Overriding felkin control: A general method for highly diastereoselective chelation-controlled additions to α-silyloxy aldehydes

Article abstract of DOI:10.1021/ja910717p

According to the Felkin-Anh and Cram-chelation models, nucleophilic additions to α-silyloxy aldehydes proceed through a nonchelation pathway due to the steric and electronic properties of the silyl group, giving rise to Felkin addition products. Herein we describe a general method to promote chelationcontrol in additions to α-silyloxy aldehydes. Dialkylzincs, functionalized dialkylzincs, and (E)-disubstituted, (E)-trisubstituted, and (Z)-disubstituted vinylzinc reagents add to silyl-protected α-hydroxy aldehydes with high selectivity for chelation-controlled products (dr of 10:1 to 20:1) in the presence of alkylzinc halides or triflates, RZnX. With the high functional group tolerance of organozinc reagents, the mild Lewis acidity of RZnX, and the excellent diastereoselectivities favoring the chelation-controlled products, this method will be useful in the synthesis of natural products. A mechanism involving chelation is supported by (1) NMR studies of a model substrate, (2) a dramatic increase in reaction rate in the presence of an alkylzinc halide, and (3) higher diastereoselectivity with larger alkyl substituents on the α-carbon of the aldehyde. This method provides access to chelation-controlled addition products with high diastereoselectivity previously unavailable using achiral organometallic reagents.

Full text of DOI:10.1021/ja910717p

Published on Web 03/10/2010
Overriding Felkin Control: A General Method for Highly
Diastereoselective Chelation-Controlled Additions to
r-Silyloxy Aldehydes
Gretchen R. Stanton, Corinne N. Johnson, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received December 20, 2009; E-mail: pwalsh@sas.upenn.edu
Abstract: According to the Felkin-Anh and Cram-chelation models, nucleophilic additions to R-silyloxy
aldehydes proceed through a nonchelation pathway due to the steric and electronic properties of the silyl
group, giving rise to Felkin addition products. Herein we describe a general method to promote chelation-
control in additions to R-silyloxy aldehydes. Dialkylzincs, functionalized dialkylzincs, and (E)-disubstituted,
(E)-trisubstituted, and (Z)-disubstituted vinylzinc reagents add to silyl-protected R-hydroxy aldehydes with
high selectivity for chelation-controlled products (dr of 10:1 to >20:1) in the presence of alkylzinc halides
or triflates, RZnX. With the high functional group tolerance of organozinc reagents, the mild Lewis acidity
of RZnX, and the excellent diastereoselectivities favoring the chelation-controlled products, this method
will be useful in the synthesis of natural products. A mechanism involving chelation is supported by (1)
NMR studies of a model substrate, (2) a dramatic increase in reaction rate in the presence of an alkylzinc
halide, and (3) higher diastereoselectivity with larger alkyl substituents on the R-carbon of the aldehyde.
This method provides access to chelation-controlled addition products with high diastereoselectivity
previously unavailable using achiral organometallic reagents.
1. Introduction
A fundamental strategy in complex molecule synthesis is to
utilize substrate stereochemistry to control the introduction of
new stereogenic centers.1-4 Within this conceptual framework,
the Felkin-Anh and Cram-chelation models for predicting
stereochemical outcomes in additions to chiral aldehydes and
ketones are among the most powerful and widely employed
(Figure 1).5-15 According to these models, stereoinduction with
protected R- and ꢀ-hydroxy aldehydes and ketones is protecting
Figure 1. Felkin-Ahn and Cram-chelation models.
group dependent.16 Small protecting groups such as benzyl and
methyl favor carbonyl addition via chelation control (Cram-
chelate model).7,17 In contrast, sterically encumbering silyl
protecting groups disfavor chelation, instead promoting a
nonchelation pathway leading to Felkin addition products with
moderate to excellent diastereoselectivity.5,7,18 Exceptions to this
paradigm are scarce19-25 and are detailed in later sections. The
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley:
New York, 1989.
(2) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II: More
Targets, Strategies, Methods; Wiley-VCH: Weinheim, Germany, 2003.
(3) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
Weinheim, Germany, 1996.
(4) Koskinen, A. Asymmetric Synthesis of Natural Products; Wiley:
Chichester, U.K., 1993.
(5) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem.
ReV. 2006, 106, 2355–2403.
(16) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in Organic
Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007.
(17) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748–2755.
(18) Anh, N.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61–70.
(19) Frye, S. V.; Eliel, E. L.; Cloux, R. J. Am. Chem. Soc. 1987, 109,
1862–1863.
(6) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556–569.
(7) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191–1224.
(8) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281–284.
(9) Keck, G. E.; Boden, E. Tetrahedron Lett. 1984, 25, 265–268.
(10) Wu, Y. D.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 908–910.
(11) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 2819–
2820.
(20) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.
Soc. 1992, 114, 1778–1784.
(21) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.
Soc. 1990, 112, 6130–6131.
(12) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353–
3361.
(22) Reetz, M. T.; Huellmann, M. J. Chem. Soc., Chem. Commun. 1986,
1600–2.
(13) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105, 1667–
1668.
(23) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem.
Soc. 2001, 123, 10840–10852.
(14) Smith, R. J.; Trzoss, M.; Bu¨hl, M.; Bienz, S. Eur. J. Org. Chem. 2002,
2770–2775.
(24) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999,
40, 4461–4462.
(15) Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc. 2006, 128,
2920–2930.
(25) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett. 1999,
40, 4457–4460.
9
10.1021/ja910717p  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 4399–4408 4399

A R T I C L E S
Stanton et al.
importance of these principles has resulted in their coverage in
many organic textbooks.26-29
A more refined approach employing R-silyloxy aldehydes
would be to override the expected Felkin control by using
achiral reagents to enable the synthesis of chelation-controlled
addition products. If successful, chemists could then prepare
either the Felkin or chelation-controlled diastereomer from chiral
R-silyloxy aldehydes by proper choice of organometallic re-
agents.25 Herein, we present a general method to achieve such
highly diastereoselective chelation-controlled additions to R-si-
lyloxy aldehydes with a variety of functionalized organozinc
reagents, including dialkylzincs and in situ generated (E)-di-,
(E)-tri-, and (Z)-disubstituted vinylzinc species.
The ability to predict stereochemical outcomes of carbonyl
addition reactions based on protecting groups has proven very
useful in natural product synthesis. Compounds containing syn-
vicinal diols may be synthesized from R-hydroxyl aldehydes
or ketones bearing small, coordinating protecting groups such
as Me, MOM, Bn, or PMB. In contrast, anti-vicinal diol motifs
can be generated with good to excellent diastereoselectivity
when an R-silyloxy aldehyde or ketone is employed, resulting
from Felkin addition. Despite the well-documented utility of
this paradigm, it is not without drawbacks. Namely, the
protecting group strategy is dictated by the relative stereochem-
istry of the diol-containing motif. Thus, rather than employing
the most suitable protecting group for the global synthetic
approach, the protecing group is chosen to achieve the desired
diastereoselectivity in the carbonyl addition step.16
In cases where the most advantageous protecting group for
the global synthesis does not provide the requisite stereochem-
istry in the addition to enantioenriched protected R- and
ꢀ-silyloxy aldehydes and ketones, chemists have relied on chiral
reagents and catalysts or a deprotection/reprotection strategy.
Substrate stereocontrol can be overridden by use of enantioen-
riched stoichiometric auxiliaries, optically active stoichiometric
additives,5,30-38 or chiral catalysts.39-43 Successful examples
using stoichiometric Lewis acids are illustrated in Scheme
1A-C. Although these techniques led to the desired stereoiso-
mer with moderate to high diastereoselectivity, they are not
ideal. They employ large amounts of enantioenriched additives
(A-C), which must be prepared and ultimately separated from
the product. The chiral catalyst approach (D) gave excellent
diastereoselectivity in both the matched and mismatched cases,
although yields were low to moderate (24-68%).39 These
examples highlight a long-standing problem in organic synthesis:
there are no general methods for highly diastereoselective
chelation-controlled or anti-Felkin addition of organometallic
reagents to R-silyloxy aldehydes.
2. Background
Inspiration for this study stemmed from our research into the
additions of various vinylzinc reagents to enantioenriched
R-silyloxy aldehydes. We recently developed a protocol for the
synthesis of (Z)-allylic alcohols beginning with 1-bromo-1-
alkynes (Scheme 2).44 Hydroboration of 1-bromo-1-alkynes with
dicyclohexylborane followed by addition of a nucleophile,45-51
in this case a hydride delivered from t-BuLi,48 to the coordi-
natively unsaturated boron initiates a rearrangement that results
in generation of a (Z)-vinylborane intermediate. Srebnik52 and
Oppolzer53 had reported that vinylboranes undergo boron to zinc
vinyl exchange (i.e., transmetalation) in the presence of dialkyl-
zinc reagents.54 Thus, treatment of the resulting (Z)-vinylborane
with dialkylzinc reagents generated (Z)-vinylzinc intermediates.
The greater nucleophilicity of vinylzinc organometallics over
their vinylborane counterparts enabled additions to aldehydes
to proceed smoothly to generate (Z)-allylic alcohols.44,55 When
enantioenriched R-silyloxy aldehydes were employed, low
diastereoselectivity (dr 4:1) favoring chelation-controlled ad-
dition was observed. Surprisingly, however, addition of the (Z)-
vinylzinc reagent to TBS-protected R-hydroxy propanal in the
presence of 2 equiv of BF3 ·OEt2, a monodentate Lewis acid,
resulted in formation of the anti-Felkin or Cram-chelation
addition product with 8:1 dr (Scheme 2).44 We observed a
similar enhancement in the diastereoselectivity in the addition
of heterobimetallic vinylzinc reagents56,57 to trialkylsilyl-
protected R-hydroxy propanals in the presence of BF3 ·OEt2.56
It is noteworthy that monodentate Lewis acids such as BF3 are
expected to increase the ratio of Felkin to anti-Felkin products.7
The role of the BF3 ·OEt2 and the origin of the diastereoselec-
(26) Clayden, J.; Greeves, N. Organic Chemistry; Oxford University Press:
New York, 2001; p 889.
(27) Bruckner, R. AdVanced Organic Chemistry: Reaction Mechanisms;
Academic Press: San Diego, 2002, p 315.
(28) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry: Part A:
Structure and Mechanisms, 5th ed.; Springer: New York, 2007; p 179.
(29) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry;
University Science Books: Salslito, CA, 2006; p 564.
(30) Marshall, A. J.; Eidam, P. Org. Lett. 2004, 6, 445–448.
(31) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197–3199.
(32) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner,
M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258–1262.
(33) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3, 3017–
3020.
(44) Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2006, 128, 9618–9619.
(45) Zweifel, G.; Arzoumanian, H. J. Am. Chem. Soc. 1967, 89, 5086–
5088.
(46) Negishi, E.; Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 606–
607.
(34) Rodriguez-Escrich, C.; Olivella, A.; Urpi, F.; Vilarrasa, J. Org. Lett.
2007, 9, 989–992.
(47) Negishi, E.; Williams, R. M.; Lew, G.; Yoshida, T. J. Organomet.
Chem. 1975, 92, C4–C6.
(35) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348–6359.
(48) Campbell, J. B. J.; Molander, G. A. J. Organomet. Chem. 1978, 156,
71–79.
(36) Kolakowski, R. V.; Williams, L. J. Tetrahedron Lett. 2007, 48, 4761–
4764.
(49) Brown, H. C.; Imai, T.; Bhat, N. G. J. Org. Chem. 1986, 51, 5277–
5282.
(37) Sharon, O.; Monti, C.; Gennari, C. Tetrahedron 2007, 63, 5873–5878.
(38) Georges, Y.; Ariza, X.; Garcia, J. J. Org. Chem. 2009, 74, 2008–
2012.
(50) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 3702–3703.
(51) Kerrigan, M. H.; Jeon, S.-J.; Chen, Y.; Salvi, L.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2009, 131, 8434–8445.
(52) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449–2452.
(53) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170–173.
(54) Hussain, M. H.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883–893.
(55) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2007, 129, 16119–16125.
(39) Soai, K.; Shimada, C.; Takeuchi, M.; Itabashi, M. J. Chem. Soc., Chem.
Commun. 1994, 1994, 567–578.
(40) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729–1732.
(41) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis;
University Science Books: Sausalito, CA, 2008.
(42) Soai, K.; Hatanaka, T.; Yamashita, T. J. Chem. Soc. Perkin. Trans. 1
1992, 927–929.
(56) Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 3521–
3531.
(43) Watanabe, M.; Komota, M.; Nishimura, M.; Araki, S.; Butsugan, Y.
J. Chem. Soc., Perkin Trans. 1 1993, 2193–2196.
(57) Hussain, M. M.; Li, H.; Hussain, N.; Uren˜a, M.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2009, 131, 6516–6524.
9
4400 J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010

Overriding Felkin Control
A R T I C L E S
Scheme 1. Overriding Substrate Control with Enantioenriched Stoichiometric Additives (A-C) and Catalysts (D)
Scheme 2. One-Pot Synthesis of (Z)-Disubstituted Allylic Alcohols in the Presence of BF3 ·OEt2 with Unexpected Anti-Felkin Stereoselectivity
tivity in these reactions were unprecedented and remained
unclear until the results outlined below were obtained.
controlled product with excellent diastereoselectivity. Although
unprecedented, we speculated that a similar mechanism might
be responsible for the stereocontrol in our additions in the
presence of BF3 ·OEt2.56
Greater insight into our unexpected stereoselectivities in
Scheme 2 was obtained when (Z)-trisubstituted vinylzinc
reagents were added to TBS or TIPS protected R-hydroxy
propanals.50,51 (Z)-Trisubstituted vinylzinc intermediates were
generated from 1-bromo-1-alkenylboranes. Instead of addition
of a hydride source (t-BuLi), a dialkylzinc reagent was added
to first promote the rearrangement and then to effect the
transmetalation to generate the (Z)-trisubstituted vinylzinc
intermediates.50 Addition of R-silyloxy aldehydes to the resultant
vinylzinc solution led to chelation-controlled addition products
Given the Lewis acidity of BF3 and low diastereoselectivity
in its absence, we hypothesized that it was responsible for the
observed stereoselectivity. In a series of elegant studies,23-25
Evans and co-workers demonstrated that ClAlMe2 and Cl2AlMe,
which are monodentate Lewis acids like BF3, engage in
chelation-controlled addition reactions with enantioenriched
ꢀ-silyloxy aldehydes. For example, the Mukayama aldol reaction
is proposed to proceed by the mechanism outlined in Scheme
3.23 The key feature of this proposal is the abstraction of an
aluminum halide by a second equiv of Lewis acidic aluminum
reagent to afford a cationic aluminum species capable of
chelating chiral ꢀ-silyloxy aldehydes and forming the chelation
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4401

A R T I C L E S
Stanton et al.
Scheme 3. Evans’ Proposal for Chelation Control with Aluminum Lewis Acids in the Diastereoselective Mukayama Aldol Reaction (PG )
Protecting Group)
Scheme 4. One-Pot Generation of (Z)-Trisubstituted Allylic Alcohols with High Diastereoselectivity
with very high diastereoselectvity (dr >20:1).51 Importantly, no
Table 1. Diastereoselective Ethyl Additions to Silyl-Protected
BF3 ·OEt2 was employed in this process. If the BF3 was not
responsible for the observed anti-Felkin addition pathway in
Scheme 4, was it possible that the EtZnBr byproduct was
activating the R-silyloxy aldehydes by chelation? A priori, it
seemed unlikely that a mild Lewis acid such as EtZnBr would
chelate sterically encumbered R-silyloxy aldehydes. Based on
these results, we hypothesized that the diastereoselectivity in
Scheme 2 might be due to alkyl abstraction from ZnR2 by BF3,
to form a cationic zinc Lewis acid58 or that EtZnF is generated.
Both of these species have at least two open coordination sites
and would be capable of chelating a bidentate substrate. As
outlined below, we set out to determine if EtZnCl and EtZnBr
were responsible for the high diastereoselectivity in additions
of organozinc reagents to R-silyloxy aldehydes.
R-Hydroxy Propanal
entry
PG
EtZnX
mol %a
yield (%)
drb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
TBS
EtZnCl
0
150
100
50
77
90
93
94
91
92
94
89
81
69
77
85
72
60
80
1:1
28:1c
31:1c
14:1
6.7:1
22:1
25
TBS
TES
TIPS
EtZnBr
EtZnCl
EtZnCl
150
100
25
10
0
150
100
50
0
150
20:1
13:1
6:1
1:1
3. Results and Discussion
>20:1
>20:1
15.4:1
1:2
3.1. Addition of Dialkylzinc Reagents to Silyl Protected
r-Hydroxy Aldehydes. Our initial experiments involved the use
of commercially available diethylzinc with the TBS or TES-
protected (S)-R-hydroxy propanal. We first determined the
diastereoselectivity of the addition of diethylzinc to the aldehyde
substrates. As illustrated in Table 1 (entries 1 and 10) diethylzinc
reacts sluggishly with R-silyloxy aldehydes in the absence of a
Lewis acid with no selectivity, providing a 1:1 ratio of the Felkin
to the chelation-controlled products. The reactions were then
performed in the presence of 0.1-1.5 equiv EtZnX (X ) Cl,
Br). Lewis acidic RZnX (R ) Et, Me, n-Bu) were easily
prepared by conproportionation of ZnX2 and ZnR2 in toluene
at 70 °C for 3 d followed by filtration and removal of the
volatiles (Scheme 5).59,60 These materials could be used directly
or stored under a nitrogen atmosphere for months.
>20:1d
a Mol % EtZnX relative to aldehyde. b dr (Cram-chelation:Felkin)
determined by 1H NMR of crude products. c dr (Cram-chelation:Felkin)
determined by GC analysis of TMS-protected derivative. d Reaction
conducted at -50 °C.
Scheme 5. Synthesis of RZnX via Conproportionation
Performing the addition of diethylzinc to TBS or TES-
protected (S)-R-hydroxy propanal in toluene in the presence of
1.0-1.5 equiv EtZnCl or EtZnBr provided addition product of
very high diastereoselectivity favoring the chelation-controlled
products (entries 2, 3, 6, 7, 11, and 12). The relative configura-
tions were ascertained by 1H NMR analysis using the modified
(58) Walker, D. A.; Woodman, T. J.; Hughes, D. L.; Bochmann, M.
Organometallics 2001, 20, 3772–3776.
(59) Guerrero, A.; Martin, E.; Hughes, D. L.; Kaltsoyannis, N.; Bochmann,
M. Organometallics 2006, 25, 3311–3313.
(60) Fabicon, R. M.; Richey, H. G. Organometallics 2001, 20, 4018–4023.
9
4402 J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010

Overriding Felkin Control
A R T I C L E S
Table 2. Selected Results for the Addition of MgMe2 to R-Hydroxy
(Table 3, entries 1 and 2). Functionalized dialkylzinc reagents,
prepared by the method of Knochel,64-66 were likewise used
in additions to TBS-protected R-hydroxy propanal. In these
cases, the Lewis acid employed was generated by reaction of
2.7 equiv of the dialkylzinc reagent with 1.5 equiv triflic acid.
The resulting mixture then contained 1.5 equiv of RZn(OTf)67
and 1.2 equiv of the functionalized dialkylzinc reagent, ZnR2.
Reaction of this mixture with TBS-protected R-hydroxy propanal
provided the chelation-controlled addition products with high
diastereoselectivities. The yields, however, were diminished due
to partial reduction of the aldehyde substrate. Reduction most
likely occurred via a ꢀ-hydrogen transfer mechanism.68-70 At
this time, we have not successfully inhibited the reduction
pathway.
Propiophenones by Eliel and Coworkers.20
entry
SiR3
relative rate
dra
1
2
3
4
5
SiMe3
SiEt3
Si(t-Bu)Me2
Si(t-Bu)Ph2
Si(i-Pr)3
∼100
8
2.5
0.8
0.5
99:1
96:4
88:12
63:37
42:58
a dr ) Cram-chelation:Felkin.
Having demonstrated the ability to control diastereoselectivity
with silyl protected R-hydroxy propanals, we examined alkyl
additions to related aldehydes (Table 3, entries 5-8). If the
additions occur via chelated intermediates, larger alkyl and aryl
substituents on the R-carbon should increase the chelation-
controlled diastereoselectivity by more effectively blocking the
Felkin addition pathway. As representative substrates, the methyl
in the TBS protected R-hydroxy propanal substrate was
substituted with i-Pr and Ph. As shown in Table 3, high
diastereoselectivities were again obtained with the chelation-
controlled product dominating (entries 5-8). As seen in entries
3 vs 6, larger substituents on the R-carbon do in fact lead to
higher diastereoselectivity. Although the phenyl-substituted
aldehyde in entry 8 contains an acidic R-hydrogen, addition to
the aldehyde occurred more rapidly than deprotonation. The high
diastereoselectivities observed in the additions to three different
aldehydes indicate that the methods introduced herein should
be applicable to a host of related substrates.
3.2. Additions Involving (E)-Di- and Trisubstituted
Vinylzinc Reagents. Allylic alcohols are important intermediates
in organic synthesis and are common structural motifs in natural
products.71,72 It can be difficult, however, to simultaneously
control both the double bond geometry and the formation of
the stereocenter in the vinylation of chiral aldehydes. We
therefore applied our approach, as described in the previous
sections, to additions with vinylzinc reagents. In this context,
Oppolzer’s procedure52,53,73,74 was used to generate (E)-
vinylzinc intermediates. Thus alkyne hydroboration with Et2BH
and B to Zn transmetalation with Et2Zn in dichloromethane was
followed by addition of TBS- or TES-protected (S)-R-hydroxy
propanal at 0 °C. In the absence of additional Lewis acid, Felkin
addition narrowly predominated (1.5:1 dr, Table 4, entry 1).
Mosher method.61,62 Substoichiometric EtZnX also afforded
chelation-controlled products, albeit with diminished diastereo-
selectivity (entries 4, 5, 8, 9, and 13). Ethyl addition to the
extremely bulky TIPS-protected aldehyde in the absence of
additional Lewis acid favored the expected Felkin addition
product (dr ) 2:1). Conducting the reaction in the presence of
1.5 equiv EtZnCl at -50 °C resulted in formation of the
chelation-controlled addition product with excellent diastereo-
selectivity (dr > 20:1, entry 14 vs 15). It is noteworthy that at
-50 °C no product was formed upon addition of Et2Zn to the
TBS-protected R-hydroxy propanal after 8 h, whereas the
identical reaction employing 1.5 equiv EtZnCl reached 65%
conversion in 16 min. A considerable increase in addition rate
would be expected if the reaction proceeded via a chelated
intermediate.19,20
The significant increase in the rate of reaction in the
presence of EtZnX can be compared with prior investigations
by Eliel and Frye.19-21 Using dimethylmagnesium in THF
at -70 °C, the methylation of silyl protected 3-hydroxy-2-
butanone was performed. With smaller protecting groups,
such as TMS, very high diastereoselectivities were observed
favoring the chelation-controlled product (Table 2, entry 1,
dr ) 99:1). As the size of the protecting group was increased,
the dr steadily diminished.20 Ultimately, with the TIPS
protecting group, the Felkin addition product predominated
(entry 5, 58:42) and the reaction was proposed to occur by
monodentate activation of the ketone carbonyl. These authors
observed a rate acceleration with the TMS protected substrate,
which was around 2 orders of magnitude faster than the TIPS
derivative and a model ketone devoid of the R-silyloxy group
(propiophenone). Although the results in this mechanistic
study are conceptually related to chemistry reported herein,
the scope was limited to MgMe2 and protected chiral
R-hydroxy propiophenones. Reetz also observed chelation-
controlled addition to TBS-protected 2-hydroxy-3-pentanone
with MeTiCl3 with dr’s as high as 85:15.22
(64) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956–
1958.
(65) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel,
P. J. Org. Chem. 1996, 61, 8229–8243.
(66) Knochel, P.; Jones, P. Organozinc Reagents; Oxford University Press:
Oxford, U.K., 1999.
We next explored the substrate scope of the addition with
respect to the other dialkylzinc reagents. Due to the rapid alkyl
exchange between alkylzinc species, it was necessary that the
R groups on ZnR2 and RZnX be identical to avoid a mixture of
products.63 Additions of Me2Zn and (n-Bu)2Zn in the presence
of MeZnCl and n-BuZnCl, respectively, exhibited diastereose-
lectivities g18:1 favoring the chelation-controlled products
(67) Oppolzer, W.; Schroder, F.; Kahl, S. HelV. Chim. Acta 1997, 80, 2047–
2057.
(68) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.;
Kozlowski, M. C. Tetrahedron 2005, 61, 6249–6265.
(69) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781–3784.
(70) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124,
12668–12669.
(71) Katsuki, T.; Martin, V. S. Org. React. 1996, 1.
(72) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307–
1370.
(61) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(73) Oppolzer, W.; Radinov, R. N.; Brabander, J. D. Tetrahedron Lett. 1995,
36, 2607–2610.
(62) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90, 3732–3738.
(63) Blake, A. J.; Shannon, J.; Stephens, J. C.; Woodward, S. Chem.sEur.
J. 2007, 13, 2462–2472.
(74) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org. Chem. 2001, 66,
4766–4770.
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4403

A R T I C L E S
Stanton et al.
Table 3. Determination of the Scope with Respect to Dialkylzinc Reagents and Aldehyde
3.3. Diastereoselective Additions of (Z)-Disubstituted
Vinylzinc Reagents to Silyl Protected r-Hydroxy Aldehydes.
As outlined in Scheme 2, we developed a method for the
diastereoselective addition of (Z)-vinylzinc reagents to alde-
hydes.44 An asymmetric version of this reaction was recently
introduced.51,55 In the addition to TBS protected R-hydroxy
propanal (Scheme 2), the dr was 4:1 in the absence of added
Lewis acid and increased to 8:1 in the presence of BF3 ·OEt2.
Both reactions favored the chelation-controlled addition products.
For the present study, we investigated the impact of EtZnCl
on the diastereoselective (Z)-vinylation of TBS protected
R-hydroxy aldehydes with the goal of increasing the diastereo-
selectivity of the addition and circumventing the use of the harsh
Lewis acid BF3. In our initial reports on the (Z)-vinylation of
aldehydes, the reactions were conducted in THF or TBME to
stabilize the polar intermediates.44 These solvents are not
compatible with the Lewis acids RZnX, because they effectively
After screening various addition temperatures, we found that
-30 °C provided a balance between EtZnCl solubility in
dichloromethane and suppression of the background addition
(Table 4, entry 1). As shown in Table 4, terminal alkynes were
successfully utilized to afford (E)-disubstituted allylic alcohols
with dr’s of 10:1 to >20:1, favoring the chelation-controlled
addition products (entries 2-6). Use of an enyne afforded the
syn-dienyl alcohol with >20:1 dr and 70% yield (entry 7).
Finally, the internal alkyne 4,4-dimethyl-2-pentyne enabled the
synthesis of (E)-trisubstituted allylic alcohols with >20:1 dr
using the TBS or TES protecting groups in g85% yield (entries
8 and 9).
For any method to be synthetically useful, scalability must
be demonstrated. When phenyl acetylene was employed on a 5
mmol scale, the allylic alcohol was obtained in 82% yield (dr
>20:1, entry 2). In each entry in Table 4 only a single double
1
bond isomer was observed by H NMR spectroscopy.
9
4404 J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010

Overriding Felkin Control
A R T I C L E S
Table 4. Diastereoselective Generation of (E)-Di- and Trisubstituted Allylic Alcohols and Dienyols
a dr determined by 1H NMR of the crude product and refers to the ratio of Cram-chelation:Felkin addition products. b Absolute configurations of
alcohols were determined by modified Mosher ester analysis. c The yield and dr correspond to the reaction without EtZnCl.
compete with the aldehyde substrate for the open coordination
sites on RZnX and nullify its impact on the diastereoselective
addition. Thus, the hydroboration 1-bromo-1-alkynes and ad-
dition of tert-butyllithium were conducted in THF solvent. The
volatiles were then removed under reduced pressure, toluene
was added, and the volatiles again evacuated to ensure that as
much THF as possible was removed. Fresh toluene was then
added followed by transmetalation, addition of EtZnCl (1.5
equiv) and the TBS protected aldehyde at -30 °C. After 12 h,
protected R-hydroxy propanal, dr’s were g14:1 favoring che-
lation-controlled addition products and the yields ranged from
72-90% (entries 1 and 3).
It is noteworthy that both the dr’s and yields were higher in
the (Z)-vinylations with EtZnCl (Table 5) than in the BF3
promoted reaction (Scheme 2). Use of the isopropyl-substituted
aldehyde resulted in higher diastereoselectivity than the propanal
derivative (compare entries 2 and 4). Although the greater
diastereoselectivity with the isopropyl-substituted aldehyde, with
respect to the methyl analog, is not proof of chelation control,
1
the reactions were quenched and the H NMR of the crude
material acquired to determine the dr. In the case of the TBS
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4405

A R T I C L E S
Stanton et al.
Table 5. Diastereoselective (Z)-Vinylation of R-Silyloxy Aldehydes in the Presence of EtZnCl
it is consistent with it. The question of substrate chelation with
EtZnCl is further explored in the next section.
oxygen was dominant (Table 6, entries 2 vs 3).20 The
decreasing binding strength can also be seen in comparison
of the R-CH-OSi shifts as the protecting group is varied
(entries 4-6). The observations in entries 2 vs 3 and 5 vs 6
are consistent with the relative rates of carbonyl additions
of MgMe2 to these aldehydes presented in Table 2.
3.4. NMR Binding Studies with EtZnCl and a Substrate
Model. Chelation-controlled additions to silyloxy aldehydes
or ketones are uncommon,57,19-25 and we are not aware of
any examples of chelation with the very bulky TIPS group.
The possibility of chelation of protected R-hydroxy aldehydes
and ketones to Lewis acids has been examined by NMR
spectroscopy6,8,75-78 and X-ray crystallography.79 Ketones
are usually preferred for these studies over aldehydes due to
their greater stability in the presence of Lewis acids. With
strong Lewis acids like MeTiCl3 and substrates with benzyl
protecting groups, Reetz observed tight κ2-binding of the
substrate to form a five membered chelate.75 In this case,
significant shifts were observed in the 13C NMR spectra of
the carbonyl and R-CH-OPG moiety (Table 6, entry 1). When
the substrate contained a bulky silyl protecting group,
however, binding was less favorable for steric and electronic
reasons. In these cases chelation may not be observed at all,
as ascertained by smaller chemical shift changes (∆′s, defined
as the change in chemical shift) of the CH bearing the
silyloxy group. As a model for the observed reactivity of
silyl protected R-hydroxy propiophenones with MgMe2, Eliel
and Frye20,21 examined the NMR shifts of a series of ketones
in the presence of the stronger Lewis acid MgBr2 in CD2Cl2.
They observed larger shifts in the R-CH-OSi than the R′-
CH’s in the 1H NMR spectra when chelation was predominant
and similar shifts when η1-coordination of the carbonyl
To indirectly probe the possibility of chelation of silyloxy
aldehydes to EtZnX, we employed TBS-protected 3-hydroxy
butanone as a substrate analogue, because it is more stable in
the presence of EtZnCl than the aldehyde substrates. The NMR
spectrum of TBS-protected 3-hydroxy butanone was recorded
in CD2Cl2 before and after combination with one equiv of
EtZnCl. A distinct downfield shift, ∆, of 0.34 ppm of the R-CH-
OSi was observed in the presence of one equiv EtZnCl (Table
6, entry 8). The R′-CH3 protons exhibited a smaller shift (∆ )
0.19 ppm). Another 0.38 ppm downfield shift for the R-CH-
OSi was measured upon addition of 3 more equiv of EtZnCl,
vs a 0.19 ppm shift for the R′-CH3 (entry 8). Significantly, a
downfield shift of 0.29 ppm was measured for the diastereotopic
Si(CH3)2 protons in the presence of 4 equiv of EtZnCl and the
single resonance for the diastereotopic SiMe2 groups in the free
ketone split into two resonances separated by 0.017 ppm (see
SI for spectra). With 4 equiv EtZnCl, the shifts in the 13C{1H}
NMR spectra for the R-CH-OSi and R′-CH3 resonances show
less pronounced differences (Table 6, entries 8 and 9). The larger
∆′s for the R-CH-OSi, relative to the R′-CH3 protons, in the 1H
NMR spectra of 1 + EtZnCl and the shift of the SiMe2
resonance are consistent with chelation of both oxygens of the
silyloxy ketone to EtZnCl. These results provide anecdotal
support that the additions to R-silyloxy aldehydes proceed via
a Cram-chelation mechanism. It is also noteworthy that smaller
shifts were observed with EtZnCl than MgBr2, consistent with
the lower Lewis acidity of EtZnCl (compare entries 5 and 7).
(75) Reetz, M. T.; Hullmann, M.; Seitz, T. Angew. Chem.-Int. Ed. Engl.
1987, 26, 477–479.
(76) Reetz, M. T.; Kesseler, K.; Schmidtberger, S.; Wenderoth, B.;
Steinbach, R. Angew. Chem., Int. Ed. 1983, 22, 989–990.
(77) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847–3849.
(78) Reetz, M. T.; Keꢀeler, K.; Schmidtberger, S.; Wenderoth, B.;
Steinbach, R. Angew. Chem. Suppl. 1983, 22, 1511–1526.
(79) Reetz, M. T.; Harms, K.; Reif, W. Tetrahedron Lett. 1988, 29, 5881–
5884.
9
4406 J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010

Overriding Felkin Control
A R T I C L E S
Table 6. 1H and 13C NMR Studies of Protected R-Hydroxy Ketones Binding to Lewis Acidsa
a NMR studies by Reetz (entry 1)75 and Eliel and Frye (entries 2-6),20 NA) Not applicable, NR) not reported, ∆ values reported in ppm. b Mixture
of two diastereomers formed. c Average of two diastereomers. d Minimum values, peaks not assigned in original report. m. e In CD2Cl2 solvent.
4. Summary and Outlook
case for Cram-chelation control can be made. The approach
described herein to chelation-controlled addition with substrates
that rarely chelate is counterintuitive. Typically stronger Lewis
acids are employed with weakly coordinating substrates to favor
binding. In our approach, however, it is the combination of a
weakLewisacidandweaktomoderateorganozincnucleophile80,81
that favors chelation control. We are currently extending this
strategy to related nucleophiles and electrophiles.
We have developed the first general and highly diastereose-
lectivity method for the chelation-controlled addition of orga-
nometallic reagents to R-silyloxy aldehydes. These substrates
normally provide Felkin addition products independent of the
Lewis acid employed. With introduction of this method it is no
longer necessary to switch protecting groups or add stoichio-
metric quantities of chiral auxiliaries to favor chelation-
controlled addition of organometallic nucleophiles to R-silyloxy
aldehydes. The generality of this procedure is demonstrated by
the highly diastereoselective additions of alkyl, functionalized
alkyl, and (E)-disubstituted, (E)-trisubstituted, and (Z)-disub-
stituted vinyl groups to a range of silyl protected R-hydroxy
aldehydes. These results, in combination with our recent studies
employing (Z)-trisubstituted vinylzinc additions to chiral alde-
hydes (Scheme 4), represent a powerful new method that is
tolerant of functionality and suitable for late stage use in
complex natural product synthesis.
1H NMR studies with a substrate analogue indicate that RZnX
chelates the carbonyl and O-silylated ether. These results provide
circumstantial support for chelation-controlled additions in the
presence of EtZnX Lewis acids. When combined with the
observed high levels of chelation control, the considerable rate
accelerations observed in the presence of RZnX, and higher
diastereoselectivities with iso-propyl substituted aldehydes
compared to their methyl substituted analogues, a compelling
5. Experimental Section
Representative procedures are described herein. Full experimental
details and characterization of all compounds are provided in the
Supporting Information.
General Methods. All reactions were performed under a nitrogen
atmosphere using oven-dried glassware and standard Schlenk or
vacuum line techniques. The progress of all reactions was monitored
by thin-layer chromatography. Toluene and dichloromethane were
dried through alumina columns. Chiral aldehydes were prepared
by literature method; Parrikh-Doering oxidation of the requisite
primary alcohol was performed just prior to carbonyl addition
reactions.82,83 Alkyl zinc halides were prepared by literature methods.60,84
Functionalized organozinc reagents were prepared from the corre-
sponding alkyl iodide or from the alkene via hydroboration as outlined
(80) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028–4036.
(81) Jeon, S. J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416–
16425.
9
J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010 4407

A R T I C L E S
Stanton et al.
in the literature procedures.64,65,85,86 All chemicals were obtained from
Acros, Sigma-Aldrich, or GFS Chemicals unless otherwise described.
The 1H NMR and 13C{1H} NMR spectra were obtained using a Bruker
AM-500 Fourier transform NMR spectrometer at 500 and 125 MHz,
respectively. Chemical shifts are reported in units of parts per million
(ppm) downfield from tetramethylsilane and all coupling constants are
reported in hertz. The infrared spectra were obtained using a Perkin-
Elmer 1600 series spectrometer. Thin-layer chromatography was
carried out on Whatman precoated silica gel 60 F-254 plates and
visualized by ultraviolet light or by staining with ceric ammonium
molybdate stain. Silica gel (230-400 mesh, Silicycle) was used for
air-flashed chromatography. Analysis of diastereomeric ratios was
performed by gas chromatography of TMS derivatives using a Hewlett-
Packard 6890 GC with a Beta-Dex Column or by1H NMR of the crude
reaction products. High resolution mass spectra were measured using
a Waters LCTOF- Xe Premier ESI mass spectrometer. Relative
stereochemistry was determined by modified Mosher ester analysis.87
Cautionary Note. Dialkylzinc reagents and tert-butyllithium are
pyrophoric. Extreme caution should be used in their handling and
proper laboratory attire is highly recommended.
General Dialkylzinc Procedure. General Procedure A. A dry
10 mL Schlenk flask, which was evacuated under vacuum and
backfilled with N2 three times, was charged with the alkyl zinc chloride
(0.35 mmol, neat solid), chiral aldehyde (0.35 mmol, neat), and toluene
(1 mL). The flask was then cooled to 0 °C, and dialkylzinc (0.42 mmol)
was added dropwise. The reaction mixture was gradually warmed to
room temperature and monitored by TLC until completion (usually
30 min). The reaction mixture was quenched with saturated aq. NH4Cl
(2 mL) followed by addition of 2 N HCl (1 mL) and Et2O (5 mL).
The organic layer was separated and the aqueous solution extracted
with EtOAc (3 × 10 mL). The combined organic layers were
successively washed with NaHCO3 and brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo and purified by column
chromatography on silica gel.
Additions to TIPS Protected Aldehyde. General Procedure
B. A dry 10 mL Schlenk flask, which was evacuated and backfilled
with N2 three times, was charged with the alkyl zinc chloride (0.35
mmol, neat solid), dialkylzinc (0.42 mmol), and toluene (1 mL).
The flask was then cooled to -50 °C followed by slow addition of
aldehyde solution (0.35 mmol, in 0.5 mL toluene). The reaction
was monitored by TLC until completion (usually 30 min). The
reaction mixture was quenched with saturated aq. NH4Cl (2 mL)
followed by addition of 2 N HCl (1 mL) and Et2O (5 mL). The
organic layer was separated and the aqueous solution extracted with
EtOAc (3 × 10 mL). The combined organic layers were succes-
sively washed with NaHCO3 and brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo and purified by
column chromatography on silica gel.
Functionalized Dialkylzinc Procedure. General Procedure
C. A dry 10 mL Schlenk flask, which was evacuated under vacuum
and backfilled with N2 three times, was charged with the functionalized
dialkylzinc reagent (0.94 mL, 1 M in degassed CH2Cl2). The flask
was cooled to -78 °C and trifluoromethanesulfonic acid (50 µL, 0.52
mmol) was added dropwise.67 The flask was slowly warmed to room
temperature and stirred for 45 min. The flask was the cooled to 0 °C
and the aldehyde solution (0.35 mmol, in 0.3 mL degassed CH2Cl2)
was added dropwise. The reaction was monitored by TLC until
complete. The reaction mixture was quenched with saturated aq. NH4Cl
(2 mL) followed by addition of 2 N HCl (1 mL) and Et2O (5 mL).
The organic layer was separated and the aqueous solution extracted
with Et2O (3 × 10 mL). The combined organic layers were succes-
sively washed with NaHCO3 and brine, dried over MgSO4, and filtered.
The filtrate was concentrated in vacuo and purified by column
chromatography on silica gel.
(E)-Di- and Trisubstituted Allylic Alcohol Procedure.
General Procedure D. A dry 10 mL Schlenk flask, which was
evacuated under vacuum and backfilled with N2 three times, was
charged with diethylborane (Et2BH) (1 mL, 1 M in toluene) and
dichloromethane (1 mL). The solution was cooled to 0 °C followed
by slow addition of alkyne (1 mmol). After 5 min the reaction was
warmed to room temperature and stirred for an additional 15 min.
The solution was cool to -78 °C and dimethylzinc (0.6 mL, 2 M
in toluene) was added. After stirring at -78 °C for 30 min, the
reaction flask was warmed to -30 °C and EtZnCl (1.25 mmol)
was added under a steady flow of N2. Immediately thereafter, the
aldehyde (0.833 mmol) was added neat. The reaction mixture stirred
at -30 °C and was monitored by TLC until completion (usually
1 h). The reaction mixture was quenched with saturated aq. NH4Cl
(2 mL) and 2 N HCL (1 mL) and 5 mL Et2O was added. The
organic layer was separated, and the aqueous layer was extracted
successively with Et2O (2 × 5 mL). The combined organic layers
were successively washed with NaHCO3 and brine, dried over
MgSO4, and filtered. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel.
General Procedure for (Z)-Disubstituted Allylic Alcohols.
General Procedure E. A dry 10 mL Schlenk flask, which was
evacuated under vacuum and backfilled with N2 three times, was
charged with diethylborane (0.42 mL, 1 M toluene) and 1 mL dry
THF. After cooling the flask to 0 °C, the bromoalkyne (0.42 mmol)
was added dropwise and the flask was stirred at room temperature
for 20 min. t-BuLi (0.25 mL, 1.7 M in pentanes) was added to the
flask at -78 °C and stirred for 35 min, warmed to room temperature
and stirred for an additional 40 min. The volatiles were then
removed under vacuum over 30 min and the residue redissolved in
toluene (1 mL). Dimethylzinc was slowly added to the reaction
mixture at -78 °C and stirred for 30 min. The EtZnCl (67 mg,
0.52 mmol) was then added followed by the aldehyde solution (0.35
mmol, in 0.2 mL toluene). The reaction mixture stirred at -30 °C
and was monitored by TLC until complete. The reaction mixture
was quenched with saturated aq. NH4Cl (2 mL) and 2 N HCL (1
mL) and 5 mL Et2O was added. The organic layer was separated
and the aqueous layer was extracted successively with Et2O (2 ×
5 mL). The combined organic layers were successively washed with
NaHCO3 and brine, dried over MgSO4, and filtered. The filtrate
was concentrated in vacuo and purified by column chromatography
on silica gel.
Acknowledgment. This manuscript is dedicated to Prof. Masakat-
su Shibasaki on the occasion of his retirement from the University of
Tokyo. We thank the NSF (CHE-065210 and 0848467) and NIH
(National Institute of General Medical Sciences GM58101) for partial
support of this work. We are grateful to Profs. Marisa Kozlowski
(University of Pennsylvania) and David Evans (Harvard) for helpful
discussions. G.R.S. thanks the UNFC Merck and NOBCChE/Glaxo-
SmithKline programs for graduate scholarships. We would like to thank
the NIH for the purchase of a Waters LCTOF-Xe Premier ESI mass
spectrometer (Grant No. 1S10RR23444-1).
(82) Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128,
9433–9441.
(83) Ji, N.; O’Dowd, H.; Rosen, B. M.; Myers, A. G. J. Am. Chem. Soc.
2006, 128, 14825–14827.
(84) Guerrero, A.; Hughes, D. L.; Bochmann, M. Organometallics 2006,
25, 1525–1527.
Supporting Information Available: Procedures and full
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(85) Rozema, M. J.; Eisenberg, C.; Lu¨tjens, H.; Ostwald, R.; Belyk, K.;
Knochel, P. Tetrahedron Lett. 1993, 34, 3115–3118.
(86) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35, 9007–9010.
(87) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451–
2458.
JA910717P
9
4408 J. AM. CHEM. SOC. VOL. 132, NO. 12, 2010