Enantioselective allylation and crotylation of in situ generated β,γ-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0031-1289565

β,γ-Unsaturated aldehydes generated in situ by treatment of 2-vinyloxiranes with a catalytic amount of Sc(OTf)₃ are effectively trapped by ring-strained allyl- and crotylsilane reagents to afford bishomoallylic alcohols as single diastereomers in high enantiomeric excess. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289565

LETTER
2857
Enantioselective Allylation and Crotylation of in situ Generated
b,g-Unsaturated Aldehydes
E
nantiosel
.
e
ctive Allyla
A
tion and Crotylati
d
on of
b
,
g
-U
n
a
saturatedA
m
ldehydes McCubbin, Matthew L. Maddess, Mark Lautens*
Department of Chemistry, University of Toronto, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9468185; E-mail: mlautens@chem.utoronto.ca
Received 11 August 2011
diisopinocampheylborane9 does not directly afford the re-
active nucleophile but rather results in the formation of an
‘ate’ complex which must be subsequently decomposed
with 1.33 equivalents of BF3·OEt2.10 The resulting crotyl-
dialkylborane is then immediately used in reaction with
various electrophiles. Although (E)-2 [and (Z)-2] are con-
figurationally stable below –45 °C,7d borotropic rear-
rangement occurs at higher temperatures precluding
isolation of these compounds. The additional additives
imparted from the metalation of 2-butene (K+ and Li+
ions) and necessary decomposition of the intervening
‘ate’ complex proved to be incompatible with the sensi-
tive rearrangement sequence required of the 2-vinyl-
oxiranes. Control experiments with allylB(Ipc)2
demonstrated that the large excess of BF3·OEt2 was not
the culprit,11 and it is likely that the large amount of meth-
oxide present is the principle cause. We speculated that a
less Lewis basic counterion than methoxide might avoid
the formation of that ‘ate’ complex and negate the neces-
sity of adding BF3·OEt2. To this end we prepared
TfOB(Ipc)212 and tested its ability to act as a substitute for
MeOB(Ipc)2 (Scheme 1). With the model vinyl oxirane 6a
we were pleased to observe the formation of a single dia-
stereomer of the desired bishomoallylic alcohol 7a in high
enantiomeric excess. Unfortunately, the yield was low,
and most probably is due to over-addition of the highly
nucleophilic anion of metalated 2-butene to the boron cen-
ter forming an unreactive ate complex [(crotyl)2B(Ipc)2]–.13
We were unable to improve the yield by modification of
the order of addition of reagents or by changing the nature
of the leaving group. Consequently, we were forced to
consider the application of other nucleophilic species.
Abstract: b,g-Unsaturated aldehydes generated in situ by treatment
of 2-vinyloxiranes with a catalytic amount of Sc(OTf)3 are effec-
tively trapped by ring-strained allyl- and crotylsilane reagents to af-
ford bishomoallylic alcohols as single diastereomers in high
enantiomeric excess.
Key words: vinyloxiranes, enantioselective crotylation, silanes,
Lewis acid catalysis, rearrangement reaction
The in situ generation of unstable intermediates and their
subsequent conversion to diversified products has been a
useful strategy for the preparation of compounds that are
difficult to prepare by other means. For example, b,g-un-
saturated aldehydes have rarely been used1 as building
blocks in synthetic organic chemistry due to their very
low stability with respect to olefin isomerization.2 They
can, however, be generated in solution by treatment with
an appropriate Lewis acid (LA).3,4 In recent years we have
been interested in exploiting this rearrangement by the ap-
plication of a variety of nucleophilic traps.5 We were par-
6
ticularly pleased to observe that use of allylB(Ipc)2 (1,
Figure 1) gave enantiomerically enriched bishomoallylic
alcohols in high yield with exceptional selectivity and
good substrate scope.5b
4-BrC6H4
R1
R1
N
B
R2
Si
R2
Cl
N
4-BrC6H4
1: R1 = R2 = H
3: R1 = R2 = H
(E)-2: R1 = H, R2 = Me
(Z)-2: R1 = Me, R2 = H
(E)-4: R1 = H, R2 = Me
(Z)-4: R1 = Me, R2 = H
O
1) Ph
Figure 1 Reagents for asymmetric allylation and crotylation
1) KOt-Bu, n-BuLi
THF, –78 °C
6a
With this result in hand, it seemed that effecting asymmet-
ric crotylation would be a relatively simple extension,
since the corresponding (E)- and (Z)-crotylB(Ipc)2 [(E)-2
and (Z)-2, respectively] derivatives are well known.7 Un-
fortunately, this was not the case and the difficulty lay in
the required protocol for their preparation.7c The addition
of metalated (E)- or (Z)-2-butene8 to B-methoxy-
(Z)-2
Ph
2) TfOB(Ipc)2
Sc(OTf)3 (cat.)
OH
2) NaOH, H2O2
(R,R)-7a
15%
dr > 99:1, ee = 93%
Scheme 1 Enantioselective crotylation
Since the seminal report by Hoffmann14 over two decades
ago, many classes of allylic organometallic reagents15
have been developed to prepare nonracemic homoallylic
alcohols. Of these we selected the recently developed al-
lyl- (3) and crotylsilane reagents [(E)-4 and (Z)-4] as they
SYNLETT 2011, No. 19, pp 2857–2861
x
x
.x
x
.2
0
1
1
Advanced online publication: 31.10.2011
DOI: 10.1055/s-0031-1289565; Art ID: S07811ST
© Georg Thieme Verlag Stuttgart · New York

2858
J. A. McCubbin et al.
LETTER
most closely satisfied our perceived requirements Attempts to lower the reaction temperature resulted in sig-
(Figure 1).15c–h Namely, the reagent must be isolable, pre- nificantly decreased enantioselectivity (Table 1, entry 4),
pared as either antipode, nonbasic, nonnucleophilic in the an effect that was observed previously with 3.15f Using ei-
absence of a carbonyl species, compatible with Lewis ac- ther THF or toluene as the solvent resulted in decreased
ids, and afford products in predictable high diastereo- yield and enantioselectivity of the reaction.
selectivity and enantioselectivity.
Optimization of the crotylation reaction using 6b was lim-
Conditions for the rearrangement–allylation sequence ited to solvent effects, and the mode of addition was the
with Leighton’s allylating reagent 3 were briefly surveyed same as for allylation. The use of CH2Cl2 afforded the
(Table 1). Combining the conditions established for the products (R,S)- and (R,R)-7b in moderate yield and good
racemic5a and enantioselective5b allylation of in situ gen- ee, employing (E)- and (Z)-13, respectively (Table 1, en-
erated b,g-unsaturated aldehydes with those used for tries 7 and 10). Surprisingly, when the conditions used for
Leighton allylation of conventional aldehydes,15f imposed allylation were applied to the crotylation reaction
significant limitations on the conditions (LA, solvent, and (Table 1, entries 8 and 11), a large decrease in both yield
temperature) that could be used for our purposes with a and enantioselectivity was observed. However, we were
reasonable chance of success. With some experimenta- pleased to find that by using toluene as the solvent
tion, we found that slow addition of a solution of the vinyl (Table 1, entries 9 and 12), both the enantioselectivity and
oxirane 6b (over 3 h) to a cooled solution of the LA and 3 yields of the products (R,S)- and (R,R)-7b were improved.
was the best method to limit byproduct formation.
With optimal conditions in hand, we began studies on the
scope of the allylation reaction (Table 2). Better results, in
terms of both enantioselectivity and yield, were obtained
for electron-neutral substrates (e.g., 6b) than for electron-
Table 1 Optimization of Reaction Conditions
O
Ph
Lewis acid
(10 mol%)
rich (6c) or electron-poor (6d) ones (Table 2, cf. entry 1
and entries 2 and 3). Sterically hindered substrates 6e and
6f (Table 2, entries 4 and 5) also performed well under
these conditions. Allylation of aliphatic vinyloxiranes 6g
and 6h afforded products (S)-8g and (S)-8h, respectively,
in high ee, but with slightly decreased yields as compared
to the aromatic substrates. In most cases, the yields and
enantioselectivites obtained with vinyloxiranes 6 are
comparable to those observed in the allylation of conven-
tional aldehydes with 3.15f As compared to the previously
reported Brown allylation of vinyloxiranes 6,5b the enan-
tioselectivities observed for the Leighton allylation are in
some cases slightly diminished and the yields are some-
what lower for most examples. A notable exception to
these trends is the result for 6e (Table 2, entry 4), a sub-
strate that failed completely using the Brown protocol.5b
Significantly, this demonstrates the complimentarity of
these methods, and we have shown that the product (S)-8e
of this reaction has high synthetic utility in the preparation
of complex structures.17
R5 R6
6b
+
Ph
solvent, temp
3 or (E)-4 or (Z)-4
OH
(S)-8b: R5 = R6 = H
(R,S)-7b: R5 = Me, R6 = H
(R,R)-7b: R5 = H, R6 = Me
Entry Conditions
Product
Yield (%)a ee (%)b
1
2
3, BF3·OEt2, CH2Cl2, 0 °C
3, Sc(OTf)3, CH2Cl2, 0 °C
3, Sc(OTf)3, Et2O, 0 °C
3, Sc(OTf)3, Et2O, –10 °C
3, Sc(OTf)3, THF, 0 °C
3, Sc(OTf)3, PhMe, 0 °C
(E)-4, CH2Cl2, 0 °C
(E)-4, Et2O, 0 °C
(S)-8b
0c
45
–
(S)-8b
85
96
86
64
81
92
62
89
82
82
86
3
(S)-8b
72
67
62
21
51
12
51
4
(S)-8b
5
(S)-8b
6
(S)-8b
7
(R,S)-7b
(R,S)-7b
(R,S)-7b
8
Using the protocol developed for the enantioselective cro-
tylation of 6b (Table 1), we began expanding the scope of
the reaction (Table 3). There did not appear to be a signif-
icant difference in yield or enantioselectivity obtained
with (E)- and (Z)-4, and in all cases diastereoselectivity
was in excess of 19:1. The yields in all cases were modest,
but the enantioselectivities ranged from good to excellent.
In contrast to the allylation reaction, aromatic substrates
bearing electron-withdrawing substituents (6d and 6e) af-
forded the products in somewhat higher ee (Table 3, en-
tries 5–8) than those with electron-donating or electron-
neutral substituents (Table 3, entries 1–4), but with slight-
ly decreased yields.
9
(E)-4, PhMe, 0 °C
10
11
12
(Z)-4, CH2Cl2, 0 °C
(R,R)-7b 39
(R,R)-7b 19
(R,R)-7b 58
(Z)-4, Et2O, 0 °C
(Z)-4, PhMe, 0 °C
a Isolated yields.
b The ee were determined by CSP-HPLC.
c Complete decomposition of starting materials.
In an early experiment, we found the reagent 3 to be in-
compatible with BF3·OEt2 (Table 1, entry 1), however, the
use of Sc(OTf)3, another optimal LA for the rearrange-
ment reaction,5 gave more promising results (Table 1, en- Sterically hindered substrates (e.g., 6f) faired relatively
try 2).16 The best results, in terms of both yield and ee well in both of these aspects (Table 3, entries 9 and 10),
were obtained with Et2O as the solvent (Table 1, entry 3). although the diastereoselectivities (with respect to the
Synlett 2011, No. 19, 2857–2861 © Thieme Stuttgart · New York

LETTER
Enantioselective Allylation and Crotylation of b,g-Unsaturated Aldehydes
2859
Table 2 Allylation Scope18
come with the use of Leighton’s crotylating reagents in
complete diasteroselectivity, good to excellent enantio-
selectivity, and moderate to good yield in most cases. The
products resulting from the crotylation reaction afford
useful products with substitution patterns that would be
difficult to achieve by other means.
Sc(OTf)3
(10 mol%)
R3
OH
R3
O
R1
R1
+
3
Et2O, 0 °C
R2
R4
R2
R4
6
(S)-8
Entry 6
8
Yield ee
(%) (%)
Table 3 Crotylation Scope19
R3
O
R1
O
Ph
1
73 96
Ph
OH
R2
R4
R2
R4
R5 R6
6b
6c
Sc(OTf)3
(10 mol%)
(S)-8b
6
O
O
+
R1
toluene, 0 °C
(E)-4 or (Z)-4
R3
OH
2
61 90
OH
(R,S)-7: R5 = Me; R6 = H
(R,R)-7: R5 = H; R6 = Me
OMe
NO2
OMe
NO2
(S)-8c
Entry
1
6
4
7
Yield ee
(%)
(%)
3
4
57 93
OH
(S)-8d
Ph
6d
Ph
6e
6b
(E)
51
89
86
Ph
O
O
OH
OH
67 94
(R,S)-7b
Br
OH
OH
Br
(S)-8e
2
3
6b
6c
(Z)
(E)
58
50
Ph
BnO
BnO
68 97a
(R,R)-7b
5
Ph
Ph
6f
(S)-8f
94
92
95
97
OH
OH
OH
O
OMe
C4H9
6
7
53 95b
C4H9
(R,S)-7c
OH
6g
(S)-8g
O
4
5
6
6c
6d
6d
(Z)
(E)
(Z)
16
46
38
61 93b
OMe
NO2
NO2
OH
(R,R)-7c
(R,S)-7d
(S)-8h
6h
a The product was a 1:1 mixture of diastereomers.
b The ee were determined by CSP-HPLC analysis of the 4-nitroben-
zoate derivatives [(S)-9g and (S)-9h] for (S)-8g and (S)-8h, respec-
tively.
CH2OBn group) for these cases were somewhat lower
than for the racemic ones.20 As compared to the crotyla-
tion of conventional aldehydes,15g enantioselectivities are
comparable, whereas product yields are somewhat lower.
The sensitive rearrangement process coupled with the
lower reactivity of the crotylation reagents may be respon-
sible for the decreased yields. Despite this minor draw-
back, the consistently high diastereoselectivites observed
and the potential utility of the uniquely substituted prod-
ucts makes this method a synthetically useful one.
OH
(R,R)-7d
7
8
6e
6e
(E)
(Z)
36
31
96
97
Ph
Br
OH
OH
(R,S)-7e
Ph
In summary, we have developed an alternative and com-
plimentary method to the previously reported Brown ally-
lation of in situ generated b,g-unsaturated aldehydes.
Difficulties with the enantioselective crotylation of these
substrates using crotylB(Ipc)2 reagents have been over-
Br
(R,R)-7e
Synlett 2011, No. 19, 2857–2861 © Thieme Stuttgart · New York

2860
J. A. McCubbin et al.
LETTER
(5) Racemic allylation and crotylation: (a) Lautens, M.;
Table 3 Crotylation Scope19 (continued)
Ouellet, S. G.; Raeppel, S. Angew. Chem. Int. Ed. 2000, 39,
4079. Enantioselective allylation: (b) Lautens, M.;
Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett.
2002, 4, 83 . Racemic and enantioselective propargylation:
(c) Maddess, M. L.; Lautens, M. Org. Lett. 2005, 7, 3557.
(6) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(7) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108,
293. (b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org.
Chem. 1989, 54, 1570. (c) Brown, H. C.; Bhat, K. S. J. Am.
Chem. Soc. 1986, 108, 5919. (d) For a review, see:
Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23.
(8) Fujita, K.; Schlosser, M. Helv. Chim. Acta 1982, 65, 1258.
(9) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C.
J. Org. Chem. 1986, 51, 432.
R3
O
R1
R2
R4
R2
R4
R5 R6
Sc(OTf)3
6
(10 mol%)
+
R1
toluene, 0 °C
(E)-4 or (Z)-4
R3
OH
(R,S)-7: R5 = Me; R6 = H
(R,R)-7: R5 = H; R6 = Me
Entry
9
6
4
7
Yield ee
(%)
(%)
BnO
(10) Brown, H. C.; Sinclair, J. A. J. Organomet. Chem. 1977,
99b,
95c
131, 163.
6f
(E)
53a
Ph
(11) Diminished but still substantial yields of the bishomoallylic
alcohol were observed.
OH
OH
(12) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann,
R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron 1990,
46, 4663. (b) Paterson, I.; Lister, M. A. Tetrahedron Lett.
1988, 29, 585. (c) Paterson, I.; Lister, M. A.; McClure, C. K.
Tetrahedron Lett. 1986, 27, 4787.
(13) The bright yellow color of metalated 2-butene is observed to
fade after addition of approximately 0.5 equiv of TfOB(Ipc)2
while for MeOB(Ipc)2 the yellow color persists until a full
equivalent has been added.
(R,S)-7f
BnO
94b,
88c
10
6f
(Z)
55d
Ph
(R,R)-7f
a dr = 2.2:1.
b Major isomer.
c Minor isomer.
d dr = 1.2:1.
(14) Herold, T.; Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1978, 17, 768.
(15) Boron: (a) Roush, W. R. Stereoselective Synthesis, In
Methods of Organic Chemistry (Houben-Weyl); 21st. ed.,
Vol. 3, Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., Eds.; Thieme: Stuttgart, 1966, 1410–1486.
Titanium: (b) Hoppe, D. Stereoselective Synthesis, In
Methods of Organic Chemistry (Houben-Weyl), 21st ed.,
Vol. 3; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., Eds.; Thieme: Stuttgart, 1966, 1551–1583.
(c) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A.
J. Am. Chem. Soc. 2005, 127, 8044. Silicon: (d) Wang, Z.;
Wand, D.; Sui, X. Chem. Commun. 1996, 2261. (e) Kubota,
K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 48, 946.
(f) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org.
Lett. 2004, 6, 4375. (g) Zyang, X.; Houk, K. N.; Leighton, J.
L. Angew. Chem. Int. Ed. 2005, 44, 938. (h) Masse, C. E.;
Panek, J. S. Chem. Rev. 1995, 95, 1293 . Tin: (i) Nishida,
M.; Tozawa, T.; Yamada, K.; Mukaiyama, T. Chem. Lett.
1996, 1125. (j) Yamada, K.; Tozawa, T.; Nishida, M.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1997, 70, 2301.
(k) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1989, 1529.
(16) The absolute stereochemistry of the product [(S)-8b] was
established by comparison of HPLC traces with material
obtained from enantioselective Brown allylation of 6b.5b
This assigned configuration is consistent with that observed
by Leighton et al.15e
(17) McCubbin, J. A.; Maddess, M. L.; Lautens, M. Org. Lett.
2006, 8, 2993.
(18) The following procedure is representative for the allylation
reaction. See Supporting Information for full characteri-
zation data of all products.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Merck Frosst Canada and NSERC (Canada) for an Indu-
strial Research Chair, and the University of Toronto for financial
support of this work. M.M. thanks NSERC (Canada) for financial
support in the form of a postgraduate fellowship.
References and Notes
(1) For examples, see: (a) Saha, G.; Basu, M. K.; Kim, S.; Jung,
Y.; Adiyaman, Y.; Powell, W. S.; Fitzgerald, G. A.; Rokach,
J. Tetrahedron Lett. 1999, 40, 7179. (b) Crimmins, M. T.;
Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653.
(c) Paquette, L. A.; Braun, A. Tetrahedron Lett. 1997, 38,
5119. (d) Roush, W. R. J. Org. Chem. 1991, 56, 4151.
(e) Ahmar, M.; Bloch, R.; Mandville, G.; Romain, I.
Tetrahedron Lett. 1992, 33, 2501.
(2) (a) Bachmann, W. E.; Horwitz, J. P.; Warzynshi, R. J. J. Am.
Chem. Soc. 1953, 75, 3268. (b) Serramedan, D.; Marc, F.;
Pereyre, M.; Filliatre, C.; Chabardes, P.; Delmond, B.
Tetrahedron Lett. 1992, 33, 4457. (c) Marc, F.; Soulet, B.;
Serramedan, D.; Delmond, B. Tetrahedron 1994, 50, 3381.
(3) (a) Hertweck, C.; Boland, W. J. Org. Chem. 2000, 65, 2458.
(b) Bideau, F. L.; Gilloir, F.; Nilsson, Y.; Aubert, C.;
Malacria, M. Tetrahedron 1996, 52, 7487. (c) Wipf, P.; Xu,
W. J. Org. Chem. 1993, 53, 825.
Synthesis of (S)-8b
A 25 mL round-bottom flask was flame dried under a stream
of nitrogen and allowed to cool to r.t. To this was added 3
(250 mg, 0.45 mmol) and Et2O (3.0 mL). The mixture was
cooled to 0 °C, and Sc(OTf)3 (14.8 mg, 0.03 mmol) was
added followed by the slow addition of 6b (44 mg, 0.3
(4) For an alternative to the use of b,g-unsaturated aldehydes,
see: Hughes, G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2,
107.
Synlett 2011, No. 19, 2857–2861 © Thieme Stuttgart · New York

LETTER
Enantioselective Allylation and Crotylation of b,g-Unsaturated Aldehydes
2861
mmol) over 3 h as a solution in Et2O (2.0 mL). After the
(44 mg, 0.3 mmol) over 3 h as a solution in toluene (2.0 mL).
After 2 h at 0 °C, an equal volume of aq HCl (1 N) was
added, and the mixture was stirred for 10 min at r.t. The
reaction mixture was diluted with H2O and transferred to a
separatory funnel with Et2O. The organic layer was isolated,
and the aqueous layer was extracted with Et2O (2×), the
combined organic layers were dried with MgSO4, filtered,
and concentrated in vacuo. The crude residue was purified
by flash chromatography (10% EtOAc–hexane) to afford the
desired product (R,S)-7b as a colorless oil (yield 51%). 1H
NMR (400 MHz, CDCl3): d = 7.38–7.35 (m, 2 H), 7.32–7.27
(m, 2 H), 7.23–7.18 (tt, J = 4.3, 1.8 Hz, 1 H), 6.51–6.45 (d,
J = 15.9 Hz, 1 H), 6.31–6.23 (ddd, J = 15.8, 7.8, 6.7 Hz, 1
H), 5.86–5.76 (ddd, J = 16.6, 11.0, 8.2 Hz, 1 H), 5.16–5.15
(s, 1 H), 5.14–5.10 (ddd, J = 8.2, 1.9, 0.9 Hz, 1 H), 3.59–3.48
(ddt, J = 7.8, 5.9, 3.7 Hz, 1 H), 2.52–2.45 (dddd, J = 14.2,
6.6, 3.9, 1.5 Hz, 1 H), 1.74–1.71 (d, J = 3.4 Hz, 1 H), 1.10–
1.07 (d, J = 6.9 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
140.0, 137.3, 132.7, 128.5, 127.1, 126.5, 126.0, 116.3, 74.2,
43.5, 38.0, 16.2. FTIR (neat): n = 3392, 2971, 2930, 1640,
1598, 1495, 1450, 1418, 1028, 999, 966, 915, 745, 693 cm–1.
HRMS (EI): m/z calcd for C14H18O [M+] 202.1358; found:
202.1363. HPLC [CHIRACEL OD, 1 mL/min, hexane–2-
PrOH (95:5), 30 °C, 1 mL injection]: tR1 = 13.1 min,
tR2 = 14.3 min (major); 92% ee; [a]D20 +29.7 (c 0.024,
CHCl3).
addition was complete the reaction was stirred for 2 h at
0 °C, and then an equal volume of aq HCl (1 N) was added,
and the mixture stirred for 10 min at r.t. The reaction mixture
was diluted with H2O and transferred to a separatory funnel
with Et2O. The organic layer was isolated, and the aqueous
layer was extracted with Et2O (2×). The combined organic
layers were dried with MgSO4, filtered, concentrated in
vacuo, and the crude residue was purified by flash chroma-
tography (5–10% EtOAc–hexane) to afford the desired
product (S)-8b as a colorless oil (yield 73%). 1H NMR (300
MHz, CDCl3): d = 7.38–7.35 (m, 2 H), 7.33–7.28 (m, 2 H),
7.24–7.19 (m, 1 H), 6.48 (d, J = 15.9 Hz, 1 H), 6.24 (ddd,
J = 15.9, 7.4, 7.4 Hz, 1 H), 5.92–5.81 (m, 1 H), 5.19–5.13
(m, 2 H), 3.84–3.74 (m, 1 H), 2.50–2.21 (m, 4 H), 1.81 (d,
J = 3.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 137.5,
134.8, 133.3, 128.7, 127.5 126.3, 126.3, 118.4 70.4, 41.6,
40.7. HPLC [CHIRALCEL OD, 1 mL/min, hexane–2-PrOH
(95:5), 30 °C, 1 mL injection]: tR1 = 14.4 min (minor),
tR2 = 17.7 min (major);96% ee.
(19) The following procedure is representative for the crotylation
reaction. See Supporting Information for full
characterization data of all products.
Synthesis of (R,S)-7b
To a 25 mL round-bottom flask was added Leightons’
reagent [(E)-4, 256 mg, 0.45 mmol] and toluene (3.0 mL).
The mixture was cooled to 0 °C, and Sc(OTf)3 (14.8 mg,
0.03 mmol) was added followed by the slow addition of 6b
(20) See Supporting Information.
Synlett 2011, No. 19, 2857–2861 © Thieme Stuttgart · New York

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