Enantioselective and catalytic method for α-crotylation of aldehydes with a kinetic self-refinement of stereochemistry

Article abstract of DOI:10.1002/chem.200802224

A practical and catalytic approach towards enantioenriched homoallylic alcohols, using a two-step protocol combining a highly enantioselective Lewis base-catalyzed addition of crotyltrichlorosilanes to an auxiliary non-chiral aromatic aldehyde, was presen

Full text of DOI:10.1002/chem.200802224

DOI: 10.1002/chem.200802224
Enantioselective and Catalytic Method for a-Crotylation of Aldehydes with a
Kinetic Self-Refinement of Stereochemistry
Andrei V. Malkov,*[a, b] Mikhail A. Kabeshov,[a] Maciej Barłog,[a] and Pavel Kocˇovsky*[a]
´
Dedicated to Professor Rudolf Zahradnꢀk on the occasion of his 80th birthday
Asymmetric allylation of carbonyl compounds with allylsi-
lanes has evolved into a valuable synthetic tool for the con-
asymmetric variant, the best results were attained by using
tertiary alcohols derived from chiral ketones, such as men-
thone[7] or camphor;[8] notably, these reagents were either
used in up to a three-fold excess and/or required additional
chromatographic purification. In the case of chiral secon-
dary alcohols of type 3, anti isomers react with aldehydes in
a stereospecific manner, giving exclusively (E)-4 with inver-
sion of configuration of the parent alcohol 3, whereas the
analogous rearrangement of the corresponding syn isomers
3 is less stereoconvergent.[4] However, to date, only a hand-
ful of examples employing chiral secondary alcohols 3 as
allyl-transfer reagents have been reported.[9]
[1,2]
ꢀ
struction of C C bonds.
As a rule, allylation of aldehydes
1 with organosilicon 2 and other organometallic reagents af-
fords g-adducts 3, resulting from the attack at carbonyl by
the distal carbon of the allylic system (Scheme 1). High
enantio- and diastereoselectivities have been attained for
this reaction by using various chiral catalysts.[1,2] On the
other hand, stereoselective synthesis of linear products 4
represents a formidable synthetic challenge.[3]
Herein, we present a practical, catalytic approach towards
the enantioenriched homoallylic alcohols (E)-8, using a two-
step protocol combining a highly enantioselective Lewis
base-catalyzed addition of crotyltrichlorosilanes (E)-5 to an
auxiliary non-chiral aromatic aldehyde 1, followed by a
Lewis acid-catalyzed allyl transfer from the resulting alco-
hols 6 to the receptor aldehydes 7 (Scheme 2).
Scheme 1. Allylation of aldehydes with allylsilanes.
It has been shown that branched alcohols 3 can rearrange
into their linear isomers 4 in the presence of aldehyde 1 and
a Lewis acid,[4,5] or Lewis acid only.[5] In fact, the stoichio-
metric allyl transfer from secondary and tertiary alcohols to
aldehydes constitutes an established method.[4,6] In the
[a] Prof. Dr. A. V. Malkov, M. A. Kabeshov, M. Barłog,
ˇ
´
Prof. Dr. P. Kocovsky
Department of Chemistry, WestChem, University of Glasgow
Glasgow G12 8QQ (UK)
Fax : (+44)141-330-4888
E-mail: pavelk@chem.gla.ac.uk
[b] Prof. Dr. A. V. Malkov
Current Address: Department of Chemistry
Loughborough University
Leicestershire, LE11 3TU (UK)
Fax : (+44)1509-22-3925
Scheme 2. A two-step, double catalytic g-allylation sequence; for a–m in
1, 6, 7, and 8, see Tables 1 and 2.
E-mail: a.malkov@lboro.ac.uk
Recently, we have developed a family of pyridine N-oxide
catalysts for the enantioselective allylation of aromatic alde-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802224.
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COMMUNICATION
hydes with allyltrichlorosilane.[10–12] We envisioned that this
methodology could be applied to the synthesis of the requi-
site enantio- and diastereoisomerically enriched anti alco-
hols 6 by employing trans-crotyltrichlorosilanes 5, readily
obtained on a large scale from the corresponding trans-
crotyl chlorides 10 in one step (Scheme 2).[13] The Lewis
base-catalyzed addition of 5 to aldehydes 1, proceeding via
a cyclic chair-like transition state,[12b] generally displays an
excellent diastereocontrol.[1,2] With majority of the known
catalysts, the anti/syn ratio of the products reflects the trans/
cis ratio of the starting crotylsilane 5.[1,2] The notable excep-
tions include quinox, an isoquinoline-derived N-oxide,[12]
which reacts faster with cis-crotyltrichlorosilane (Z)-5a, and
the pinene-derived N-oxide methox 9[11b] that exhibits a
strong kinetic preference towards the trans-isomer (E)-5a,
leaving the cis-isomer unreacted.[11b] As an important conse-
quence, the latter catalyst 9 allows the use of crotyl silane
5a (E/Z 6:1), obtained from the technical-grade crotyl chlo-
ride 10a (E/Z 6:1) without additional purification, giving
the homoallylic alcohols 6a–d in excellent diastereo- and
enantiopurity (ꢁ98% ee and ꢂ96% de).[11b,14]
and clean conversion of 6a into 8b.[16] In earlier reports,[4]
6a proved to be a poor allyl-transfer reagent as the benzal-
dehyde released became involved in the reaction, giving 8a
as an undesired byproduct. We found that using a three-fold
excess of the receptor aldehyde 7b completely suppressed
the side reaction (entry 2). However, we felt that the substi-
tution pattern in the auxiliary aldehyde 1 may affect the re-
activity and consequently improve the efficiency of the
cross-crotylation. Therefore, we examined alcohols 6b–d (ee
ꢂ96%, anti/syn ꢂ25:1; entries 3–5), which in turn were syn-
thesised by using the procedure described for 6a. According
to the mechanism formulated by Nokami (Scheme 3),[4] the
driving force for the key oxonia-Cope rearrangement (B!
D, via the transition state C), is the formation of the more
stable cation D, complemented by the shift of the terminal
double bond to an internal position and by the release of
the steric constrains existing in B/C (note the all-equatorial
substituents in the transition state C in the case of anti alco-
hols 6). Indeed, the more electron-rich p-tolyl derivative 6d
(entry 5) emerged as a clear winner, presumably owing to its
enhanced capability to stabilize the positive charge in D,
compared to the phenyl in 6a (entry 2). On the other hand,
the even more electron-rich methoxy analogue 6c (entry 4)
was found to be unstable under the reaction conditions, re-
To probe the synthetic potential of alcohols 6 for the
enantioselective allyl-transfer reaction, we first carried out
the rearrangement of g- to a-product (6a!8a; Table 1,
entry 1). A 1:1 mixture of benzaldehyde and (1S,2R)-6a
(R1 =Ph, R2 =Me; anti/syn 50:1, 97% ee), obtained by ally-
lation of benzaldehyde with 5a (1.2 equiv, E/Z 6:1) in the
presence of (+)-9 (5 mol%), was treated with (TfO)2Sn
1
(5 mol%) in CDCl3. Monitoring of the reaction by H NMR
spectroscopy showed a complete conversion in just 20 min;
the product (R)-8a (R2 =Me, R3 =Ph) was obtained in 96%
ee and (E/Z)>50:1 (entry 1), indicating a complete preser-
vation of the stereochemical information.[15]
Next, we focused on cross-crotylation, employing hydro-
cinnamaldehyde (7b) as
a model receptor aldehyde
(Table 1). A brief screening led to the identification of
(TfO)2Sn as an optimal Lewis-acidic catalyst, ensuring fast
Scheme 3. Mechanism of crotyl transfer.
sulting mainly in the formation
of degradation products, where-
as the electron-poor nitro deriv-
ative 6b (entry 3) was virtually
inactive. As an additional bene-
fit of 6d, the reduced electro-
philic character of p-tolualde-
Table 1. Crotyl transfer from 6a–d (R2 =Me) to aldehydes 7a–c.[a]
Entry
6
R1
7
R3
8
Yield [%][b,c]
ee [%][d]
hyde released during the reac-
tion makes it less competitive
with the receptor aldehyde 7 in
the allyl-transfer process, there-
by avoiding the formation of
the corresponding alcohol (8c).
Indeed, a competition experi-
ment (entry 6), employing a 1:1
mixture of 7b and 7c, showed
that the crotyl transfer from 6d
to 7c proceeded at least 4 times
slower than that to 7b.[17]
1
2
3
4
5
6
7
6a
6a
Ph
Ph
7a
7b
7b
7b
Ph
Ph
Ph
Ph
Ph
Ph
8a
8b
8b
8b
95
50
96
97
n.d.
n.d.
97
G
6b[e]
6c[f]
6d[g]
6d
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
E
trace
10[k]
95
N
7b
R
8b
7b, c[h]
7c
A
8b[i]
8c[j]
72[l]
70
97
55
6d
4-MeC6H4
[a] The reactions were carried out with 0.3 mmol of 6 in CDCl3 (2 mL). [b] Determined by 1H NMR. [c] In all
cases the (E/Z) ratio was>100:1 (determined by GC). [d] Determined by 19F NMR of the corresponding
Mosher ester for 8a and 8c; determined by GC for 8b. [e] Ref. [19]. [f] Ref. [20]. [g] 98% ee (determined by
GC). [h] A 1:1 mixture of 7b and 7c. [i] 8b was formed as a major product (see the Supporting Information).
[j] 8c was formed as a major product, unstable in the system. [k] Decomposition was mainly taking place.
1
[l] Determined by H NMR after 7 min.
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ˇ
´
A. V. Malkov, P. Kocovsky et al.
Table 2. Allyl transfer with 6d–g (R1 =p-tolyl).[a]
tate as eluent (100:0
afford 6d as a colorless oil (237 mg,
90%, 98% ee).
!
70:30) to
Crotyl transfer: Tin(II) triflate (21 mg,
0.05 mmol) was added in one portion
to a solution of 6d (176 mg, 1 mmol)
and 7b (400 mg, 3 mmol[17]) in CHCl3
(15 mL; passed through a pad of basic
Al2O3 before use) at room tempera-
ture and the mixture was stirred at
room temperature for 1 h. Subsequent-
ly, the mixture was diluted with ethyl
acetate (150 mL) and washed with a
saturated NaHCO3 solution (2ꢂ
100 mL). The organic layer was dried
over sodium sulfate and the solvents
were removed in vacuum. The product
was purified on a column of silica gel
(2.5ꢂ15 cm), using a gradient of petro-
leum ether and ethyl acetate (100:0 !
80:20) to afford pure 8b as a colorless
liquid (161 mg, 85%, 97% ee).
Entry
6
R2
7
R3
8
Yield [%][b,c]
ee [%][d]
1
2
3
4
5
6
7
8
6d
6d
6d
6d
6d
6d
6d
6e
6 f
Me
Me
Me
Me
Me
Me
Me
nPr
Bn
7d
7e
7 f
7g
7h
7i
4-NO2C6H4
PhCH2
tBu
cC6H11
Et2CH
nC6H11
8d
8e
8 f
8g
8h
8i
8j
8k
8l
75
82
60
80
98
96
93
97
ꢂ95
ꢂ97
ꢂ97
97
96
95
83
85
7j
MeS
G
72[e]
83
7b
7b
7b
Ph
Ph
Ph
G
9
10
R
85
6g
CH2OBn
A
8m
85[e]
[a] The reactions were carried out with 1 mmol of 6 and 3 mmol of 7 (ref. [17]) in CHCl3 (15 mL). [b] Isolated
yield. [c] In all cases the E/Z ratio was>100:1 (determined by GC). [d] Determined by HPLC for 8d,e,k–m
and by 19F NMR of the corresponding Mosher ester for 8 f,i,j; determined by GC for 8g,h. [e] After 12 h.
Alcohol 6d was employed in crotylation of a range of re-
cipient aldehydes (Table 2). The reaction proved to be very
efficient in every instance, with the enantioselectivity vary-
ing in the range of 93–98% ee, essentially irrespective of the
nature of aldehyde 7.
Acknowledgements
We thank the EPSRC for grants No. G/T27051/01 and EP/E011179/1 and
the University of Glasgow for a fellowship to M.A.K.
Significantly, this allyl transfer is not restricted to the
products of crotylation (6a–d). Thus, a set of g-derivatives
6e–g, obtained from (E)-3-alkyl allyltrichlorosilanes 5b–d
(Scheme 2), were converted into the corresponding linear
homoallylic alcohols 8k–m in high yields and enantioselec-
tivities (Table 2, entries 8–10).[18]
Keywords: allylation
rearrangement · silanes · stereoselectivity
·
asymmetric
catalysis
·
In summary, we have developed a practical, highly stereo-
selective, two-step catalytic protocol for the a-allylation of
aldehydes 7a–j, starting from crotyltrichlorosilanes 5a–d. In
each reaction step (1 + 5!6 and 6 + 7!8), one of the ste-
reoisomers [(E)-5 and anti-6, respectively] reacted faster
than the other, which resulted in a kinetic stereochemical
(E/Z) self-refinement of the system and led to the formation
of virtually enantiomerically and geometrically pure prod-
ucts 8. Since the direct highly enantioselective allylation
with allyltrichlorosilanes is currently limited to aromatic al-
dehydes (6), this methodology represents a significant ex-
pansion into the aliphatic realm (8).[21]
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ˇ
´
ˇ
´
Kocovsky, Eur. J. Org. Chem. 2007, 29–36; b) P. Kocovsky, A. V.
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Experimental Section
Crotylation: (E)-Crotyltrichlorosilane (5a; 570 mg, 3 mmol; E/Z 6:1) was
added to a solution of p-tolualdehyde (180 mL, 1.5 mmol), Hꢁnig base
(1.57 mL, 9 mmol), and methox (+)-9 (28 mg, 0.075 mmol) in a freshly
distilled CH3CN (10 mL) under argon at ꢀ408C. The reaction mixture
was stirred at that temperature for 24 h and monitored by TLC. The re-
action was quenched with a saturated solution of NaHCO3 (30 mL) and
ethyl acetate (150 mL) was added. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate (2ꢂ100 mL). The
combined organic layers were dried over sodium sulfate and the solvent
was removed in vacuum. The crude product was purified on a column of
silica gel (3.5ꢂ15 cm), using a gradient of petroleum ether and ethyl ace-
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Enantioselective Catalysis
COMMUNICATION
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[15] Using a catalytic amount of benzaldehyde (10 mol%) did not affect
diastereo- and enantioselectivity of the rearrangement (for details,
see Supporting Information).
[16] Other acids, such as TsOH and (TfO)3Yb·3H2O exhibited low con-
version (10 and 5%, respectively). On the other hand, Me3SiOTf
proved to be equal to (TfO)2Sn; these results will be published in a
full paper.
[17] Since the p-TolCHO released during the rearrangement is character-
ized by a reduced propensity to compete with the receptor aldehyde
7 (compared to PhCHO), we could reduce the loading of the recep-
tor aldehyde to 1.5–2.0 equiv with no effect on the conversion. How-
ever, for the sake of consistency, we kept the aldehyde 7 loading at
3 equiv throughout this study.
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[18] The reaction of alkenol (S)-p-TolCH(OH)CH2CH=CH2 (91% ee)
with aldehyde 7b proceeded at much slower pace and resulted in a
gradual
loss
of
enantiopurity
of
the
product
Ph-
[10] a) A. V. Malkov, M. Orsini, D. Pernazza, K. W. Muir, V. Langer, P
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14% ee after 24 h.; in agreement with an earlier report by Nokami
(ref. [7a]).
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diastereoisomer from (E/Z) mixtures of MeCH=CHCH2-SiACTHNUTRGENUG(N OMe)3
in an allylation reaction catalyzed by BINAP·AgF. However, in his
Received: October 27, 2008
case the mechanism was different and involved a silver-catalyzed
Published online: January 2, 2009
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