Diastereoselective chelation-controlled additions to β-silyloxy aldehydes

Article abstract of DOI:10.1021/ol301354w

A general diastereoselective method for the addition of dialkylzincs and (E)-di- and (E)-trisubstituted vinylzinc reagents to β-silyloxy aldehydes is presented. This method employs alkyl zinc triflate and nonaflate Lewis acids and affords chelation-controlled products (6:1 to > 20:1 dr).

Full text of DOI:10.1021/ol301354w

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3368–3371
Diastereoselective Chelation-Controlled
Additions to β-Silyloxy Aldehydes
Gretchen R. Stanton, Meara C. Kauffman, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, University of Pennsylvania, Department of
Chemistry, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323,
United States
pwaslsh@sas.upenn.edu
Received May 16, 2012
ABSTRACT
A general diastereoselective method for the addition of dialkylzincs and (E)-di- and (E)-trisubstituted vinylzinc reagents to β-silyloxy aldehydes is
presented. This method employs alkyl zinc triflate and nonaflate Lewis acids and affords chelation-controlled products (6:1 to > 20:1 dr).
The traditional approach to complex molecule synthesis
is to utilize existing substrate stereogenic centers to influ-
ence the introduction of new stereocenters.1 In particular,
this strategy has proven useful in the addition of
organometallic reagents to protected R- and β-hydroxy
aldehydes and ketones to afford diol moieties. For quite
some time, the paradigm that rationalizes the stereoche-
mical outcomes of these additions has encompassed the
FelkinÀAnh,2 CornforthÀEvans,3 and Cram-chelation4
models.5 According to these models, stereoinduction in
such additions is dependent on the size of the protecting
group.6 Sterically undemanding protecting groups such as
Me, Bn, and MOM promote chelation (Figure 1, Cram-
chelation model).7 In contrast, bulky silyl protecting
groups disfavor chelation and give Felkin addition products
(Figure 1). One major shortcoming in the application of
this paradigm is that the protecting group is chosen to
afford the desired stereochemistry during the carbonyl
addition step and may not be best suited for the global
protecting group strategy. To override substrate control,
chemists have utilized chiral catalysts,8 enantioenriched
stoichiometric auxiliaries, and optically active stoichio-
metric additives.9 Our approach is to develop methods
to reverse the diastereoselectivity predicted by the
(1) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
Wiley: New York, 1989. (b) Koskinen, A. Asymmetric Synthesis of Natural
Products; Wiley: Chichester, NY, 1993. (c) Hoveyda, A. H.; Evans, D. A.;
Fu, G. C. Chem. Rev. 1993, 93, 1307–1370. (d) Nicolaou, K. C.; Sorensen,
E. J. Classics in Total Synthesis; VCH: Weinheim, Germany, 1996. (e)
Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II: More Targets,
Strategies, Methods; Wiley-VCH: Weinheim, Germany, 2003. (f) Carreira,
E. M.; Kvaerno, L. Classics in Stereoselective Synthesis; Wiley-VCH:
Weinheim, Germany, 2009.
ꢀ
(2) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
ꢀ
2199–2204. (b) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205–
2208. (c) Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 17, 155–158.
(d) Anh, N.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61–70. (e) Anh, N. T.
Top. Curr. Chem. 1980, 88, 145–162.
(3) (a) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem.
Soc. 1959, 112–127. (b) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew.
Chem., Int. Ed. 2003, 42, 1761–1765. (c) Cee, V. J.; Cramer, C. J.; Evans,
D. A. J. Am. Chem. Soc. 2006, 128, 2920–2930.
(4) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74,
5828–5835. (b) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748–2755. (c) Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90,
4019–4026.
(5) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1224.
(6) (a) Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982, 23,
2355–2358. (b) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem.
1986, 51, 5478–5480. (c) Kahn, S. D.; Keck, G. E.; Hehre, W. J.
Tetrahedron Lett. 1987, 28, 279–280. (d) Keck, G. E.; Castellino, S.
Tetrahedron Lett. 1987, 28, 281–284. (e) Keck, G. E.; Andrus, M. B.;
Castellino, S. J. Am. Chem. Soc. 1989, 111, 8136–8141. (f) Reetz, M. T.;
Huellmann, M. J. Chem. Soc., Chem. Commun. 1986, 1600–1602. (g)
Frye, S. V.; Eliel, E. L. Tetrahedron Lett. 1986, 27, 3223–3226. (h) Frye,
S. V.; Eliel, E. L. J. Am. Chem. Soc. 1988, 110, 484–489.
(7) (a) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847–
3849. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462–468. (c) Evans,
D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem. Soc. 2001,
123, 10840–10852.
(8) (a) Soai, K.; Hatanaka, T.; Yamashita, T. J. Chem. Soc., Chem.
Commun. 1992, 927–929. (b) Watanabe, M.; Komota, M.; Nishimura,
M.; Araki, S.; Butsugan, Y. J. Chem. Soc., Perkin Trans. 1 1993, 2193–
2196. (c) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729–
1732. (d) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: Sausalito, CA, 2008.
€
r
10.1021/ol301354w
Published on Web 06/21/2012
2012 American Chemical Society

aforementioned paradigm through introduction of Lewis
acids capable of chelating substrates that normally under-
go Felkin addition.
allylation of aldehyde ent-1 using allyltrichlorostannane
(Scheme 1c).13
Scheme 1. Previous Examples of β-Chelation to β-Silyloxy
Aldehydes
Figure 1. Models for 1,2-asymmetric induction for protected R-
methyl β-hydroxy aldehydes.
To date, few exceptions to the current stereoinduction
models have been reported.6f,7c,10 In particular, there are
limited examples of methods to promote chelation in
additions to β-silyloxy aldehydes and ketones. Evans and
co-workers have demonstrated the remarkable ability of
Me2AlCl and MeAlCl2 to chelate β-silyloxy aldehydes in
Mukaiyama aldol reactions.7c As shown in Scheme 1a, the
active Lewis acid results from the disproportionation of
MeAlCl2. Somfai and co-workers have disclosed interest-
ing studies to elucidate the origin of reversed diastereos-
electivity of Mukaiyama aldol additions to R-silyloxy and
chloro aldehydes.11 En route to developing methods for
the in situ generation of (Z)-vinylzinc reagents, our group
observed unexpected chelation-controlled additions to
β-silyloxy aldehydes in the presence of ZnBr2, albeit in
modest selectivity (Scheme 1b).12 In efforts toward the
synthesis of mycolactone polyketides, Burkart observed
high selectivity for the chelation-controlled product in the
More recently, wehaveshown that alkyl zinc halidesand
triflates are viable Lewis acids to chelate R-silyloxy alde-
hydes and ketones toenablechelation-controlled additions
to these substrates.14 Given the high levels of diastereos-
electivity of these reactions and their generality, we set out
to determine whether highly diastereoselective additions of
organozinc reagents to β-silyloxy aldehydes could be
achieved. We perceived this to be a challenge considering
that R-chelation is more favorable than β-chelation and
usually furnishes a product of higher dr.15 Furthermore,
general chelation-controlled additions of organometallic
reagents to β-silyloxy aldehydes are unknown.
Initially, we investigated the reaction of diethylzinc with
aldehyde 1. Interestingly, in the absence of EtZnX Lewis
acids, the reaction of diethylzinc (1.2 equiv) with (R)-3-
TBS-2-methylpropanal 1 provided the chelation con-
trolled product with 3.5:1 dr in <10% yield (Table 1,
entry 1). The absolute stereochemistry of the major dia-
stereomer was ascertained through comparison to litera-
ture data16 and confirmed by modified Mosher ester
analysis.17 To achieve synthetically useful diastereoselec-
tivities and yields, Lewis acids that could chelate the
substrates were utilized. Additions employing 25À150 mol %
(9) (a) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348–6359. (b) El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017–3020. (c) Marshall, J. A.; Bourbeau, M. P. Org.
Lett. 2003, 5, 3197–3199. (d) Marshall, J. A.; Eidam, P. Org. Lett. 2004,
ꢀ
6, 445–448. (e) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudre-
chy, A. Chem. Rev. 2006, 106, 2355–2403. (f) 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. (g) Rodriguez-Escrich, C.; Olivella,
A.; Urpi, F.; Vilarrasa, J. Org. Lett. 2007, 9, 989–992. (h) Kolakowski,
R. V.; Williams, L. J. Tetrahedron Lett. 2007, 48, 4761–4764. (i) Sharon,
O.; Monti, C.; Gennari, C. Tetrahedron 2007, 63, 5873–5878. (j)
Georges, Y.; Ariza, X.; Garcia, J. J. Org. Chem. 2009, 74, 2008–2012.
(10) (a) Frye, S. V.; Eliel, E. L.; Cloux, R. J. Am. Chem. Soc. 1987,
109, 1862–1863. (b) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J.
Am. Chem. Soc. 1990, 112, 6130–6131. (c) Chen, X.; Hortelano, E. R.;
Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114, 1778–1784. (d)
Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett. 1999, 40,
4457–4460. (e) Mohanta, P. K.; Davis, T. A.; Gooch, J. R.; Flowers,
R. A., II. J. Am. Chem. Soc. 2005, 127, 11896–11897.
(13) (a) Ko, K.-S.; Alexander, M. D.; Fontaine, S. D.; Biggs-Houck,
J. E.; La Clair, J. J.; Burkart, M. D. Org. Biomol. Chem. 2010, 8, 5159–
5165. (b) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883–
1886.
(14) (a) Kerrigan, M. H.; Jeon, S.-J.; Chen, Y. K.; Salvi, L.; Carroll,
P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 8434–8445. (b) Stanton,
G. R.; Johnson, C. N.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132, 4399–
4408. (c) Stanton, G. R.; Koz, G.; Walsh, P. J. J. Am. Chem. Soc. 2011,
133, 7969–7976.
(15) Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry:
Part A: Structure and Mechanisms, 5th ed.; Springer: New York, 2007;
p 179.
(11) (a) Borg, T.; Danielsson, J.; Somfai, P. Chem. Commun. 2010, 46,
1281–1283. (b) Borg, T.; Danielsson, J.; Mohiti, M.; Restorp, P.; Somfai,
P. Adv. Synth. Catal. 2011, 353, 2022–2036.
(12) Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2006, 128, 9618–9619.
(16) Pilli, R. A.; Riatto, V. B. J. Braz. Chem. Soc. 1999, 10, 363–368.
(17) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90, 3732–
3738. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096. (c) Hoye, T. R.; Jeffrey, C. S.; Shao, F.
Nat. Protoc. 2007, 2, 2451–2458.
Org. Lett., Vol. 14, No. 13, 2012
3369

Table 1. Optimization of Diethylzinc Addition to 1
Scheme 2. Chelation-Controlled Addition of Dialkylzincs to 1
required due to the facile formation of a reduction side
product via a β-hydride reduction mechanism.19
Chiral allylic alcohols are important structural motifs
that are commonly used as key intermediates in synthesis
and are found in many natural products.1c,20 To broaden
the substrate scope of our method, we studied the addition
of (E)-vinylzinc reagents to silyl-protected β-hydroxy
a Concentration is with respect to the aldehyde. b mol % of Lewis acid
is with respect to the aldehyde. c dr determined by 1H NMR of the
unpurified product or by GC analysis of the TMS-protected product
derivatives and refers to the ratio of chelation/Felkin addition products.
d Refers to yield of isolated, purified product.
Table 2. Generation of (E)-Di- and Trisubstituted Allylic Alcohols
of EtZnCl led to chelation-controlled products with slightly
improved dr (entries 2À5). Lowering the temperature did
not improve the diastereoselectivity of the reaction (entries
6 and 7). Furthermore, increasing the concentration of the
reaction afforded the addition product in 89% yield with
8.9:1 dr (entry 8). Encouraged by these results, we next
surveyed other zinc Lewis acids (entries 9À12). Employing
either EtZnOTf or EtZnONf gave the expected addition
product with 15.5:1 and 10:1 dr, respectively (entries 10
and 11). These Lewis acids can be prepared simply by
reaction of the dialkylzinc with the sulfonic acid at low
temperature.18
The optimized reaction conditions in Table 1 (entry 10)
were applied to the addition of other dialkylzincs to
aldehyde 1. It is important to note that R groups on the
dialkylzinc and Lewis acid must be the same due to
expeditious alkyl exchange. As shown in Scheme 2, the
addition of dimethylzinc to afford 3 was less selective
(dr = 5:1) and can be attributed to the smaller size of the
nucleophile, resulting in a reduced energy difference between
the transition states leading to the chelation or Felkin
addition products. Additionally, MeZnOTf has limited
solubility in dichloromethane. Addition of di-n-butylzinc
to aldehyde 1 occurred to give 4 with comparable dr to
diethylzinc (16:1). An excess of di-n-butylzinc (3 equiv) was
(18) Oppolzer, W.; Schroder, F.; Kahl, S. Helv. Chim. Acta 1997, 80,
2047–2057.
(19) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781–
3784. (b) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002,
124, 12668–12669. (c) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.;
Annamalai, V.; Kozlowski, M. C. Tetrahedron 2005, 61, 6249–6265.
a dr determined by 1H NMR of the unpurified product and refers to
the ratio of chelation/Felkin addition products. b The relative stereo-
chemistry was determined by modified Mosher ester analysis (see
Supporting Information).
3370
Org. Lett., Vol. 14, No. 13, 2012

aldehydes. The (E)-vinylzinc reagents were generated
in situ using the Srebnik/Oppolzer procedure.21 Hydro-
boration of alkynes and subsequent B to Zn transmetalation
with Et2Zn gave the (E)-vinylzinc intermediates. These
vinylzinc reagents were then added to β-silyloxy aldehydes
in the presence of EtZnX Lewis acids. It is well precedented
that vinyl- and arylzinc reagents add to aldehydes signifi-
cantly faster that alkylzinc reagents.22
After extensive screening, we found that optimal yields
and diastereoselectivities were achieved at À15 °C in 1:1
toluene to dichloromethane solvent. Similar to the addi-
tion of dialkylzincs, initially EtZnOTf proved to be the
most effective Lewis acid, providing the chelation-con-
trolled addition product with moderate to good dr (Table 2).
However, employing EtZnONf further improved the
diastereoselectivity of the reaction. For example, a 2-fold
increase in the dr of product 5 is seen in entry 1 when
EtZnONf is used compared to the same reaction using
EtZnOTf (dr = 10:1 vs 4.8:1). It is conceivable that this
improved diastereoselectivity is due to the greater solubi-
lity of EtZnONf in dichloromethane at low temperature.
As shown in Table 2, a variety of terminal alkynes can be
employed in the reaction with 1.5 equiv of EtZnONf and
both TBS or TES-protected 3-hydroxy-2-methylproponal.
The (E)-disubstituted allylic alcohol products were furn-
ished with g 5.8:1 dr and 61À80% yield (entries 1À3 and
6À8). Lower yields were observed in some cases owing to
the formation of ethyl addition byproducts (entries 2 and 8
using EtZnOTf). Furthermore, when internal alkynes were
utilized in the reaction, (E)-trisubstituted allylic alcohols
were generated with g 17:1 dr (entries 4, 5, and 9).
Reactions with less sterically hindered TES-protected 3-
hydroxy-2-methylproponal generally yielded products
with higher dr, most likely due to more favorable chelate
formation.
In summary, chelation-controlled addition of organo-
zinc reagents to TBS and TES-protected β-hydroxy alde-
hydes can be accomplished in the presence of EtZnOTf or
EtZnONf. Our method represents an alternative approach
to the use of stoichiometric amounts of chiral auxiliaries to
reverse the diastereoselectivity in additions of organome-
tallic reagents to R-chiral β-silyloxy aldehydes.
Acknowledgment. We thank the NSF (CHE-0848467
and 1152488). We are also grateful to Prof. Marisa
Kozlowski (University of Pennsylvania) for helpful discus-
sions. G.R.S. thanks the UNCFÀMerck and NOBCChE/
GlaxoSmithKline programs, ACS Organic Division, and
Amgen for graduate scholarships. We would also like to thank
the NIH for the purchase of a Waters LCTOF-Xe Premier
ESI mass spectrometer (Grant No. 1S10RR23444-1).
(20) Katsuki, T.; Martin, V. S. In Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, 1996; Vol. 48, pp 1À300.
(21) (a) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449–2452. (b)
Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170–173. (c)
Oppolzer, W.; Radinov, R. N.; Brabander, J. D. Tetrahedron Lett. 1995,
36, 2607–2610. (d) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org.
Chem. 2001, 66, 4766–4770.
Supporting Information Available. Experimental pro-
cedures and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N.
Angew. Chem., Int. Ed. 2001, 40, 3285–3308. (b) Rudolph, J.; Rasmus-
sen, T.; Bolm, C.; Norrby, P.-O. Angew. Chem., Int. Ed. 2003, 42, 3002–
3005. (c) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
Rev. 2006, 35, 454–470. (d) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am.
Chem. Soc. 2005, 127, 1548–1552.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3371