Stereoselective 1,2-additions of α-alkoxymethyllithiums to aldehydes

Article abstract of DOI:10.1021/ol016384v

(equation presented) A chiral derivative of tributylstannymethanol, readily prepared from L-valine, undergoes Sn-Li exhange to provide an α-alkoxyorganolithium that adds to aldehydes with up to 91:9 dr. The diastereoselectivity depends on the solvent and alkyllithium used for transmetalation. Treatment of adducts with acid allowed recovery of the chiral auxiliary and diol with complete stereochemical integrity.

Full text of DOI:10.1021/ol016384v

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2903-2906
Stereoselective 1,2-Additions of
r-Alkoxymethyllithiums to Aldehydes
Robert P. Smyj and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC)2,
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario, Canada N2L3G1
jmchong@uwaterloo.ca
Received July 3, 2001
ABSTRACT
A chiral derivative of tributylstannylmethanol, readily prepared from L-valine, undergoes Sn−Li exchange to provide an r-alkoxyorganolithium
that adds to aldehydes with up to 91:9 dr. The diastereoselectivity depends on the solvent and alkyllithium used for transmetalation. Treatment
of adducts with acid allowed recovery of the chiral auxiliary and diol with complete stereochemical integrity.
The asymmetric addition of organometallic reagents, par-
ticularly organozincs, to carbonyl compounds is now an
important synthetic method.1 However, these reactions are
mostly restricted to unfunctionalized alkyl and aryl groups,
and the stereoselective addition of heteroatom functionalized
chiral organometallics2 is a relatively unexplored area. With
R-heteroatom substituted organometallics,3 McGarvey has
demonstrated high levels of asymmetric induction in the
addition of R-substituted (i.e., 2°) R-alkoxyorganometallics
to aldehydes.3a As well, highly diastereoselective additions
using diheteroatom-substituted organometallics (which are
formyl anion equivalents) have been demonstrated.4 In
principle, diastereoselective addition of R-alkoxymethyl or
R-aminomethyl (i.e., 1°) organometallics to aldehydes could
be achieved by using a chiral auxiliary attached to the hetero-
atom (Scheme 1). This would constitute a new asymmetric
(1) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
Scheme 1
(2) Asymmetric γ-alkoxyallyl additions: (a) Brown, H. C.; Jadhav, P.
K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535-1538. (b) Yamamoto,
Y.; Kobayashi, K.; Okano, H.; Kadota, I. J. Org. Chem. 1992, 57, 7003-
7005. (c) Roush, W. R.; VanNieuwenhze, M. S. J. Am. Chem. Soc. 1994,
116, 8536-8543. (d) Coleman, R. S.; Kong, J.-S.; Richardson, T. E. J.
Am. Chem. Soc. 1999, 121, 9088-9095. Heteroatom functionalized chiral
organozincs: (e) Eisenberg, C.; Knochel, P. J. Org. Chem. 1994, 59, 3760-
3761. (f) Ostwlad, R.; Chavant, P.-Y.; Stadmu¨ller, H.; Knochel, P. J. Org.
Chem. 1994, 59, 4143-4153. (g) Lu¨tjens, H.; Nowotny, S.; Knochel, P.
Tetrahedron: Asymmetry 1995, 6, 2675-2678. Related organotitaniums:
(h) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473-7484.
(3) (a) McGarvey, G. J.; Kimura, M. J. Org. Chem. 1982, 47, 5422-
5424. (b) McDougal, P. G.; Condon, B. D.; Laffosse, M. D., Jr.; Lauro, A.
M.; VanDerveer, D. Tetrahedron Lett. 1988, 29, 2547-2550. (c) Yamada,
J.-I.; Abe, H.; Yamamoto, Y. J. Am. Chem. Soc. 1990, 112, 6118-6120.
(d) Tsunoda, T.; Fujiwara, K.; Yamamoto, Y.; Shoˆ, I. Tetrahedron Lett.
1991, 32, 1975-1978. (e) Furuta, T.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1992, 863-864. (f) Furuta, T.; Yamamoto, Y. J. Org. Chem.
1992, 57, 2981-2982. (g) Pearson, W. H.; Lindbeck, W. H.; Kampf, J. W.
J. Am. Chem. Soc. 1993, 115, 2622-2636. (h) Gawley, R. E.; Zhang, Q. J.
Org. Chem. 1995, 60, 5763-5769. (i) Gawley, R. E. AdV. Asym. Synth.
1998, 3, 77-111.
synthesis of â-amino alcohols and 1,2-diols, compounds of
interest as biologically active materials or synthetic inter-
mediates.5
(4) (a) Gaul, C.; Seebach, D. Org. Lett. 2000, 2, 1501-1504. (b) Gawley,
R. E.; Zhang, Q.; McPhail, A. T. Tetrahedron: Asymmetry 2000, 11, 2093-
2106.
10.1021/ol016384v CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/10/2001

There are examples that demonstrate stereoselective ad-
dition of chiral R-aminomethyl3g,6 or R-alkoxymethyl7 car-
banions to aldehydes. Thus by using proline6 or menthol-
based chiral directing groups,7 diastereomeric ratios of up
to 78:22 were obtained. However, the chiral groups used in
these studies were not intended to be removed. We now
report our efforts in developing the first method for the
stereoselective addition of R-alkoxymethyl carbanions to
aldehydes employing a removable chiral auxiliary.8
using chiral pool starting materials (L-valine). (b) The
isopropyl and phenyl groups should help in biasing the
conformation of the six-membered ring to a single chair. (c)
The oxygen of the tetrahydropyran is expected to coordinate
to the organolithium to decrease conformational mobility.
(d) The phenyl group provides steric bulk to aid in enan-
tiofacial discrimination with approaching aldehydes.
The synthesis of 12 involved only five steps from known
epoxide 710 (Scheme 3). A copper-catalyzed addition of
Grignard reagent 6 gave alcohol 8, which cyclized under
acidic conditions to lactol 9. PCC oxidation of 9 then
furnished the lactone 10, to which PhLi was added to afford
keto alcohol 11. Finally, treatment of 11 with Bu3SnCH2-
OH in the presence of acid gave the desired ketal 12 as a
single diastereomer. Formation of the R-anomer was expected
on the basis of well-established precedence11 and was verified
using NOESY experiments.
Our general strategy employs a cyclic chiral acetal
containing a Bu3SnCH2O unit (1, Scheme 2). Sn-Li
Scheme 2
Transmetalation/trapping studies on 12 were carried out
using benzaldehyde as the electrophile under typical condi-
tions (THF, -78 °C, Scheme 4). We were gratified to
Scheme 4
exchange9 generates R-alkoxyorganolithium 2, which is then
trapped with an aldehyde to afford an addition adduct 3.
Exposure of 3 to acidic conditions should then allow recovery
of the auxiliary 4 and enantiomerically enriched 1,2-diol
product 5.
Substituted tetrahydropyran 12 (Scheme 3) was chosen as
observe a reasonable level of diastereoselectivity (78:22 dr).
In addition, treatment of the addition product 13 with CSA
allowed for the recovery of auxiliary 11 and 1,2-diol 14 (80:
20 er) with no detectable epimerization.
Scheme 3
Since an excess (2 equiv) of n-BuLi was used to facilitate
complete transmetalation, 1-phenyl-1-pentanol was also
formed in this reaction. This alcohol proved to be inseparable
from adduct 13. Thus the reaction was repeated with 1 equiv
of n-BuLi. Surprisingly, this resulted in a significant decrease
in selectivity (Table 1). A larger excess (4 equiv) of n-BuLi
gave a result similar to that observed with 2 equiv.
Furthermore, other alkyllithiums gave selectivities different
from those observed with n-BuLi. Thus it seems that the
alkyllithium used is not simply involved in transmetalation
and formation of a bystander tetraalkylstannane but also
complexes with the alkoxymethyllithium generated.
(6) Coldham, I.; Holman, S.; Lang-Anderson, M. M. S. J. Chem. Soc.,
Perkin Trans. 1 1997, 1481-1485.
(7) (a) Ortiz, J.; Guijarro, A.; Yus, M. An. Quim. Int. Ed. 1997, 93, 44-
48. (b) Ponzo, V. L.; Kaufman, T. Can. J. Chem. 1998, 76, 1338-1343.
(8) Presented, in part, at the 221st American Chemical Society annual
meeting, April 1-5 2001, San Diego, CA; Abstract ORGN523.
(9) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481-1487.
(10) Koppenhoefer, B.; Schurig, V. Organic Syntheses; Heathcock, C.
H., Ed.; John Wiley & Sons: New York, 1988; Vol. 66, pp 160-172.
(11) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983; pp 5-20.
the chiral organolithium precursor for several reasons: (a)
Enantiomerically pure material should be readily accessed
(5) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547. (b) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 451-454.
2904
Org. Lett., Vol. 3, No. 18, 2001

Best results were obtained with 30% THF in Et2O, which
provided diol 14 in 91% yield with 88:12 er.
In all examples studied, (S)-14 was the major product
formed.12 This may be explained by considering the model
shown in Figure 1. This model incorporates an alkyllithium
Table 1. Effect of Alkyllithium on Selectivity
entry
RLi
equiv
yield (%)
er (S:R)
1
2
3
4
5
n-BuLi
n-BuLi
n-BuLi
s-BuLi
t-BuLi
2
1
4
2
2
85
56
90
56
21
80:20
66:34
80:20
72:28
73:27
Although 2 equiv of n-BuLi was usually used in these
experiments, it should be noted that only 1 equiv is required
for complete transmetalation. This was ascertained by
experiments using 1 equiv of n-BuLi in which all of the
alkoxystannane was consumed and >90% yields of Bu4Sn
were isolated. However, transmetalations did not always
proceed to completion when only 1 equiv of n-BuLi was
used; in these cases, no 1-phenylpentanol (i.e., PhCHO +
n-BuLi product) was detected, suggesting that adventitious
moisture was sometimes a problem. Thus excess n-BuLi was
used initially primarily for practical reasons.
Figure 1. Possible approaches of PhCHO.
and THF/THP molecule such that the aldehyde approaches
from the bottom face of the chiral auxiliary. The preferred
orientation of the aldehyde would then be expected, for steric
reasons, to be as shown in 15 [leading to (S)-14] as opposed
to 16 [which leads to (R)-14]. While we have no spectro-
scopic evidence for this model, it is consistent with the
known propensity of alkyllithiums to form aggregates13 as
well as the absolute configuration of 14 observed and the
effects of alkyllithiums and solvents/additives observed.
Also, while there have been speculations that pentacoor-
dinate stannylate (“ate”) complexes might be responsible for
the chemistry of organolithiums derived from Sn-Li ex-
change,14 our results suggest that is not the case here.
Stannylates have been detected spectroscopically in THF-
HMPA14 but were not observed when alkoxystannanes and
alkyllithiums were admixed in THF.15 Nonetheless, it is still
possible that they are short-lived intermediates in the
generation of R-alkoxyorganolithiums or are involved in
reactions of these species. In our case, since the same
stannylate would be formed from either 1 or 2 equiv of
n-BuLi, one would not expect to observe different selectivi-
ties. Since the amount of n-BuLi does affect the selectivity,
a discreet ate complex is not indicated. The present model
is a simple way to explain the results observed. However,
more complex scenarios involving aggregates of stannylates
and alkyllithiums cannot be discounted completely.
Other solvents and additives were also studied (Table 2).
Table 2. Effect of Solvents and Additives on Selectivity
entry
solvent
yield (%)
er (S:R)
1
2
3
4
5
6
7
8
9
THF
Et2O
DME
85
49
97
59
91
28
52
26
18
19
24
80:20
63:37
69:31
87:13
88:12
78:22
85:15
53:47
72:28
89:11
91:9
15% THF/Et2O
30% THF/Et2O
0.9% THF/Et2O
15% THF/TBME
15% Et3N/Et2O
15% TMEDA/Et2O
15% THP/Et2O
30% THP/Et2O
In summary, it has been demonstrated for the first time
that a chiral auxiliary directed stereoselective addition of an
R-heteroatom methyl carbanion to aldehydes along with the
subsequent recovery of the chiral auxiliary and enantiomeri-
10
11
Solvents less polar (Et2O) and more polar (DME) than THF
both gave significantly lower selectivities. However, use of
15% THF in either Et2O or TBME resulted in higher
selectivity over that observed in neat THF. These results
suggest that THF plays an important coordinative role with
the organolithiums involved in these reactions. Indeed, the
amount of THF used had a dramatic influence on the
selectivity observed. The use of tetrahydropyran (THP) gave
similar selectivities (but lower yields due to incomplete
transmetalation) to that observed with THF, but other
additives (Et3N, TMEDA) gave much lower selectivities.
(12) Determined by comparison of retention times on a chiral HPLC
column (Chiralcel OD) using authentic commercial samples.
(13) (a) Fraenkel, G.; Henrichs, M.; Hewitt, J. M.; Su, B. M.; Geckle,
M. J. J. Am. Chem. Soc. 1980, 102, 3345-3350. (b) Seebach, D.; Ha¨ssig,
R.; Gabriel, J. HelV. Chim. Acta 1983, 66, 308-337. (c) Fraenkel, G.;
Henrichs, M.; Hewitt, M.; Su, B. M. J. Am. Chem. Soc. 1984, 106, 255-
256. (d) McGarrity, J. F.; Ogle, C. A. J. Am. Chem. Soc. 1985, 107, 1805-
1810. (e) McGarrity, J. F.; Ogle, C. A.; Brich, Z.; Loosli, H.-R. J. Am.
Chem. Soc. 1985, 107, 1810-1815. (f) Williard, P. G.; Sun, C. J. Am. Chem.
Soc. 1997, 119, 11693-11694.
(14) Reich, H. J.; Phillips, N. H. J. Am. Chem. Soc. 1986, 108, 2102-
2103.
(15) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J. J.
Am. Chem. Soc. 1988, 110, 842-853.
Org. Lett., Vol. 3, No. 18, 2001
2905

cally enriched product can be accomplished. Furthermore
the level of stereoselectivity observed (up to 91:9 dr) is
considerably higher than what is currently in the literature
for 1,2-additions of R-alkoxymethyl carbanions (64:36 dr).7a
Finally, and perhaps most importantly, the observations that
we have made regarding the effects of alkyllithiums and
solvents/additives will be very useful in guiding future efforts
in this area.
providing financial support. We also thank the reviewers for
their very helpful and insightful comments and suggestions.
Supporting Information Available: Compound charac-
terization data and experimental procedures for the prepara-
tion of compounds 6-14 and analytical procedures for
determining the er and absolute configuration of 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
OL016384V
2906
Org. Lett., Vol. 3, No. 18, 2001