CH2Cl2 20
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
67
ndc
42d
52
Figure 1. Marine oxylipids 2 and 4 and the chelation model 6 for
diastereoselective Grignard additions to tetrahydrofurfural 5.
20
20e
20g
40
60
83
40
83
83
52
ndf
ndf
ndf
ndf
70
9
10
11
12
13
14
15
common intermediate (DOI 10.1021/ol802711s). As an
extension of this work, we demonstrated these methods in
short syntheses of the diastereomeric marine natural products
2 and 4. The final step in both syntheses involved the addition
of 8-nonenyl magnesium bromide to an unprotected 3-hy-
droxytetrahydrofurfural (e.g., 1 and 3). During the optimiza-
tion of these syntheses we uncovered a remarkable, inverse-
temperature-dependent diastereoselective Grignard addition
reaction. The discovery of this reaction as well as mechanistic
insight based on Kohn-Sham hybrid B3LYP calculations
are described below.
While the chelation model (e.g., 6) predicts that addition of
8-nonenyl magnesium bromide to 1 would provide the desired
10S diastereomer 2, we were aware that a similar reaction
carried out on a protected analogue (i.e., 1, OH ) OBn) in
THF affords a 4:1 mixture of diastereomeric alcohols faVoring
the undesired R configuration at C10.4 Bearing this in mind,
we set out to explore this process on the readily available and
unprotected tetrahydrofurfural 18 and focused our initial efforts
on addition reactions involving EtMgBr.9 As summarized in
Table 1, we observed a pronounced relationship between solvent
and diastereoselectivity for this reaction. For example, while
the addition was nonselective in THF, the production of one
diastereomer was favored in noncoordinating solvents (entries
1-3).10 Each of the reactions described in entries 1-3 were
sluggish at -78 °C and were consequently allowed to gradually
warm to room temperature to ensure complete consumption of
the aldehyde 1. The diastereomeric alcohols 10a and 10b proved
to be separable by chromatography, and the major product from
the reaction carried out in CH2Cl2 (entry 3) was converted to
ndf
73
8-nonenyl DCE
65
a Ratio determined from analysis of 1H NMR spectra of crude reaction
mixtures. b Combined isolated yield of both diastereomers over two steps
from 8. c After 20 h the reaction had reached 60% conversion. d After 17 h
the reaction had reached 55% conversion. e 10 equiv of 15-crown-5 was
added. f Yield not determined. g 10 equiv of MgBr2 was added.
the corresponding acetonide 13 (eq 1). As indicated (see inset),
a series of 1D NOESY experiments carried out on this
conformationally rigid acetonide permitted unambiguous as-
signment of the relative configuration of the newly formed
carbinol chirality center as 10S.11 Consequently, the major
diastereomer produced from the addition of EtMgBr to the
aldehyde 1 in CH2Cl2 (entry 3) was confidently assigned as
the 10S diastereomer 10a.
Surprisingly, repetition of the reaction described in entry 3
(Table 1) at -40 or -35 °C led to an erosion in diastereose-
lectivity, while at room temperature in either CH2Cl2 or
dichloroethane (DCE) the stereoselectivity was restored (entries
4-7). Addition of 15-crown-5 caused a significant decrease in
the diastereomeric ratio, but MgBr2 had little effect (entries 8
(8) The tetrahydrofurfural 1 was prepared by ozonolysis of 8 followed
by reductive workup with polymer-supported triphenylphosphine (PS-PPh3).
As the tetrahydrofurfural 1 decomposes on silica gel, following the removal
of the PS-PPh3 by filtration and concentration, the resulting aldehyde was
used without further purification. A full account of the synthesis of
compound 1 is described in the preceding manuscript.
(10) For examples of Grignard reactions in CH2Cl2, see: (a) Brown,
D. S.; Charreau, P.; Ley, S. V. Synlett 1990, 749. (b) Franck, X.;
Hocquemiller, R.; Figade`re, B. Chem. Commun. 2002, 160.
(9) Ethyl magnesium bromide was purchased from Aldrich as a 3.0 M
solution in Et2O.
2058
Org. Lett., Vol. 11, No. 10, 2009

and 9),12 highlighting the importance of chelation in directing
the Grignard addition to the si face of the aldehyde. Remarkably,
further increases to the reaction temperature resulted in in-
creased selectiVity for the desired 10S diastereomer 10a (entries
10-12). In fact, in DCE at reflux (83 °C), 10a was produced13,14
as the major component of an 8:1 mixture of diastereo-
mers.15,16 A similar trend was observed using n-hexyl
magnesium bromide17 in DCE (entries 13 and 14). Employ-
ing these optimized conditions, 8-nonenyl magnesium bro-
mide was added to 1 (entry 15) in DCE at reflux to provide
the natural product 2 as the major component of a 5.5:1
mixture of diastereomers.
Considering the diversity of factors20,21 that may contribute
to the results summarized in Table 1 and our incomplete
understanding of the addition of organometallic reagents to
oxygenated tetrahydrofurfurals (vide supra), we were in-
trigued as to whether or not DFT calculations would provide
insight into the role played by the 3-hydroxy group in these
reactions.25 Accordingly, the low energy first-order saddle
points pro-(S)-TS1 (∆∆G ) 0 kcal/mol) and pro-(R)-TS1
(∆∆G ) 1.41 kcal/mol) that correspond to stereofacial
additions of CH3MgBr to the magnesium alkoxide derived
from a cis-3-hydroxytetrahydrofurfural were computed at the
B3LYP/6-21G(d) level using the Gaussian 03 suite of
programs (Figure 2).26 As indicated in Figure 2, an intricate
On the basis of the results summarized in Table 1, it is clear
that the formation of the 10S diastereomers 10a, 11a, and 2
are favored in polar, noncoordinating solvents, consistent with
a chelation-controlled addition.18,19 Unfortunately, a series of
1H NMR spectra recorded on a mixture of EtMgBr and 1 in
CD2Cl2 at various temperatures (-50 °C to rt) failed to offer
any additional insight into this unusual process.20,21 However,
it is worth considering the nature of the Grignard reagent
and the structure and solvation of the intermediate magne-
sium alkoxide 9 generated by deprotonation of the alcohol
function in the tetrahydrofurfural 1. More specifically, as the
reaction temperature is decreased, a shift in the Schlenk
equilibrium22 that favors a more reactive23 Et2Mg species
may account for the poor diastereocontrol.24 Alternatively,
temperature-dependent changes in the solvation and/or ag-
gregation of the magnesium alkoxide 9 may account for the
associated changes in diastereoselectivity. Interestingly, the
stereoselective addition of EtMgBr or n-HexMgBr to the C9-
epimeric trans-aldehyde 3 (Figure 1) showed little depen-
dence on solvent or temperature,25 suggesting the cis-
relationship between the aldehyde and hydroxyl group in 1
is key to the temperature-dependent diastereoselectivity.
Figure 2. Lowest energy transition structures corresponding to (a)
pro-(S) and (b) pro-(R) additions of CH3MgBr to the magnesium
alkoxide of a cis-3-hydroxyetrahydrofurfural.
(11) In the 1H NMR spectra of 10a and 10b (CDCl3) the protons at
C10 resonate at δ 3.40 and δ 3.76 ppm, respectively. These chemical shift
values are consistent with those reported for threo and erythro diastereomers
of R-substituted 2-tetrahydrofuranmethanols. For the use of this mnemonic
in the configurational assignment of R-substituted 2-tetrahydrofuranmetha-
nols, see: (a) Harmange, J.-C.; Figade`re, B.; Cave´, A. Tetrahedron Lett.
1992, 33, 5749. (b) Gale, J. B.; Yu, J.-G.; Hu, X. E.; Khare, A.; Ho, D. K.;
Cassady, J. M. Tetrahedron Lett. 1993, 34, 5847.
network of chelation modes was found in both transition
structures that involved a γ-chelate between the magnesium
alkoxide and the aldehyde oxygen measured at 2.14 Å in
pro-(S)-TS1 and 2.03 Å in pro-(R)-TS1. This chelation mode
effectively locks the aldehyde and tetrahydrofuran oxygens
(12) When the reactions described by entries 9-11 were repeated with
the addition of MgBr2 (10 equiv), a considerable number of byproducts
were formed and the observed ratio of 10a:10b differed only slightly from
those reported in entries 9-11.
1
(13) For selected crude H NMR spectra, see Supporting Information.
(20) For discussions regarding temperature-dependent effects in stereo-
selective synthesis, see: (a) Sivaguru, J.; Solomon, M. R.; Poon, T.;
Jockusch, S.; Bosio, S.; Adam, W.; Turro, N. J. Acc. Chem. Res. 2008, 41,
387. (b) Pracejus, H. Liebigs Ann. Chem. 1960, 634, 9. (c) Hamuda, T.;
Fukuda, T.; Imanishi, F. H.; Katsuki, T. Tetrahedron 1996, 52, 515. (d)
Meyer-Stork, M. A.; Haag, D.; Scharf, H.-D. J. Chem. Soc., Perkin Trans.
2 1997, 593. (e) Muzart, J.; He´nin, F.; Aboulhoda, S. J. Tetrahedron:
Asymmetry 1997, 8, 381. (f) Enders, D.; Gielen, H.; Breuer, K. Tetrahedron:
Asymmetry 1997, 8, 3571. (g) Li, B.; Wang, Y.; Du, D.-M.; Xu, J. J. Org.
Chem. 2007, 72, 990. (h) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas,
M. D.; D´ıez, R.; Ga´lvez, J. A. Eur. J. Org. Chem. 2003, 2268. (i) Cainelli,
G.; Galletti, P.; Giacomini, D.; Orioli, P. Angew. Chem., Int. Ed. Engl. 2000,
39, 523. (j) Cainelli, G.; Giacomini, D.; Galletti, P.; Orioli, P. Eur. J. Org.
Chem. 2001, 4509. (k) Lombardo, M.; Fabbroni, S.; Trombini, C. J. Org.
Chem. 2001, 66, 1264. (l) Inoue, Y.; Ikeda, H.; Kaneda, M.; Sumimura,
T.; Everitt, S. R. L.; Wada, T. J. Am. Chem. Soc. 2000, 122, 406. (m) Go¨bel,
T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1993, 32, 1329. (n) Hei,
X.-M.; Song, Q.-H.; Li, X.-B.; Tang, W.-J.; Wang, H.-B.; Guo, Q.-X. J.
Org. Chem. 2005, 70, 2522. (o) Adam, W.; Stegmann, V. R. J. Am. Chem.
Soc. 2002, 124, 3600. (p) Abe, M.; Kawakami, T.; Ohata, S.; Nozaki, K.;
Nojima, M. J. Am. Chem. Soc. 2004, 126, 2838.
(14) For temperature and solvent effects in the diastereoselective addition
of nucleophiles to carbonyl compounds, see: (a) Badorrey, R.; Cativiela,
C.; D´ıaz-de-Villegas, M. D.; D´ıez, R.; Ga´lvez, J. A. Eur. J. Org. Chem.
2003, 2268. (b) Cainelli, G.; Giacomini, D.; Galletti, P.; Orioli, P. Eur. J.
Org. Chem. 2001, 4509. (c) Cainelli, G.; Giacomini, D.; Galletti, P. Chem.
Commun. 1999, 567
.
(15) When a solution of 10a and 10b (8:1 mixture) in DCE was treated
with EtMgBr and heated at reflux for 1 h, there was no change in the ratio
of these substances. This result indicates that the diastereoselectivities
summarized in Table 1are not the result of a selective decomposition of
10b under the reaction conditions.
(16) For examples of inverse temperature dependence in Grignard
additions to aldehdyes see ref 3a and Marko´, I. E.; Chesney, A.; Hollinshead,
D. M. Tetrahedron: Asymmetry 1994, 5, 569
(17) n-Hexyl magnesium bromide was purchased from Aldrich as a 2.0
M solution in Et2O.
.
(18) For a detailed description of chelation controlled Grignard additions,
see: Eliel, E. L.; Frye, S. V.; Hortelano, E. R.; Chen, X.; Bai, X. Pure
Appl. Chem. 1991, 63, 1591
.
(19) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191
.
Org. Lett., Vol. 11, No. 10, 2009
2059

in a synclinal orientation in pro-(S)-TS1 (-54.0°) and a
synperiplanar orientation in pro-(R)-TS1 (-15.1°). Beyond
the similarity of this γ-chelate, however, the two first-order
saddle points were decidedly different. For example, a cyclic
chelation mode consistent with 66 (Figure 1) was found in
pro-(S)-TS1, whereas pro-(R)-TS1 contained a hybrid-type
R/γ-chelate involving the aldehyde and tetrahydrofuran
oxygens and the magnesium alkoxide, as well as an interac-
tion between the magnesium alkoxide oxygen and the second
equivalent of CH3MgBr. Interestingly, the calculated prefer-
ence for pro-(S)-TS1 is related to a favorable entropy for
this transition structure (∆∆ST ) 1.54 kcal/mol), as the ∆∆H
term (-0.13 kcal/mol) actually favors pro-(R)-TS1. Impor-
tantly, the calculated energetics correctly predict preferential
formation of the 10S diastereomer (theoretical dr ) 7.3:1,
experimental dr ) 8:1) and highlight the key role played by
the magnesium alkoxide function in the low energy transition
structure pro-(S)-TS1.
possessed a chelate between the magnesium alkoxide and
tetrahydrofuran oxygen and a cyclic five-membered ring
coordination motif consistent with that proposed by Wolfrom
and Hanessian (Figure 1).6 Indeed, aside from the obvious facial
selectivity of the Grignard reagent, the only major difference
between these structures was the presence of a single van der
Waals contact (2.32 Å) in pro-(S)-TS2 associated with approach
of CH3MgBr from underneath the tetrahydrofuran ring. Again,
these calculations correctly predict the preferential formation
of the 10R diastereomer (theoretical dr ) 3.9:1, experimental
dr ) 2.3:1), which is consistent with the sense and relative
magnitude of diastereoselectivity observed in the addition of
Grignard reagents to the trans-tetrahydrofurfural 3.25
In summary, a remarkable example of inverse-temperature-
dependent diastereoselectivity was uncovered while investigating
the addition of Grignard reagents to a 3-hydroxytetrahydrofurfural.
Notably, the optimized conditions for this process involve the
addition of Grignard reagent to a solution of the tetrahydrofurfural
1 in DCE at reflux. While a temperature-dependent shift in the
Schlenk equilibrium or change in solvation of the intermediate
magnesium alkoxide may play an important role in this unusual
process, it is clear that the cis-relationship between the alcohol and
aldehyde functions on the tetrahydrofuran ring is paramount.
Furthermore, on the basis of DFT calculations, a γ-chelate between
the magnesium alkoxide and the aldehyde oxygen and an entropic
preference for the pro-(S)-transition structure serve as the key
factors responsible for the observed diastereoselectivity. Impor-
tantly, these results highlight the effect of additional coordination
sites in the diastereoselective addition of organometallic reagents
to oxygenated tetrahydrofurfurals and pave the way for a concise,
protecting-group-free synthesis of the marine oxylipid 2. Efforts
to improve our understanding of the relationship between temper-
ature and diastereoselectivity in these reactions using computational
methods are currently underway in one of our laboratories, and
the results from these studies will be reported in due course.
The low energy transition structures pro-(R)-TS2 (∆∆G )
0 kcal/mol) and pro-(S)-TS2 (∆∆G ) 0.96 kcal/mol) (Figure
3), corresponding to CH3MgBr addition to a trans-3-hydro-
Acknowledgment. This research was supported by NSERC-
Canada, Merck Frosst Canada, NSERC CGSD (B.K.) PGSD
(J.M.), Michael Smith Foundation for Health Research (B.K.,
J.M.), Merck, SHARCNET, and CFI.
Note Added after ASAP Publication. Reference to
companion paper OL802711S was added in the text below
Figure 1 in the version published ASAP April 16, 2009.
Figure 3. Lowest energy transition structures corresponding to (a)
pro-(R) and (b) pro-(S) additions of CH3MgBr to the magnesium
alkoxide of a trans-3-hydroxytetrahydrofurfural.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for each new
compound. This material is available free of charge via the
Internet at http://pubs.acs.org.
xytetrahydrofurfural, were also calculated. As a result of the
positioning of the magnesium alkoxide and aldehyde functions
on opposite faces of the tetrahydrofuran ring, these transition
structures differed significantly from those discussed above
(Figure 2). Notably, both pro-(R)-TS2 and pro-(S)-TS2 share
nearly identical geometries, and both first-order saddle points
OL900324S
(23) Ashby, E. C. Pure Appl. Chem. 1980, 52, 545.
(24) Addition of Bu2Mg (1 M solution in heptane) to a solution of 1 in
DCE at room temperature provided (in low yield) a 1.3:1 mixture of
diastereomeric alcohols favoring the 10S diastereomer, along with a number
of byproducts.
(21) For discussions regarding inverse-temperature-dependent effects and
the “isoinversion princple”, see: (a) Heller, D.; Buschmann, H.; Neumann,
H. J. Chem. Soc., Perkin Trans 2 1999, 175. (b) Buschamnn, H.; Scharf,
H.-D.; Hoffmann, N.; Plath, M. W.; Runsink, J. J. Am. Chem. Soc. 1989,
111, 5367. (c) For a review, see: Buschamnn, H.; Scharf, H.-D.; Hoffmann,
N.; Esser, P. Angew. Chem., Int. Ed. Engl. 1991, 30, 477. (d) Hale, K. J.;
Ridd, J. H. J. Chem. Soc., Chem. Commun. 1995, 357.
(25) The addition of n-hexyl magnesium bromide to 3 was investigated
in a variety of solvents at room temperature with the following results (ratio
of 10R:10S diastereomers in brackets): THF (1.5:1), CH2Cl2 (2.1:1), Et2O
(1.8:1). In DCE, the ratio of 10R:10S diastereomers (2.3:1) was unchanged
when the addition was carried out at temperatures ranging from room
temperature to 83 °C.
(26) See Supporting Information for theoretical references as well as a
comprehensive explanation of methods used to locate the transition states.
(22) Paris, G. E.; Ashby, E. C. J. Am. Chem. Soc. 1971, 93, 1206.
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Org. Lett., Vol. 11, No. 10, 2009