An enantioselective catalytic approach to syn deoxypropionate units combining asymmetric Cu-catalyzed 1,6- and 1,4-conjugate addition

Article abstract of DOI:10.1016/j.tetasy.2010.04.057

A novel iterative approach to the synthesis of the naturally ubiquitous syn deoxypropionate motif is reported. The route comprises a new Horner-Wadsworth-Emmons reagent to prepare α,β,γ,δ- bisunsaturated thioesters. Next, two Me-substituents are introduced in high yield, regio- and enantioselectivity using sequential asymmetric Cu-catalyzed 1,6-conjugate addition, base-catalyzed olefin isomerization and Cu-catalyzed enantioselective 1,4-conjugate addition. After reduction to the aldehyde these transformations can be repeated to install three or more Me groups with a syn 1,3-relationship.

Full text of DOI:10.1016/j.tetasy.2010.04.057

Tetrahedron: Asymmetry 21 (2010) 1574–1584
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An enantioselective catalytic approach to syn deoxypropionate units
combining asymmetric Cu-catalyzed 1,6- and 1,4-conjugate addition
*
*
Tim den Hartog, Derk Jan van Dijken, Adriaan J. Minnaard , Ben L. Feringa
University of Groningen, Stratingh Institute for Chemistry, Nijenborgh 4, 9747 AG Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel iterative approach to the synthesis of the naturally ubiquitous syn deoxypropionate motif is
reported. The route comprises a new Horner–Wadsworth–Emmons reagent to prepare ,b, ,d-bisunsat-
Received 9 March 2010
Accepted 26 April 2010
Available online 11 June 2010
a
c
urated thioesters. Next, two Me-substituents are introduced in high yield, regio- and enantioselectivity
using sequential asymmetric Cu-catalyzed 1,6-conjugate addition, base-catalyzed olefin isomerization
and Cu-catalyzed enantioselective 1,4-conjugate addition. After reduction to the aldehyde these transfor-
mations can be repeated to install three or more Me groups with a syn 1,3-relationship.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri B. Kagan on the
occasion of his 80th birthday
1. Introduction
aldehydes (route b).9,10 However, for our envisioned iterative route
we developed the novel extended Horner–Wadsworth–Emmons
The enantioselective synthesis of the biologically relevant poly-
deoxypropionate motif has been a topic of intensive research in re-
cent years.1 As a consequence, a number of highly efficient
catalytic iterative methods have been developed.1 In particular,
the methods based on asymmetric zirconium-catalyzed carboalu-
mination,2 as well as iterative Ir-catalyzed hydrogenation3 and
asymmetric Cu-catalyzed conjugate addition (1,4-ACA)4,5 have
been employed successfully to synthesize a variety of biologically
relevant lipids.6
Although the described methods feature high enantioselectivity
in combination with low catalyst loading and high yield, alterna-
tive routes are still highly warranted. Recently, we reported the
asymmetric catalytic 1,6-addition7 (1,6-ACA) providing access to
(HWE) reagent 11. Coupling of 11 with an aldehyde 10 would pro-
vide a general route to a variety of
(route c).
a,b,c,d-bisunsaturated thioesters
Using isobutyraldehyde 10c and the conditions reported for the
extended HWE reaction11 with the oxoester analogue of 11,12 the
product 7c was obtained in low, poorly reproducible yields but
excellent E/Z-selectivity (Table 1, entry 1). The use of LHMDS as a
base improved the yield slightly but still gave poorly reproducible
results (entry 2). Optimization of the reaction conditions identified
that strict temperature control (addition of aldehyde at ꢀ78 °C and
allowing the reaction to warm up in 30 min to ꢀ40 °C) in combina-
tion with high dilution conditions (0.039 V in 10c) for the reaction
was essential to give 7c in good and reproducible yield and excel-
lent E/Z-selectivity (entry 3). With these optimized conditions the
d-substituted b,
c
-unsaturated esters and thioesters 2 (Scheme 1).
,b-unsatu-
We envisioned that subsequent isomerization to the
a
aldehydes 10d and 10e were converted and the desired a,b,c,d-bis-
unsaturated thioesters 7d and 7e were obtained in lower, but
acceptable, yields (entries 4 and 5). Presumably, the more accessible
rated thioester 3 followed by 1,4-ACA4 would provide an efficient
route to construct 1,3-dimethyl arrays 4. Herein we report the
combined use of 1,6-ACA7 and 1,4-ACA4 in a new protocol for the
construction of deoxypropionate subunits.
a-H of 10d and 10e compared to the sterically encumbered a-H in
10c causes side reactions to occur. Finally, DIBAL-H reduction and
extended HWE reaction of 12à provided the chiral 1,6-ACA substrate
7f in 64% yield over two steps (Scheme 3).
2. Results and discussion
With the substrates in hand, the scope of the 1,6-ACA7 of
MeMgBr§ was explored (Table 2). Employing CuBrꢁSMe2 and (+)-re-
versed Josiphos L1, the 1,6-ACA of MeMgBr to substrate 7b proceeds
A first prerequisite for a straightforward route to deoxypropio-
nate units is facile access to
a,b,c,d-bisunsaturated thioesters
(Scheme 2). Current methods for the synthesis of
rated thioesters comprise thioesterification of an
a
a
,b,
c
,d-bisunsatu-
,b,c
,d-bisunsatu-
All reported yields are for reactions at
a 0.5 mmol scale. The reaction was
rated acid (route a),8 as well as Wittig olefination of
a,b-unsaturated
performed at a larger scale with the conditions reported for entry 2 and gave low
yield (ꢂ30%). Presumably strict control of the temperature is needed to obtain good
yields at a larger scale.
For the synthesis of 12 see the Experimental.
A limitation of the current method was discovered when 7a was subjected to 1,6-
ACA of the more reactive EtMgBr or nBuMgBr leading to the 1,6-addition products in
high yield and regioselectivity but moderate enantioselectivity.
à
* Corresponding authors. Tel.: +31 50 363 4258; fax: +31 50 363 4296 (A.J.M.);
tel.: +31 50 363 4235; fax: +31 50 363 4296 (B.L.F.).
E-mail addresses: a.j.minnaard@rug.nl (A.J. Minnaard), b.l.feringa@rug.nl (B.L.
Feringa).
§
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.057

T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
1575
R2MgBr
CuBr SMe2, (+)-L1
O
R2
O
R1
X
R1
X
57-88%
1
2
CH2Cl2
-70 °C, 16 h
96-98% regioselectivity
90-96% ee
X= OEt, SEt
for X= SEt
R2= Me
B
Me
R32P
R42P
Me
R1
O
Fe
SEt
3
MeMgBr
(S,R)-(+)-L1, reversed Josiphos
R3= Ph, R4= Cy
CuBr SMe2, (+)-L2
tBuOMe
(S,R)-(+)-L2, Josiphos
-78 °C, 16 h
R3= Cy, R4= Ph
Me
O
Me
R1
SEt
4
Scheme 1. Asymmetric catalytic 1,6-addition and envisioned route to deoxypropionate units.
DCC
DMAP
O
O
+
a)
b)
HSEt
OH
SEt
5
6
7a: 80%
O
O
O
Ph3P
+
SEt
nBu
H
nBu
SEt
7b: 61%
E:Z 14:1
8
9
O
O
O
1) 11, B
2) 10
(EtO)2P
+
c)
SEt
R
H
10
11
Scheme 2. Synthetic routes to a,b,c,d-bisunsaturated thioesters. Reagents and conditions: route a: 5, 6 (1.3 equiv), DCC (1.05 equiv), DMAP (0.1 equiv) in CH2Cl2 (0.22 V in 5),
0 °C to RT, 16 h; route b: 8, 9 (1.3 equiv) in CH2Cl2 (0.14 V in 8), 40 °C, 20 h.
Table 1
HWE reaction leading to
a
,b,
c
,d-bisunsaturated thioestersa
O
O
O
O
11
1) , B
(EtO)2P
+
SEt
R
SEt
R
H
10
2) , THF
7
10
11
Entry
Aldehyde
Product
Base
Conditions step 2
Molarity (V)
Yieldb (%)
1
2
3
4
5
10c; R = iBu
10c; R = iBu
10c; R = iBu
10d; R = CH2Bn
10e; R = (CH2)3OBn
7c
7c
7c
7d
7e
LDA
ꢀ78 °C to RT, 3 h
0.074
0.29
0.039
0.039
0.039
50c
70d
70
39
47
LHMDS
LHMDS
LHMDS
LHMDS
ꢀ78 to ꢀ40 °C, 16 h
ꢀ78 to ꢀ40 °C, 16 h
ꢀ78 to ꢀ40 °C, 16 h
ꢀ78 to ꢀ40 °C, 16 h
a
Conditions: entry 1: (1) 11 (1.43 equiv), LDA (1.4 equiv), THF (0.13 M in 11), ꢀ78 to ꢀ20 °C, 3 h, then (2) 10c, THF (total 0.074 M in 10c); entry 2: 11 (1.5 equiv), LHMDS
(1.4 equiv), THF (0.63 M in 11), ꢀ78 °C, 0.5 h, then (2) 10c, THF (total 0.29 M in 10c); entries 3–5: 11 (1.5 equiv), LHMDS (1.4 equiv), THF (0.07 M in 11), ꢀ78 °C, 0.5 h, then 2)
10, THF (total 0.039 M in 10).
b
In all cases the products were obtained with over 95:5 E/Z-ratio according to 1H NMR.
Yields in the range of 30–50% were obtained.
Yields in the range of 30–70% were obtained.
c
d
in high yield and excellent regio- and stereoselectivity (entry 1).
When the more bulky f-Me-substituted substrate 7c was subjected
to 1,6-ACA, a slight drop in regio- and enantiocontrol was observed
(entry 2). This drop in regio- and enantioselectivity is a continuing
trend; the more sterically encumbered the R-groups the lower both
enantio- and regioselectivity for the 1,6-ACA are.– The substrates
incorporating a phenyl- or benzyl-protected hydroxy functionality
gave good yields and good to excellent regio- and stereocontrol
(entries 3 and 4). Finally, the ability of the catalyst to override
substrate control13 was tested by the 1,6-ACA of MeMgBr to chiral
substrate 7f. Syn-addition proceeded in high yield, regio- and diaste-
reoselectivity (entry 5), while anti-addition gave high yield and
regioselectivity, but moderate diastereoselectivity (entry 6).
For the next step in the iterative sequence, the isomerization to
the
a,b-unsaturated thioester 15b, a variety of methods were
investigated. The olefin was resistant to isomerization by heat
(xylene, 140 °C) and various transition metal catalysts (Pd(OAc)2,
Pd(PPh3)4, Wilkinsons catalyst, and RuCl3). Base-catalyzed
–
This trend is even more apparent when the results in Table 2 are compared to the
results of 1,6-ACA to the R=Et substituted
Ref. 7 (93% ee and 97% regioselectivity).
a,b,c,d-bisunsaturated thioester reported in

1576
T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
O
O
O
DIBAL-H
1) 11, LHMDS
2) 10d, THF
BnO
BnO
BnO
SEt
SEt
H
3
3
3
12
7f: 64% (2 steps)
10f
Scheme 3. Synthesis of the chiral 1,6-ACA substrate 7f. Reagents and conditions: reduction: 12, DIBAL-H (1.2 equiv), CH2Cl2 (0.29 M in 12), ꢀ75 °C, 3 h; extended HWE
reaction: see Table 1, entries 3–5.
Table 2
1,6-ACA to
a
,b,
c
,d-bisunsaturated thioestersa
MeMgBr
CuBr SMe2, (+)-
O
Me
O
Me
*
14
O
L1
+
R
SEt
R
SEt
R
SEt
13:14c
7
13
Entry
Substrate
Product
Yieldb (%)
eed (%)
1
2
3
7b, R = nBu
7c, R = iBu
7d, R = CH2Bn
7e, R = (CH2)3OBn
7f, R = CH2((R)-CHMe)(CH2)3OBn
7f, R = CH2((R)-CHMe)(CH2)3OBn
13b
13c
13d
13e
13f
83
84
78
86
88
83
99:1e
95:5
89
82
82
86
99:1e
94:6
4
5f
6h
85:15
87:13
(87:13)g
(22:78)g
13g
a
Conditions: 7 in CH2Cl2 was added to a solution of MeMgBr (3.0 M in Et2O, 2.0 equiv), (+)-L1 (5.25 mol %) and CuBrꢁSMe2 (5 mol %) in CH2Cl2 (0.2 M in 7), ꢀ70 °C, 16 h.
b
c
Yields include both 13 and 14.
Ratio of 13:14 was determined by 1H NMR.
Enantioselectivity was determined by chiral GC or HPLC.
Ratio of 13:14 was determined by chiral GC or HPLC.
Compound 7f was prepared in 93% ee.
Diastereoselectivity syn:anti.
Compound 7f was prepared in 93% ee, (ꢀ)-L1 was used.
d
e
F
g
h
Table 3
Isomerization of b,
c
-unsaturated thioester 13 to a
,b-unsaturated thioester 15a
Me
O
Me
O
DBU
R
SEt
R
SEt
13
15
CH2Cl2
40 °C
Entry
Substrate
Product
Equiv DBU
Reaction time (h)
13:15b
Yieldc (%)
1
2
3
4
5
6
13b; R = nBu
13b; R = nBu
13b; R = nBu
13b; R = nBu
13b; R = nBu
15d; R = CH2Bnd
15b
15b
15b
15b
15b
15d
0.1
1.5
5
10
10
5
16
16
16
16
64
16
50:50
20:80
12:88
12:88
15:85
11:89
88
87
88
88
90
n. d.
a
Conditions: 13 or 15 and DBU in CH2Cl2 (0.1 M in 13 or 15), 40 °C.
Ratio of 13:15 was determined by GC–MS.
Yields reported are combined yields for 13, 15 and the traces of 14 present from the 1,6-ACA.
Pure isolated 15d was used.
b
c
d
isomerization employing DBU was more effective to isomerize the
double bond into the desired position (Table 3, entries 1 and 2).
Optimization of the amount of DBU used for this transformation
identified that 5 equiv of DBU was optimal for isomerization in
16 h (entry 3).|| Employing the conditions described in entry 3, the
To test our alternative synthetic strategy for the iterative con-
struction of deoxypropionate units, several Me-centers starting
from 7b were introduced (Scheme 4). Both the syn-16 and anti-
product 17, incorporating two Me-substituents, were obtained in
good overall yield (respectively, 63% and 58% over three steps), re-
gio-, and stereoselectivity.àà,§§ Subsequent chain elongation gave
the 1,6-ACA substrate 19 in good yield and excellent E/Z ratio. Final-
ly, synthesis of the syn,syn-1,6-ACA product 20 proceeded in good
yield, regio-, and diastereoselectivity while the syn,anti-1,6-ACA
product 21 was obtained in good yield and regioselectivity but medi-
ocre diastereoselectivity.
a
,b-unsaturated product 15 was obtained without racemization of
the asymmetric Me-center. Use of more DBU did not lead to full
isomerization (entries 4 and 5). Furthermore, exposing isolated ,b-
unsaturated thioester 15d once more to the reaction conditions gave
a mixture of b, -unsaturated thioester 13d and ,b-unsaturated thi-
a
c
a
oester 15d (entry 6) indicating an equilibrium.
àà
The lower enantio- and diastereoselectivity of the 1,4-ACA on 15b compared to
||
Due to the hydrophobic nature of the obtained products attempts to separate the
two regioisomers were unsuccessful. Fortunately, the presence of these impurities did
not affect the subsequent 1,4-ACA.
the results reported in ref 4d can be explained by the lower ee of 15b (89% ee vs 95%
ee).
§§
Although separation of 13b, the 1,4-addition side-product of the 1,6-ACA (14b)
For the conversion of 13d to 15d no racemization was observed using chiral HPLC
(see Experimental).
and 15b in earlier stages of the synthesis was not possible, at this stage the pure
mixture of the saturated products 16 and 17 was obtained successfully.

T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
1577
MeMgBr
CuBr SMe2, (+)-L1
O
Me
O
Me
O
DBU
nBu
SEt
nBu
SEt
nBu
SEt
CH2Cl2
-70 °C, 16 h
CH2Cl2
40 °C, 16 h
7b
13b: 83%
99:1 1,6:1,4
89% ee
15b: 91%
88% isomerized
1) 11, LHMDS
THF, -78 °C
0.5 h
MeMgBr
CuBr SMe2, (+)-L2
Me Me
O
Me Me
O
DIBAL-H
nBu
SEt
nBu
H
CH2Cl2
-78 °C, 3 h
2) 18
-78 to -40 °C
16 h
tBuOMe
-78 °C, 16 h
16: 83% (63% from 7b)
96:4 syn:anti
18
92% ee
MeMgBr
CuBr SMe2, (-)-L2
Me Me
O
nBu
SEt
tBuOMe
-78 °C, 16 h
17: 77% (58% from 7b)
8:92 syn:anti
85% ee
MeMgBr
CuBr SMe2, (+)-L1
Me Me Me
O
Me Me
O
nBu
SEt
nBu
SEt
CH2Cl2
-70 °C, 16 h
20: 87% (33% from 7b)
90:10 1,6:1,4
19: 61% (2 steps)
>95:5 4E:4Z
91:9 syn:anti
MeMgBr
CuBr SMe2, (-)-L1
Me Me Me
O
nBu
SEt
CH2Cl2
-70 °C, 16 h
21: 85% (33% from 7b)
90:10 1,6:1,4
28:72 syn:anti
Scheme 4. Iterative construction of deoxypropionate units starting from 7b. Reagents and conditions: 1,6-ACA: see Table 2; isomerization: see Table 3; 1,4-ACA: 15b in
tBuOMe was added to a solution of MeMgBr (3.0 M in Et2O, 1.5 equiv) and L1–CuBrꢁSMe2 complex (1.0 mol %) in tBuOMe (0.2 M in 7), ꢀ78 °C, 16 h; Reduction and chain
elongation: see Scheme 3; 1,6-ACA: see Table 2. Yield for the 1,6-ACA includes 13 and 14; Yield for the isomerization step includes 13, 15 and 14; Yield for the subsequent 1,4-
ACA includes only 16 and 17.
The generality of the construction of deoxypropionate units via
consecutive 1,6-ACA-isomerization-1,4-ACA was illustrated by the
introduction of two consecutive Me groups on several functional-
ized substrates (Scheme 5). In all cases the products comprising
two deoxypropionate units were obtained in good yield, regio-,
and diastereoselectivity.
construction of a,b-unsaturated thioesters were developed. The
novel route was used for the construction of several Me-centers in
a syn-1,3-fashion and the corresponding products were obtained in
good yield, regio-, and enantioselectivity. It must be noted that the
current methodology is suited for the construction of syn-deoxypro-
pionate units; while the anti-deoxypropionate units are presumably
constructed more efficiently by the 1,4-ACA.4d A drawback of the
current method is the slightly lower enantioselectivity obtained
3. Conclusion
for the 1,6-ACA of MeMgBr to a,b-unsaturated thioesters compared
to the corresponding enantioselectivities for the 1,4-ACA.4d
However, this drawback is readily circumvented by the construction
of the first stereogenic center by 1,4-ACA,4d subsequent chain elon-
gation, and 1,6-ACA taking advantage of the inherent preference13
for the formation of syn deoxypropionate units. Compared to the
optimized iterative route for the construction of deoxypropionate
In conclusion, we have developed an alternative method for
the construction of deoxypropionate units exploiting Cu-catalyzed
1,6-ACA7 and 1,4-ACA.4d To allow iterative construction of deoxy-
propionate units a novel method for the construction of a,b,c,d-bis-
unsaturated thioesters and an alternative method for the
1) 11, LHMDS
MeMgBr
CuBr SMe2, (+)-L1
THF, -78 °C
Me
O
O
O
0.5 h
R
SEt
R
H
R
SEt
CH2Cl2
-70 °C, 16 h
2) 10
-78 to -40 °C
16 h
10c: R=iBu
10d: R=CH2Bn
10e: R=(CH2)3OBn
7c: 70%, >95:5 4E:4Z
7d: 39%, >95:5 4E:4Z
7e: 47%, >95:5 4E:4Z
13c: 84%, 82% ee, 95:5 13:14
13d: 78%, 82% ee, 99:1 13:14
13e: 86%, 86% ee, 94:6 13:14
MeMgBr
CuBr SMe2, (+)-L2
Me Me
O
Me
R
15c: 87%, 90:10 15:13
15d: 87%, 89:11 15:13
15e: 86%, 89:11 15:13
O
DBU
R
SEt
SEt
CH2Cl2
40 °C, 16 h
tBuOMe
-78 °C, 16 h
22c: 67% (49% from 7c)
90:10 syn:anti
22d: 73% (50% from 7d)
94:6 syn:anti
22e: 64% (46% from 7e)
94:6 syn:anti
Scheme 5. Iterative construction of deoxypropionate units on several functionalized substrates. Reagents and conditions: extended HWE: see Table 1; 1,6-ACA: see Table 2;
isomerization: see Table 3; 1,4-ACA: see Scheme 4. Yield for the 1,6-ACA include 13 and 14; yield for the isomerization step include 13, 15 and 14; Yield for the subsequent
1,4-ACA include only syn-22 and anti-22.

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T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
units via 1,4-ACA employing either Josiphos4d L2 or Tol-BINAP4c our
Data in Section 4 is ordered as follows:
newly developed methodology seems competitive.
1. Synthesis of HWE-reagent 11 (Scheme 6).
2. Synthesis of 1,6-ACA substrates.
3. Synthesis of 1,6-ACA products.
4. Synthesis of 1,4-ACA substrates.
5. Synthesis of 1,4-ACA products.
4. Experimental
4.1. General procedures
Thin-layer chromatography (TLC) was performed on commercial
Kieselgel 60F254 silica gel plates and compounds were visualized
with KMnO4 reagent. Flash chromatography was performed on silica
gel. Drying of solutions was performed with MgSO4. Concentration
of solutions was conducted with a rotary evaporator. Progress of
the reactions and conversion was determined by GC–MS (GC,
HP6890; MS, HP5973) with an HP5 column (Agilent Technologies,
Palo Alto, CA). Enantio- and regioselectivities were determined by
capillary GC analysis (HP6890, Chiraldex-B-PM 30 m ꢃ 0.25 mm ꢃ
4.1.1. Route 1 (Scheme 6)––
4.1.1.1. Unmasking of aldehyde from acetal S1. In a round-bot-
tomed flask equipped with stirring bar, the acetal S1 (1.1 mL,
4.6 mmol) was dissolved in an aq 1% HCl solution (30 mL). After
8 h stirring at room temperature the reaction mixture was ex-
tracted with Et2O (3 ꢃ 15 mL). The combined organic extracts were
washed with an aq NaHCO3 solution (saturated, 2 ꢃ 30 mL), dried,
and concentrated to a colorless oil and immediately used for the
Wittig reaction. [ꢂ30% yield (unoptimized), colorless oil].
Diethyl 2-oxoethylphosphonate S2 data in accordance with
data described in Ref. 14.
0.25
l
m; HP6890, Chiralsil-DEX-CB 25 m ꢃ 0.25 mm ꢃ 0.25
lm)
using flame ionization detection or HPLC (chiralcel OB-H,
4.6 ꢃ 250 mm, 5 m, 40 °C, 0.5 mL/min, 210 nm; chiralcel OJ-H,
4.6 ꢃ 250 mm, 5 m, 40 °C, 0.5 mL/min, 210 nm) (in comparison with
authentic samples of racemates of 1,6- and 1,4-addition products).
4.1.1.2. Wittig reaction of S2. In a round-bottomed flask equipped
with stirring bar under a N2 atmosphere, S-ethyl 2-(triphenylphos-
phoranylidene)ethanethioate (1.49 g, 4.09 mmol, 1.3 equiv) was
dissolved in anhydrous CH2Cl2 (30 mL). The aldehyde S2 (0.57 g,
3.15 mmol, 1.0 equiv) was added, the reaction mixture was heated
to reflux and stirred for 48 h, allowed to cool to room temperature,
and stirred for 4 days at room temperature. The reaction mixture
was then concentrated and the remaining solid was extracted with
n-pentane (3 ꢃ 10 mL). The combined organic extracts were con-
centrated to a yellow oil. Flash column chromatography (gradient
EtOAc/pentane 50:50 to EtOAc) yielded 11 as a colorless oil (yield
ꢂ60%) with a minor impurity of triphenylphosphine oxide. (E)-S-
Ethyl 4-(diethoxyphosphoryl)but-2-enethioate 11: [ꢂ60% yield,
colorless oil mixed with some white solid]. For spectroscopic data
vide infra.
Optical rotations were measured in CH2Cl2 or CHCl3 on
a
Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell
(c given in g/100 mL). 1H NMR spectra were recorded at 400 MHz
with CDCl3 as a solvent (Varian AMX400 spectrometer). 13C NMR
spectra were obtained at 100.59 MHz in CDCl3. The nature of the car-
bon was determined from APT 13C NMR experiments. Chemical
shifts were determined relative to the residual solvent peaks (CHCl3,
d = 7.26 for hydrogen atoms, d = 77.16 for carbon atoms). The follow-
ing abbreviations were used to indicate signal multiplicity: s, sin-
glet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet. High
resolution mass spectra were determined on a AEI-MS-902 mass
spectrometer by EI (70 eV) measurements or on a FTMS Orbitrap
FischerScientific mass spectrometer by ESI measurements in posi-
tive mode. Fragmentation patterns were determined by GC–MS
(GC, HP6890; MS, HP5973) with an HP5 column (Agilent Technolo-
gies, Palo Alto, CA). All reactions under N2 atmosphere were con-
ducted using standard Schlenk techniques. CH2Cl2 was distilled
from CaH2 under N2 prior to use. THF was distilled from Na using
benzophenone as an indicator under N2 prior to use. tBuOMe was
distilled from CaH2 under N2 prior to use. CuBrꢁSMe2 was purchased
from Sigma–Aldrich. (+)-(S,R)-Reversed Josiphos, (ꢀ)-(R,S)-reversed
Josiphos, (+)-(S,R)-Josiphos and (ꢀ)-(R,S)-Josiphos were purchased
from Sigma–Aldrich. For Josiphos the prepared CuBr complexes
were used.4c MeMgBr was purchased from Sigma–Aldrich and was
titrated using sBuOH and catalytic amounts of 1,10-phenanthroline
before use.
4.1.2. Route 2 (Scheme 6)
4.1.2.1. Bromination of crotonic acid15. In a round-bottomed flask
equipped with stirring bar, crotonic acid (20 g, 0.23 mol, 1.0 equiv)
and N-bromosuccinimide (46 g, 0.25 mol, 1.1 equiv) were dis-
solved in benzene (200 mL). After the solution was heated at reflux,
azobis(isobutyronitile) (1.14 g, 6.97 mmol, 3 mol %) was added and
refluxing was continued for 2 h. Then the reaction solution was
cooled to 0 °C and filtered over Celite. The residue was washed
with toluene (50 mL). The filtrate was concentrated and recrystal-
lized from toluene to yield S4 as a white solid in several batches.
(E)-4-bromobut-2-enoic acid (4-bromocrotonic acid) S4: [70%
yield, white solid, melting point: 74.7–75.3 °C]. 1H NMR d 11.63
(s, br, 1H), 7.10 (dt, J = 7.3 Hz, 15.3 Hz, 1H), 6.03 (d, J = 15.4 Hz,
1H), 4.01 (d, J = 7.3 Hz, 2H), spectrum contains traces of crotonic
acid; 13C NMR d 171.3 (C), 144.65 (CH), 123.99 (CH), 28.86 (CH2);
MS m/z 166 (M+[Br81], 56), 164 (M+[Br79], 56), 85 (MꢀBr, 100);
HRMS calcd for C4H5BrO2 163.9473, found 163.9471.
Diethyl phosphonoacetaldehyde diethyl acetal, crotonic acid,
N-bromosuccinimide, EtSH, DCC, triethyl phosphite, sorbic acid,
isovaleraldehyde, DBU, and DIBAL-H were purchased from Sig-
ma–Aldrich. Azobis(isobutyronitrile) was purchased from Janssen
Chimica. DMAP, (E)-2-heptenal, and hydrocinnamylaldehyde
were purchased from ACROS. EDC-HCl salt was purchased from
Fluka.
4.1.2.2. Thioesterification of 4-bromocrotonic acid16. In a round-
bottomed flask equipped with stirring bar under a N2 atmosphere,
4-bromocrotonic acid S4 (3.47 g, 21.02 mmol, 1.0 equiv), EtSH
(1.55 mL, 21.02 mmol, 1.0 equiv), and DMAP (0.26 g, 2.10 mmol,
0.1 equiv) were dissolved in CH2Cl2 (120 mL), the solution was
cooled to 0 °C and DCC (4.76 g, 23.12 mmol, 1.1 equiv) was added.
After addition the reaction mixture was stirred for 16 h at room
temperature. The reaction mixture was then filtered over Celite
S-Ethyl 2-(triphenylphosphoranylidene)ethanethioate was pre-
pared as described in Ref. 9. Triethylphosphonocrotonate was pur-
chased from Aldrich (90% technical grade) and purified by column
chromatography (gradient Et2O/pentane 25:75 to Et2O) to give
pure (2E)-triethylphosphonocrotonate.
All spectral data are available via the authors and at the www via
the library of the University of Groningen via this link: http://ir.ub
.rug.nl/search.php?Query=An+enantioselective+catalytic+approach
+to+syn+deoxypropionate+units+combining+asymmetric+Cu-cat-
alyzed+1%2C6-+and+1%2C4-conjugate+addition&Archive=&Sear-
chIn=&Year=.
––
This route was only performed on analytical scale.

T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
1579
Route 1:
O
(1.3 equiv.)
O
OEt
OEt
O
O
O
O
Ph3P
HCl (catalytic)
H2O
SEt
(EtO)2P
(EtO)2P
(EtO)2P
H
SEt
CH2Cl2
S1
S2: 30%
11: 60%
Route 2:
HSEt (1.0 equiv.)
DCC (1.1 equiv.)
DMAP (0.1 equiv.)
P(OEt)3
(1.15 equiv.)
NBS (1.1 equiv.)
AIBN (0.3 equiv.)
O
O
O
Br
Br
11:
65%
OH
OH
SEt
benzene
CH2Cl2
S3
S4: 70%
S5: 70%
Route 3:
HSEt (1.0 equiv.)
EDC HCl (1.1 equiv.)
DMAP (0.1 equiv.)
O
O
O
O
NaOH (1.0 equiv.)
H2O
(EtO)2P
(EtO)2P
11: 81%
OEt
OH
CH2Cl2
S6
S7: 70%
Scheme 6. Synthesis of extended Horner–Wadsworth–Emmons reagent 11.
3
and the residue was washed with CH2Cl2 (30 mL). The combined
organic extracts were washed with an aq NaHCO3 solution (satu-
rated, 150 mL), H2O (150 mL), and a saturated brine solution
(100 mL), dried and concentrated to a colorless oil. Flash chroma-
tography (Et2O/pentane 1:99) yielded S5 as a colorless oil. (E)-S-
Ethyl 4-bromobut-2-enethioate S5 data in accordance with data
described in Ref. 16. [70% yield, colorless oil].
(CH2), 16.11 (d JC-P 5.9, CH3), 14.40 (CH3); 31P NMR d 25.13
(t, J = 13.6 Hz); MS m/z 266 (M+, 3), 205 (MꢀSEt, 62), 177
(MꢀCOSEt, 33), 149 (C5H10O3, 100); HRMS calcd for C10H19O4PS
266.0742, found 266.0729.
4.1.3.3. Synthesis of substrates for 1,6-additio4n.1..3.3.1. Thioesteri-
fication of sorbic acid18
.
In a round-bottomed flask equipped with
stirring bar under N2 atmosphere, sorbic acid (1.12 g, 10.0 mmol,
1.0 equiv) was dissolved in anhydrous CH2Cl2 (30 mL). Subse-
quently, DMAP (0.12 g, 1.0 mmol, 0.1 equiv) and EtSH (0.97 mL,
13.0 mmol, 1.3 equiv) were added and the reaction mixture was
cooled to 0 °C using an ice bath. Then, DCC (2.17 g, 10.5 mmol,
1.05 equiv) dissolved in anhydrous CH2Cl2 (15 mL) was added
slowly. After addition, the ice bath was removed and the reaction
mixture was stirred for 16 h at room temperature. The reaction
mixture was then filtered over Celite and the residue was washed
with CH2Cl2 (50 mL). The combined organic extracts were then
washed with saturated aqueous NaHCO3-solution (50 mL), H2O
(50 mL) and a saturated brine solution (50 mL), dried, and concen-
trated. Flash column chromatography (Et2O/pentane 2.5:97.5)
yielded 7a as a colorless oil. (2E,4E)-S-Ethylhexa-2,4-dienethioate
7a: [80% yield, colorless oil] 1H NMR d 7.14 (dd, J = 15.2 Hz,
10.1 Hz, 1H), 6.22–6.06 (m, 2H), 6.02 (d, J = 15.1 Hz, 1H), 2.92
(qd, J = 7.4 Hz, 1.3 Hz, 2H), 1.82 (d, J = 5.9 Hz, 3H), 1.24 (td,
J = 7.4 Hz, 1.3 Hz, 3H); 13C NMR d 190.26 (C), 140.99 (CH), 140.85
(CH), 129.84 (CH), 126.39 (CH), 23.31 (CH2), 19.01 (CH3), 15.03
(CH3); MS m/z 156 (M+, 15), 95 (MꢀSEt, 100), 67 (MꢀCOSEt, 38);
HRMS calcd for C8H12OS 156.0609, found 156.0607.
4.1.2.3. Arbuzov reaction of S5. In
a round-bottomed flask
equipped with stirring bar, (E)-S-ethyl 4-bromobut-2-enethioate
S5 (2.0 g, 9.57 mmol, 1.0 equiv) and triethyl phosphite (2.33 mL,
13.40 mmol, 1.4 equiv) were mixed and warmed in a preheated
oil bath at 100 °C. The mixture was stirred for 30 min and allowed
to cool down to room temperature. Flash column chromatography
(EtOAc/pentane 67:33) yielded 11 as a light yellow oil. (E)-S-Ethyl
4-(diethoxyphosphoryl)but-2-enethioate 11: [65% yield, light yel-
low oil]. For spectroscopic data vide infra.
4.1.3. Route 3 (Scheme 6)
4.1.3.1. Saponification of triethylphosphonocrotonate S6. Com-
pound S7 was obtained via a known procedure.17 4-Diethoxyphos-
phorylbut-2-enoic acid S7 data in accordance with data described
in Ref. 17 (4-diethoxyphosphoryl-2-butenoic acid). [70% yield, col-
orless oil].
4.1.3.2. Thioesterification of S7. In
a round-bottomed flask
equipped with stirring bar under a N2 atmosphere, 4-diethoxy-
phosphorylbut-2-enoic acid S7 (8.98 g, 40.42 mmol, 1.0 equiv),
EtSH (3.0 mL, 40.42 mmol 1.0 equiv), and DMAP (0.49 g,
4.04 mmol, 0.1 equiv) were dissolved in CH2Cl2 (100 mL), the solu-
tion was cooled to 0 °C, and EDC-HCl salt (8.52 g, 44.46 mmol,
1.1 equiv) was added. After addition the reaction mixture was stir-
red for 16 h at room temperature. The reaction mixture was then
washed with an aq Na2CO3 solution (saturated, 3 ꢃ 100 mL), H2O
(2 ꢃ 100 mL) and a saturated brine solution (75 mL). The organic
extracts were dried and carefully concentrated to a colorless oil.
Flash column chromatography (gradient EtOAc/pentane 20:80 to
EtOAc) yielded 11 as a colorless oil. (E)-S-Ethyl 4-(diethoxyphos-
phoryl)but-2-enethioate 11: [81% yield, colorless oil]. 1H NMR d
6.85–6.67 (m, 1H), 6.20 (dd, J = 15.5 Hz, 4.8 Hz, 1H), 4.20–3.98
(m, 4H), 2.92 (q, J = 7.4 Hz, 2H), 2.70 (ddd, J = 23.0 Hz, 7.8 Hz,
1.3 Hz, 2H), 1.30 (t, J = 7.1 Hz, 6H), 1.25 (t, J = 7.4 Hz, 3H); 13C
4.1.3.4. Wittig reaction of (E)-hept-2-enal and S-ethyl 2-(triphe-
nylphosphoranylidene)ethanethioate. In a round-bottomed flask
equipped with stirring bar, triethyl phosphate S-ethyl 2-(triphenyl-
phosphoranylidene)ethanethioate (5.43 g, 14.9 mmol, 1.3 equiv)
was dissolved in anhydrous CH2Cl2 (80 mL). The (E)-hept-2-enal
(1.5 mL, 11.5 mmol, 1.0 equiv) was added, then the reaction mix-
ture was heated at reflux, and stirred for 20 h. The reaction mixture
was then concentrated and the remaining solid was extracted with
n-pentane (3 ꢃ 10 mL). The combined organic extracts were
concentrated to
a yellow oil. Flash column chromatography
(Et2O/pentane 1:99) yielded 7b as a colorless oil. (2E,4E)-S-Ethyl-
nona-2,4-dienethioate 7b: [61% yield, 14:1 E/Z-ratio, colorless
oil]. 1H NMR d 7.16 (dd, J = 15.2 Hz, 10.1 Hz, 1H), 6.22–6.09 (m,
2H), 6.05 (d, J = 15.2 Hz, 1H), 2.93 (q, J = 7.4 Hz, 2H), 2.16 (dd,
J = 13.9 Hz, 6.7 Hz, 2H), 1.39 (dt, J = 14.4 Hz, 7.2 Hz, 2H), 1.34–
1.29 (m, 2H), 1.26 (td, J = 7.4 Hz, 0.5 Hz, 3H), 0.88 (t, J = 7.2 Hz,
2
3
NMR d 188.83 (C), 133.03 (d, JC-P 11.2, CH), 132.24 (d, JC-P 13.7,
2
1H), 62.04 (d, JC-P 6.6, CH2), 30.10 (d, JC-P 138.2, CH2), 22.86

1580
T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
3H); 13C NMR d 190.33 (C), 146.56 (CH), 141.14 (CH), 128.42 (CH),
126.56 (CH), 33.06 (CH2), 30.99 (CH2), 23.35 (CH2), 22.44 (CH2),
15.08 (CH3), 14.07 (CH3); MS m/z 198 (M+, 14), 137 (MꢀSEt,
100), 81 (C5H5O, 39); HRMS calcd for C11H18OS 198.1078, found
198.1083; E/Z ratio was determined by 1H NMR.
exanethioate (0.51 g, 2.21 mmol, 1.0 equiv) was dissolved in anhy-
drous CH2Cl2 (5 mL). After 5 min stirring at room temperature, the
mixture was cooled to ꢀ75 °C and DIBAL-H (1.0 M solution in
CH2Cl2, 2.66 mL, 2.66 mmol, 1.2 equiv) was added. The solution
turned pink/orange. The reaction mixture was stirred for 5 h at
ꢀ75 °C. Subsequently the reaction mixture was poured into a
round-bottomed flask with aq Rochelle’s salt-solution (saturated,
10 mL), stirred for 1 h at rt, and the layers were separated. After
extraction with CH2Cl2 (2 ꢃ 5 mL), the combined organic extracts
were washed with the aq Rochelle’s salt solution (2 ꢃ 5 mL), dried,
and carefully concentrated. The aldehyde was used without further
purification in the subsequent HWE reaction.
4.1.3.5. General procedure for the Horner–Wadsworth–
Emmons reaction of an aldehyde and HWE reagent 11. In a
round-bottomed flask equipped with stirring bar (E)-S-ethyl 4-
(diethoxyphosphoryl)but-2-enethioate11(1.5 equiv)wasdissolved
in anhydrous THF (20.0 mL/mmol substrate) and cooled to ꢀ78 °C.
The LHMDS (1 M in THF, Aldrich, 1.4 equiv) was added dropwise
and the mixture stirred for 30 min. Then, the aldehyde (1.0 equiv)
dissolved in anhydrous THF (4.0 mL/mmol substrate) was added
dropwise. After addition, the solution was allowed to warm to
ꢀ40 °C (in approximately 3 h) and stirred for 16 h in total. A solution
of NH4Cl (1 M, 2 mL/mmol substrate) was added and the mixture
was extracted with Et2O (3 ꢃ 4 mL/mmol substrate). The combined
organic extracts were dried and concentrated. Flash column chro-
matography (Et2O/pentane 1:99) yielded 7 as a colorless oil.
(2E,4E)-S-Ethyl 7-methylocta-2,4-dienethioate 7c: [70% yield
(0.5 mmol scale), >95:5 E/Z-ratio, colorless oil]. 1H NMR d 7.16 (d,
J = 15.2 Hz, 10.0 Hz, 1H), 6.20–6.01 (m, 3H), 2.93 (q, J = 7.3 Hz,
2H), 2.03 (t, J = 6.6 Hz, 2H), 1.68 (dt, J = 13.3 Hz, 6.7 Hz, 1H), 1.25
(t, J = 7.4 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H); 13C NMR d 190.29 (C),
145.28 (CH), 141.02 (CH), 129.50 (CH), 126.64 (CH), 42.65 (CH2),
28.47 (CH), 23.33 (CH2), 22.52 (CH3), 15.06 (CH2); MS m/z 198
(M+, 18), 137 (MꢀSEt, 100); HRMS calcd for C11H18OS 198.1078,
found 198.1087; E/Z ratio was determined by 1H NMR.
4.2.1. Chain extension
Compounds 7f and 19 were obtained via the general procedure
for the Horner–Wadsworth–Emmons reaction of the correspond-
ing aldehyde and HWE reagent 11.
4.2.1.1. (S,2E,4E)-S-Ethyl 10-(benzyloxy)-7-methyldeca-2,4-
,ààà
dienethioate 7f
. Compound 7f [64% yield (two steps,
0.5 mmol scale), >95:5 E/Z-ratio, ½a D20
¼ þ1:2 (c 1.0, CHCl3), color-
ꢄ
less oil]. 1H NMR d 7.30–7.17 (m, 5H), 7.12 (dd, J = 15.2 Hz,
9.6 Hz, 1H), 6.14–5.96 (m, 3H), 4.42 (s, 2H), 3.37 (t, J = 6.6 Hz,
2H), 2.88 (q, J = 7.4 Hz, 2H), 2.16–2.06 (m, 1H), 2.00–1.90 (m,
1H), 1.66–1.44 (m, 3H), 1.39–1.27 (m, 1H), 1.25–1.07 (m, 4H),
0.82 (d, J = 6.6 Hz, 3H); 13C NMR d 190.13 (C), 144.91 (CH),
140.83 (CH), 138.70 (C), 129.63 (CH), 128.47 (CH), 127.72 (CH),
127.63 (CH), 126.59 (CH), 73.02 (CH2), 70.66 (CH2), 40.71 (CH2),
33.12 (CH), 33.01 (CH2), 27.43 (CH2), 23.27 (CH2), 19.65 (CH3),
15.03 (CH3); MS m/z 332 (M+, 1), 91 (C6H5CH2, 100); HRMS calcd
for C20H28O2SNa 355.1708, found 355.1699; E/Z ratio was deter-
mined by 1H NMR.
(2E,4E)-S-Ethyl 7-phenylhepta-2,4-dienethioate 7d: [39% yield
(0.5 mmol scale), >95:5 E/Z-ratio, colorless oil]. 1H NMR d 7.33–
7.25 (m, 2H), 7.23–7.13 (m, 4H), 6.25–6.11 (m, 2H), 6.07 (d,
J = 15.2 Hz, 1H), 2.96 (qd, J = 7.4 Hz, 1.1 Hz, 2H), 2.75 (t, J = 7.7 Hz,
2H), 2.50 (dd, J = 14.5 Hz, 7.0 Hz, 2H), 1.28 (td, J = 7.4 Hz, 1.2 Hz,
3H); 13C NMR d 190.07 (C), 144.80 (CH), 141.10 (C), 140.63 (CH),
128.92 (CH), 128.54 (CH), 128.48 (CH), 126.93 (CH), 126.20 (CH),
35.13 (CH2), 34.96 (CH2), 23.28 (CH2), 14.99 (CH3); MS m/z 246
(M+, 4), 185 (MꢀSEt, 63), 91 (C6H5CH2, 100); HRMS calcd for
4.2.1.2. (2E,4E,7S,9S)-S-Ethyl 7,9-dimethyltrideca-2,4-dienethio-
ate 19. Compound 19 [61% yield (two steps), >95:5 E/Z-ratio,
½
a 2D0
ꢄ
¼ þ9:4 (c 1.0, CHCl3), colorless oil]. 1H NMR d 7.19 (dd,
J = 15.1 Hz, 9.9 Hz, 1H), 6.23–6.02 (m, 3H), 2.95 (q, J = 7.4 Hz, 2H),
2.23–2.14 (m, 1H), 1.96 (dt, J = 14.5 Hz, 7.3 Hz, 1H), 1.72–1.61 (m,
1H), 1.53–1.41 (m, 1H), 1.33–1.15 (m, 9H), 1.11–1.00 (m, 1H),
1.00–0.91 (m, 1H), 0.91–0.78 (m, 9H); 13C NMR d 190.24 (C),
145.23 (CH), 140.95 (CH), 129.60 (CH), 126.48 (CH), 44.71 (CH2),
40.56 (CH2), 36.59 (CH2), 30.47 (CH), 30.12 (CH), 29.28 (CH2),
23.28 (CH2), 23.16 (CH2), 20.31 (2 ꢃ CH3), 15.00 (CH3), 14.30
(CH3); MS m/z 253 (M+ꢀEt, 1), 109 (C7H9O,55), 95 (C6H7O, 100),
81 (C5H5O, 100), 55 (C3H3O, 74); HRMS calcd for C17H31OS
283.2096, found 283.2090.
C
15H18OS 246.1078, found 246.1090, E/Z ratio was determined by
1H NMR.
(2E,4E)-S-Ethyl 6-(benzyloxy)hexa-2,4-dienethioate 7e:|||| [47%
yield (0.5 mmol scale), >95:5 E/Z-ratio, colorless oil, purified by flash
column chromatography (2:98 to 6:94 Et2O/pentane)]. 1H NMR d
7.30–7.15 (m, 5H), 7.09 (dd, J = 15.2 Hz, 10.0 Hz, 1H), 6.15–6.01 (m,
2H), 5.98 (d, J = 15.1 Hz, 2H), 4.40 (s, 2H), 3.39 (td, J = 6.2 Hz,
1.5 Hz, 2H), 2.87 (qd, J = 7.4 Hz, 1.7 Hz, 2H), 2.24–2.16 (m, 2H),
1.72–1.61 (m, 2H), 1.19 (td, J = 7.4 Hz, 1.8 Hz, 3H); 13C NMR d
190.11 (C), 145.37 (CH), 140.76 (CH), 138.53 (C), 128.75 (CH),
128.49 (CH), 127.76 (CH), 127.70 (CH), 126.73 (CH), 73.05 (CH2),
69.40 (CH2), 29.95 (CH2), 28.87 (CH2), 23.27 (CH2), 15.00 (CH3); MS
m/z 229 (M+ꢀSEt, 1), 91 (C6H5CH2, 100); HRMS calcd for C17H22O2S-
Na 313.1238, found 313.1228; E/Z ratio was determined by 1H NMR.
4.3. General procedure for the enantioselective 1,6-conjugate
addition:7,§§§ (exemplified for the addition of MeMgBr to 7b)
In a dried Schlenk tube equipped with a septum and a stirring
bar under
a
N2 atmosphere, CuBrꢁSMe2 (5.14 mg, 25
l
l
mol,
mol,
5.0 mol %) and (S,R)-reversed Josiphos (15.46 mg, 26
4.2. General procedure for the reduction of a thioester to an
aldehyde
The required aldehyde was prepared as described in ||||. Then subsequent Wittig
olefination and asymmetric 1,4-addition were described in van Summeren, R. P.;
Moody, D. B.; Feringa, B. L.; Minnaard, A. J. J: Am: Chem: Soc: 2006, 128, 4546-4547.
Finally, reduction to the aldehyde is described in ref 6f ((-)-(5R,7R,9S,11S,13S) -14-
(tert-butyl-diphenyl-silanyloxy)-5,7,9,11,13-pentamethyl-tetradec-2-enethioic acid
S-ethyl ester).
In a dried Schlenk tube equipped with a septum and a stirring
bar under a N2 atmosphere (S)-S-ethyl 6-(benzyloxy)-3-methylh-
ààà
||||
Enantiomeric excess and regioselectivity for (S)-S-ethyl 6-(benzyloxy)-3-meth-
The required aldehyde was prepared via known procedures. Synthesis of 4-
ylhexanethioate were determined by chiral HPLC analysis, column: Chiralcel-OB-H,
(99.5:0.5 heptane:iPrOH); retention times (min): 28.5 ((S)-enantiomer), 29.7 ((R)-
enantiomer).
This reaction has been performed up to 2.7 mmol scale. For reactions at a larger
scale extended reaction times are required. Typically >95% conversion was achieved
in up to 40 h.
benzyloxybutane-1-ol is described in van Summeren, R. P.; Moody, D. B.; Feringa, B.
L.; Minnaard, A. J.; J. Am. Chem. Soc. 2006, 128, 4546-4547. Subsequent oxidation to
the aldehyde was performed using IBX oxidation described in Harutyunyan, S. R.;
Zhao, Z.; den Hartog, T.; Bouwmeester, K.; Minnaard, A. J.; Feringa, B. L.; Govers, F.
Proc Natl. Acad. Sci. USA 2008, 105, 8507-8512 (4-(tert-butyldimethylsilanyloxy)but-2-
enethioic acid S-ethyl ester).
xxx

T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
1581
5.25 mol %) were dissolved in anhydrous CH2Cl2 (2 mL). After
5 min stirring at room temperature, the mixture was cooled to
ꢀ70 °C and MeMgBr (Aldrich, 3.0 M solution in Et2O, 0.33 mL,
1.0 mmol, 2.0 equiv) was added. After stirring for an additional
10 min, a solution of 7b (70.1 mg, 0.5 mmol, 1.0 equiv) in anhy-
drous CH2Cl2 (additional 0.5 mL) was added with syringe pump
over 2 h. The reaction mixture was stirred overnight (16 h includ-
ing addition) at ꢀ70 °C and subsequently EtOH (0.1 mL) and an aq
NH4Cl-solution (1 M, 0.5 mL) were added. The mixture was
warmed to room temperature and an additional 5 mL of the
NH4Cl-solution and 5 mL of CH2Cl2 were added and the layers were
separated. After extraction with CH2Cl2 (2 ꢃ 5 mL), the combined
organic extracts were dried and carefully concentrated to a yellow
oil. Flash column chromatography (Et2O/pentane 1:99) yielded 13b
as a colorless––– oil.
Enantiomeric excess and regioselectivity were determined by
chiral HPLC analysis, column: Chiralcel-OB-H, (99:1 heptane/
iPrOH); retention times (min): 14.7 (1,4-addition product), 19.6
((S)-enantiomer), 17.9 ((R)-enantiomer).
4.3.4. (S,E)-S-Ethyl 8-(benzyloxy)-5-methyloct-3-enethioate 13e
This product was purified with flash chromatography (gradient
1:99 to 5:95 Et2O/pentane). [86% yield, 86% ee, 94:6 regioselectiv-
ity (1,6:1,4), ½a D20
ꢄ
¼ þ5:9 (c 1.0, CHCl3), colorless oil]. 1H NMR d
7.36–7.24 (m, 5H), 5.54–5.41 (m, 2H), 4.49 (s, 2H), 3.45 (t,
J = 6.6 Hz, 2H), 3.20 (dd, J = 3.9 Hz, 1.6 Hz, 2H), 2.85 (q, J = 7.4 Hz,
2H), 2.20–2.09 (m, 1H), 1.70–1.52 (m, 2H), 1.45–1.30 (m, 2H),
1.23 (t, J = 7.4 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H).; 13C NMR d 198.37
(C), 141.91 (CH), 138.78 (C), 128.45 (CH), 127.71 (CH), 127.58
(CH), 119.97 (CH), 72.95 (CH2), 70.57 (CH2), 47.73 (CH2), 36.80
(CH), 33.34 (CH2), 27.66 (CH2), 23.42 (CH2), 20.51 (CH3), 14.85
(CH3); MS m/z 277 (M+ꢀEt, 1), 153 (C9H13O2, 14), 91 (C6H5CH2,
100); HRMS calcd for C18H26O2SNa 329.1551, found 329.1538.
Enantiomeric excess was determined by chiral HPLC analysis,
column: Chiralcel-OJ-H, (98:2 heptane/iPrOH); for (E)-methyl 8-
(benzyloxy)-5-methyloct-3-enoate;|||||| retention times (min): 23.5
((S)-enantiomer), 24.7 ((R)-enantiomer). Regioselectivity was deter-
mined by 1H NMR with 10 s d1-time.
4.3.1. (S,E)-S-Ethyl 5-methylnon-3-enethioate 13b
Compound 13b [83% yield, 89% ee, 99:1 regioselectivity
(1,6:1,4), ½a 2D0
ꢄ
¼ þ9:0 (c 1.0, CHCl3), colorless oil]. 1H NMR d
5.50–5.39 (m, 2H), 3.19 (d, J = 5.7 Hz, 2H), 2.84 (q, J = 7.4 Hz, 2H),
2.18–2.04 (m, 1H), 1.31–1.16 (m, 9H), 0.96 (d, J = 6.7 Hz, 3H),
0.86 (t, J = 6.7 Hz, 3H); 13C NMR d 198.74 (C), 142.55 (CH), 119.57
(CH), 47.89 (CH2), 36.94 (CH), 36.73 (CH2), 29.70 (CH2), 23.50
(CH2), 22.98 (CH2), 20.55 (CH3), 14.90 (CH3), 14.33 (CH3); MS m/z
214 (M+, 10), 124 (MꢀSEt-Et, 34), 83 (C6H11, 46), 69 (C5H9, 100);
HRMS calcd for C12H22OS 214.1391, found 214.1401.
4.3.5. Syn-selective enantioselective 1,6-addition
Enantiomeric excess and regioselectivity were determined by
chiral GC analysis, column: Chiraldex-B-PM, 50–98 °C in 4.8 min,
98 °C for 200 min; retention times (min): 163.8 (an enantiomer
of the 1,4-addition product), 191.1 ((R)-enantiomer), 192.3 ((S)-
enantiomer).
4.3.5.1. (5S,7S,E)-S-Ethyl 10-(benzyloxy)-5,7-dimethyldec-3-
enethioate 13f. Compound 13f [88% yield, 87% syn-product (13f)
and 13% of anti-product (13g), 85:15 regioselectivity (1,6:1,4),
½
a 2D0
ꢄ
¼ ꢀ0:9 (c 1.0, CHCl3), colorless oil]. 1H NMR d 7.38–7.23 (m,
5H), 5.52–5.25 (m, 2H), 4.50 (s, 2H), 3.44 (t, J = 6.7 Hz, 2H), 3.19
(d, J = 6.4 Hz, 2H), 2.86 (q, J = 7.4 Hz, 2H), 2.32–2.19 (m, 1H),
1.72–1.01 (m, 10H), 1.00–0.92 (m, 3H), 0.89–0.79 (m, 3H); residual
peaks 1,4-addition product: 2.75–2.64 (m, 1H), 2.50 (ddd, J = 36.1,
4.3.2. (S,E)-S-Ethyl 5,7-dimethyloct-3-enethioate 13c
Compound 13c [84% yield, 82% ee, 95:5 regioselectivity
14.4, 7.3 Hz, 2H), residual peaks
a,b-unsaturated 1,6-addition
(1,6:1,4), ½a 2D0
ꢄ
¼ þ8:3 (c 1.0, CHCl3), colorless oil]. 1H NMR d
product: 2.04–1.76 (m, 1H); 13C NMR d 198.55 (C), 142.21 (CH),
138.81 (C), 128.47 (CH), 127.73 (CH), 127.59 (CH), 119.73 (CH),
72.99 (CH2), 70.96 (CH2), 47.76 (CH2), 44.51 (CH2), 34.59 (CH),
33.93 (CH2), 30.25 (CH), 27.34 (CH2), 23.40 (CH2), 21.43 (CH3),
19.50 (CH3), 14.93 (CH3); residual peaks anti-product: 198.68 (C),
142.71 (CH), 119.28 (CH), 44.37 (CH2), 34.31 (CH), 33.22 (CH2),
30.16 (CH), 20.30 (CH3), 19.91 (CH3), 14.83 (CH3); residual peaks
1,4-addition product of the 1,6-ACA: 135.20, 128.16, 54.33, 51.35,
44.88, 42.91, 39.91, 33.09, 32.92, 21.71, 20.41; MS m/z 319
(M+ꢀEt, 1), 91 (C6H5CH2, 100); HRMS calcd for C21H32O2SNa
371.2021, found 371.2010.
5.51–5.37 (m, 2H), 3.18 (d, J = 5.6 Hz, 2H), 2.84 (q, J = 7 .4 Hz,
2H), 2.26–2.14 (m, 1H), 1.63–1.50 (m, 1H), 1.32–1.11 (m, 5H),
0.94 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.6 Hz, 6H); 13C NMR d 198.69
(C), 142.58 (CH), 119.48 (CH), 47.87 (CH2), 46.45 (CH2), 34.77
(CH), 25.63 (CH), 23.50 (CH2), 23.21 (CH3), 22.56 (CH3), 20.93
(CH3), 14.92 (CH3); MS m/z 214 (M+, 1), 89 (C3H5OS, 24), 83
(C6H11, 29), 69 (C4H5O, 100), 55 (C3H3O, 32); HRMS calcd for
C12H22OSNa 237.1289, found 237.1280.
Enantiomeric excess was determined by chiral GC analysis, col-
umn: Chiraldex-B-PM, 50–80 °C in 3 min, 80 °C for 40 min, 80–
160 °C in 8 min, 160 °C for 4 min; for 2,4-dimethylpentanoic acid;19
retention times (min): 53.7 ((S)-enantiomer), 54.0 ((R)-enantiomer).
Regioselectivity was determined by 1H NMR with 10 s d1-time.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time. Regioselectivity was determined by 1H NMR with
10 s d1-time.
4.3.3. (S,E)-S-Ethyl 5-methyl-7-phenylhept-3-enethioate 13d
Compound 13d [78% yield, 82% ee, 99:1 regioselectivity
4.3.5.2. (5S,7S,9S,E)-S-Ethyl 5,7,9-trimethyltridec-3-enethioate
20. Compound 20 [87% yield, 91% syn-product 20 and 9% of anti-
(1,6:1,4), ½a 2D0
ꢄ
¼ þ4:1 (c 1.0, CHCl3), colorless oil]. 1H NMR d
product 21, 90:10 regioselectivity (1,6:1,4), ½a D20
¼ ꢀ2:4 (c 1.0,
ꢄ
7.33–7.16 (m, 5H), 5.62–5.46 (m, 2H), 3.26 (d, J = 5.5 Hz, 2H),
2.90 (q, J = 7.4 Hz, 2H), 2.75–2.51 (m, 2H), 2.28–2.15 (m, 1H),
1.72–1.60 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H);
13C NMR d 198.22 (C), 142.69 (C), 141.78 (CH), 128.50 (CH),
128.36 (CH), 125.72 (CH), 120.35 (CH), 47.74 (CH2), 38.68 (CH2),
36.50 (CH), 33.69 (CH2), 23.41 (CH2), 20.57 (CH3), 14.85 (CH3);
MS m/z 262 (M+, 1), 200 (M+ꢀSEtH, 16), 131 (C10H11, 40), 117
(C5H9OS, 15), 104 (C4H8OS, 20), 91 (C6H5CH2, 100); HRMS calcd
for C16H24OS 263.1470, found 263.1464.
CHCl3), colorless oil]. 1H NMR d 5.53–5.25 (m, 2H), 3.20 (d,
J = 6.6 Hz, 2H), 2.90–2.81 (m, 2H), 2.26 (dt, J = 13.6 Hz, 6.7 Hz,
14H), 1.61–1.39 (m, 3H), 1.34–1.10 (m, 10H), 1.06–0.74 (m,
14H); residual peaks 1,4-addition product of the 1,6-ACA: 2.69
||||||
(E)-methyl 8-(benzyloxy)-5-methyloct-3-enoate was obtained via the following
procedure; The substrate (ꢂ10 mg) was dissolved in MeOH (0.5 mL) and stirred for
3 h in the presence of K2CO3 (excess), then an aq. NH4Cl-solution (1 M, 0.5 mL) was
added and the layers were separated. After extraction with Et2O (2x 0.5 mL), the
combined organic extracts were dried and carefully concentrated to a yellow oil.
Filtration over a short SiO2-column (eluent Et2O) and evaporation of the solvent
yielded the product as a colorless oil.
–––
Occasionally the product was polluted with
undetectable by GC/MS or NMR.
a yellow coloured side product

1582
T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
(dd, J = 13.9 Hz, 7.0 Hz, 1H), 2.50 (ddd, J = 38.1 Hz, 14.4 Hz, 7.3 Hz,
2H). residual peaks ,b-unsaturated 1,6-ACA product: 1.97 (dd,
4.4. General procedure for the isomerization of the b,
unsaturated thioester to the ,b-unsaturated thioester:
(exemplified for the isomerization of 13b)
c-
a
a
J = 12.7 Hz, 7.0 Hz, 2H), 1.79–1.69 (m, 2H); 13C NMR d 198.59 (C),
142.32 (CH), 119.76 (CH), 47.80 (CH2), 45.82 (CH2), 44.54 (CH2),
36.76 (CH2), 34.63 (CH), 30.00 (CH), 29.35 (CH2), 27.72 (CH2),
23.42 (CH), 23.20 (CH2), 21.64 (CH3), 20.33 (2 ꢃ CH3), 14.84
(CH3), 14.34 (CH3); residual peaks 1,4-addition product of the
1,6-ACA: 51.40, 39.66, 30.49; MS m/z 269 (M+ꢀEt, 1), 111
(C7H11O, 57), 97 (C6H9O,55), 69 (C4H5O, 100), 57 (C4H9, 75), 55
(C3H3O, 62); HRMS calcd for C18H34OSNa 321.2228, found
321.2217.
In a dried round-bottomed flask equipped with a cooler and a
stirring bar under N2 atmosphere, 13b (0.37 g, 1.7 mmol,
a
1.0 equiv) was dissolved in anhydrous CH2Cl2 (18 mL). After
5 min stirring at room temperature DBU (1.3 mL, 8.6 mmol,
5.0 equiv) was added and the reaction mixture immediately turned
yellow/orange. The reaction mixture was heated at reflux and stir-
red for 16 h. Subsequently an aq NH4Cl-solution (1 M, 20 mL) and
10 mL of CH2Cl2 were added and the layers were separated. After
extraction with CH2Cl2 (2 ꢃ 10 mL), the combined organic extracts
were dried and carefully concentrated to a yellow oil. Flash column
chromatography (Et2O/pentane 1:99) yielded 15b as a colorless oil.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time. Regioselectivity was determined by 1H NMR with
10 s d1-time.
4.3.6. Anti-selective enantioselective 1,6-addition
4.4.1. (S,E)-S-Ethyl 5-methylnon-2-enethioate 13b
4.3.6.1. (5R,7S,E)-S-Ethyl 10-(benzyloxy)-5,7-dimethyldec-3-
enethioate 13g. Compound 13g [83% yield, 78% anti-product
(13g) and 22% of syn-product (13f), 87:13 regioselectivity
Data are in accordance with data described in Ref. 4d. [91% yield
of a mixture of 88% a,b-, 12% b,c-unsaturated 1,6-ACA product and
traces of 1,4-addition side product from the 1,6-ACA, ½a D20
¼ þ1:0
ꢄ
(1,6:1,4), ½a 2D0
ꢄ
¼ ꢀ2:2 (c 1.0, CHCl3), colorless oil]. 1H NMR d
(c 1.0, CHCl3), literature value4d: [
a
]
D = ꢀ2.0 (c 1.0, CHCl3) for
7.38–7.24 (m, 5H), 5.53–5.25 (m, 2H), 4.51 (s, 2H), 3.50–3.40 (m,
2H), 3.24–3.15 (m, 2H), 2.86 (qd, J = 7.4 Hz, 1.4 Hz, 2H), 2.32–2.19
(m, 4H), 1.74–1.09 (m, 10H), 0.96 (dd, J = 9.0 Hz, 6.7 Hz, 3H),
0.90–0.77 (m, 3H); residual peaks 1,4-addition product of the
1,6-ACA: 2.70 (dd, J = 13.8 Hz, 6.7 Hz, 1H), 2.50 (ddd, J = 35.0 Hz,
(S)-enantiomer, colorless oil]. Ratio of
a,b- and b,c-product was
determined by 1H NMR with 10 s d1-time.
4.4.2. (S,E)-S-Ethyl 5,7-dimethyloct-2-enethioate 13c
Compound 13c [87% yield of a mixture of 90% ,b-, 10% b,c-
a
14.3 Hz, 7.2 Hz, 2H); residual peaks a,b-unsaturated 1,6-ACA prod-
unsaturated 1,6-ACA product and traces of 1,4-addition side prod-
uct from the 1,6-ACA, ½a D20
ꢄ
¼ ꢀ4:3 (c 1.0, CHCl3), colorless oil]. 1H
uct: 2.05–1.95 (m, 1H), 1.86–1.75 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H);
13C NMR d 198.55 (C), 142.72 (CH), 138.81 (C), 128.46 (CH), 127.73
(CH), 127.59 (CH), 119.28 (CH), 72.99 (CH2), 71.01 (CH2), 47.77
(CH2), 44.37 (CH2), 34.31 (CH), 33.23 (CH2), 30.17 (CH), 27.24
(CH2), 23.42 (CH2), 20.31 (CH3), 19.91 (CH3), 14.83 (CH3); residual
peaks syn-product: 142.22 (CH), 119.73 (CH), 44.51 (CH2), 34.59
(CH), 33.93 (CH2), 30.25 (CH), 27.35 (CH2), 21.44 (CH3), 19.51
(CH3), 14.93 (CH3); residual peaks 1,4-addition product of the
1,6-ACA: 135.18, 128.27, 51.37, 39.96, 33.05, 32.97, 27.45, 20.45;
MS m/z 319 (M+ꢀEt, 1), 91 (C6H5CH2, 100); HRMS calcd for
NMR d 6.86 (dt, J = 15.2 Hz, 7.5 Hz, 1H), 6.08 (dt, J = 15.4 Hz,
1.4 Hz, 1H), 2.93 (q, J = 7.4 Hz, 2H), 2.24–2.11 (m, 1H), 2.05–1.92
(m, 1H), 1.77–1.51 (m, 2H), 1.33–0.77 (m, 14H); residual peaks
b,c-unsaturated 1,6-ACA product and 1,4-addition product of the
1,6-ACA: 5.49–5.23 (m), 3.19 (d), 2.89–2.80 (m), 2.74–2.65 (m),
2.53 (dd), 2.48–2.41 (m), 1.84 (t); 13C NMR d 190.14 (C), 144.34
(CH), 129.90 (CH), 46.37 (CH2), 40.07 (CH2), 30.31 (CH), 25.34
(CH), 23.37 (CH3), 23.16 (CH2), 22.27 (CH3), 19.77 (CH3), 14.95
(CH3); residual peaks b,c-unsaturated 1,6-ACA product and 1,4-
C
21H32O2SNa 371.2021, found 371.2010.
addition side product from 1,6-ACA: 142.47, 134.92, 128.62,
119.40, 51.38, 47.78, 41.94, 34.68, 34.51, 28.48, 25.54, 22.47,
22.36, 22.32, 20.84, 20.46; MS m/z 214 (M+, 1), 153 (M+ꢀSEt, 46),
83 (C6H11, 39), 55 (C3H3O, 64); HRMS calcd for C12H22OSNa
237.1289, found 237.1279.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time. Regioselectivity was determined by 1H NMR with
10 s d1-time.
Ratio of
10 s d1-time.
a,b- and b,c
-product was determined by 1H NMR with
4.3.6.2. (5R,7S,9S,E)-S-Ethyl 5,7,9-trimethyltridec-3-enethioate
21. Compound 21 [85% yield, 72% anti-product 21 and 28% of
syn-product 20, 90:10 regioselectivity (1,6:1,4), ½a D20
¼ þ2:5 (c
ꢄ
4.4.3. (S,E)-S-Ethyl 5-methyl-7-phenylhept-2-enethioate 13d
This reaction was performed at room temperature. Reaction at
reflux gave lower yield and a side-product. [87% yield of a mixture
1.0, CH2Cl2), colorless oil]. 1H NMR d 5.54–5.24 (m, 2H), 3.23–
3.11 (m, 2H), 2.92–2.77 (m, 2H), 2.33–2.17 (m, 1H), 1.59–1.38
(m, 3H), 1.33–1.12 (m, 10H), 1.08–0.64 (m, 14H); residual peaks
1,4-addition product of the 1,6-ACA: 2.77–2.64 (m, 1H), 2.50
of 89% a,b-, 11% b,c-unsaturated 1,6-ACA product and traces of 1,4-
addition side product from the 1,6-ACA, 80% ee, ½a D20
¼ þ3:9 (c 1.0,
ꢄ
(ddd, J = 37.7 Hz, 14.4 Hz, 7.3 Hz, 1H); residual peaks
a,b-unsatu-
CHCl3), colorless oil]. 1H NMR d 7.33–7.22 (m, 2H), 7.21–7.12 (m,
3H), 6.86 (dt, J = 15.3 Hz, 7.5 Hz, 1H), 6.09 (d, J = 15.5 Hz, 1H),
2.94 (q, J = 7.4 Hz, 2H), 2.79–2.46 (m, 2H), 2.30–2.00 (m, 2H),
1.76–1.59 (m, 2H), 1.55–1.41 (m, 1H), 1.28 (td, J = 7.4 Hz, 1.8 Hz,
3H), 0.97 (d, J = 6.5 Hz, 3H); 13C NMR d 190.05 (C), 143.85 (CH),
142.44 (C), 130.03 (CH), 128.46 (CH), 128.42 (CH), 125.85 (CH),
39.63 (CH2), 38.56 (CH2), 33.48 (CH2), 32.27 (CH2), 23.16 (CH),
19.61 (CH3), 14.93 (CH3); MS m/z 262 (M+, 1), 105 (C8H9, 17), 91
(C6H5CH2, 100); HRMS calcd for C16H23OS 263.1470, found
263.1464.
rated 1,6-ACA product: 2.03–1.93 (m, 1H), 1.78–1.67 (m, 1H); 13C
NMR d 198.72 (C), 142.95 (CH), 119.13 (CH), 47.81 (CH2), 45.48
(CH2), 44.56 (CH2), 36.51 (CH2), 34.26 (CH), 30.07 (CH), 29.31
(CH2), 27.68 (CH2), 23.43 (CH), 23.21 (CH2), 20.60 (CH3), 20.50
(CH3), 20.46 (CH3), 20.10 (CH3), 14.34 (CH3); residual peaks syn-
product: 198.55 (C), 142.32 (CH), 119.76 (CH), 45.82 (CH2), 44.70
(CH2), 36.75 (CH2), 34.63 (CH), 30.45 (CH), 21.64 (CH3), 20.33
(CH3), 14.84 (CH3); residual peaks 1,4-addition product of the
1,6-ACA: 135.09, 128.40, 51.41, 39.80, 36.70, 34.51, 20.16, 14.93;
MS m/z 269 (M+ꢀEt, 1), 111 (C7H11O, 57), 97 (C6H9O,55), 69
(C4H5O, 100), 57 (C4H9, 75), 55 (C3H3O, 62); HRMS calcd for
Enantiomeric excess was determined by chiral HPLC analysis,
column: Chiralcel-OB-H, (99:1 heptane/iPrOH); retention times
(min): 16.6 ((S)-enantiomer b,c-unsaturated 1,6-ACA product),
C
18H35OS 299.2403, found 299.2404.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time. Regioselectivity was determined by 1H NMR with
10 s d1-time.
This reaction was performed from 0.3 mmol up to 1.7 mmol scale.

T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
1583
17.8 ((R)-enantiomer b,
((S)-enantiomer ,b-unsaturated 1,6-ACA product), 24.8 ((R)-enan-
tiomer ,b-unsaturated 1,6-ACA product). Ratio of ,b- and b,
product was determined by 1H NMR with 10 s d1-time.
c
-unsaturated 1,6-ACA product), 19.9
[
a
]
D = ꢀ8.9 (c 0.5, CHCl3) for (3S,5R)-enantiomer, colorless oil].
a
Ratio of syn- and anti-product and enantiomeric excess were deter-
mined by chiral GC analysis as described previously in Ref. 4d,
column: Chiralsil-Dex-CB, 50–80 °C in 3 min, 80 °C for 90 min,
80–140 °C in 60 min, retention times (min): 140.3 ((3S,5S)-enan-
tiomer), 140.9 ((3R,5R)-enantiomer), 142.1 ((3S,5R)-enantiomer),
142.5 ((3R,5S))-enantiomer).
a
a
c-
4.4.4. (S,E)-S-Ethyl 8-(benzyloxy)-5-methyloct-2-enethioate 13e
This product was purified with flash chromatography (gradient
1:99 to 5:95 Et2O/pentane). [86% yield of a mixture of 89% a,b-, 11%
b,
c
-unsaturated 1,6-ACA product and traces of 1,4-addition side
4.5.3. (3S,5S)-S-Ethyl 3,5,7-trimethyloctanethioate 22c
product from the 1,6-ACA, ½a D20
ꢄ
¼ ꢀ1:6 (c 1.0, CHCl3), colorless oil].
Compound 22c [67% yield of a mixture of 90% syn-22c and 10%
1H NMR d 7.35–7.19 (m, 5H), 6.82 (dt, J = 15.3 Hz, 7.5 Hz, 1H), 6.05
(d, J = 15.5 Hz, 1H), 4.45 (s, 2H), 3.41 (t, J = 6.6 Hz, 3H), 2.90 (q,
J = 7.4 Hz, 2H), 2.20–2.10 (m, 1H), 2.04–1.94 (m, 1H), 1.68–1.48 (m,
2H), 1.43–1.29 (m, 2H), 1.27–1.20 (m, 3H), 0.87 (d, J = 6.7 Hz, 3H);
of anti-22c, ½a 2D0
ꢄ
¼ ꢀ9:1 (c 1.0, CH2Cl2), colorless oil]. 1H NMR d
2.87 (q, J = 7.4 Hz, 2H), 2.53 (dd, J = 14.3 Hz, 5.3 Hz, 1H), 2.28 (dd,
J = 14.3 Hz, 8.5 Hz, 1H), 2.18–2.07 (m, 1H), 1.70–1.47 (m, 2H),
1.29–1.17 (m, 4H), 1.14–1.06 (m, 1H), 1.05–0.79 (m, 14H); 13C
NMR d 199.51 (C), 51.44 (CH2), 46.59 (CH2), 45.24 (CH2), 28.71
(CH), 27.75 (CH), 25.29 (CH), 23.79 (CH3), 23.43 (CH2), 22.17
(CH3), 20.31 (CH3), 20.28 (CH3), 14.98 (CH3); residual peaks anti-
product: 47.49, 44.60, 30.47, 22.52, 19.38; MS m/z 201 (M+ꢀEt,
4), 112 (M+ꢀSEt-(CH3)2CHCH2, 31), 95 (C6H7O, 95), 69 (C4H5O,
100), 57 (C4H9, 55), 55 (C3H3O, 37); HRMS calcd for C13H27OS
231.1777, found 231.1777.
residual peaks b,c-unsaturated 1,6-ACA product: 5.46–5.41 (m, 2H),
3.16 (d, J = 5.6 Hz, 3H), 2.81 (q, J = 7.4 Hz, 2H) 1.20–1.15 (m, 3H),
0.96 (dd, J = 6.7 Hz, 3.5 Hz, 3H); 13C NMR d 190.01 (C), 144.01 (CH),
138.63 (C), 129.93 (CH), 128.42 (CH), 127.69 (CH), 127.57 (CH),
72.98 (CH2), 70.52 (CH2), 39.64 (CH2), 33.14 (CH), 32.56 (CH2), 27.36
(CH2),23.11 (CH2), 19.61(CH3),14.91 (CH3);residualpeaksb,c-unsat-
urated 1,6-ACA product: 141.86 (CH), 119.91 (CH), 69.66 (CH2), 51.23
(CH2), 47.68 (CH2), 36.75 (CH), 33.29 (CH2), 27.60 (CH2), 20.45 (CH3);
MSm/z277(M+ꢀEt,1), 91(C6H5CH2, 100); HRMScalcdforC18H26O2S-
Na 329.1551, found 329.1540.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time.
Ratio of
a
,b- and b,
c
-product was determined by 1H NMR with
4.5.4. (3S,5S)-S-Ethyl 3,5-dimethyl-7-phenylheptanethioate 22d
Compound 22d [73% yield of a mixture of 94% syn-22d and 6% of
10 s d1-time.
anti-22d, ½a 2D0
ꢄ
¼ ꢀ4:8 (c 1.0, CHCl3), colorless oil]. 1H NMR d 7.42–
4.5. General procedure for the enantioselective 1,4-conjugate
addition:4d,àààà (exemplified for the addition of MeMgBr to 15b)
7.34 (m, 2H), 7.33–7.24 (m, 3H), 2.98 (q, J = 7.4 Hz, 2H), 2.83–2.73
(m, 1H), 2.72–2.58 (m, 2H), 2.40 (dd, J = 14.4 Hz, 8.3 Hz, 1H), 2.30–
2.17 (m, 1H), 1.81–1.59 (m, 2H), 1.58–1.47 (m, 1H), 1.47–1.39 (m,
1H), 1.35 (t, J = 7.4 Hz, 3H), 1.15 (ddd, J = 11.6 Hz, 10.2 Hz, 7.0 Hz,
1H), 1.06 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H); residual peaks
anti-product: 2.56 (1H), 2.47 (dd, J = 14.4, 7.8 Hz, 1H); 13C NMR d
199.37 (C), 143.00 (C), 128.40 (2 ꢃ CH), 125.70 (CH), 51.38 (CH2),
44.44 (CH2), 38.55 (CH2), 33.28 (CH2), 29.83 (CH), 28.75 (CH),
23.41 (CH2), 20.23 (CH3), 20.11 (CH3), 14.96 (CH3); residual peaks
anti-product: 44.12 (CH2), 19.38 (CH3); MS m/z 217 (M+ꢀSEt, 13),
91 (C6H5CH2, 100); HRMS calcd for C17H27OS 279.1783, found
279.1777.
In a dried Schlenk tube equipped with a septum and a stirring
bar under a N2 atmosphere, the preprepared4d Josiphos-complex
(5.54 mg, 7.5 lmol, 1.0 mol %) was dissolved in anhydrous tBuOMe
(3.05 mL). After 5 min stirring at room temperature the mixture
was cooled to ꢀ78 °C and MeMgBr (Aldrich, 3.0 M solution in
Et2O, 0.38 mL, 1.1 mmol, 1.5 equiv) was added. After stirring for
an additional 10 min, a solution of 15b (0.16 mg, 0.75 mmol,
1.0 equiv) in anhydrous tBuOMe (additional 0.75 mL) was added
with a syringe pump over 0.5 h. The reaction mixture was stirred
overnight (16 h including addition) at ꢀ78 °C and subsequently
EtOH (0.1 mL) and an aq NH4Cl-solution (1 M, 0.5 mL) were added.
The mixture was warmed to room temperature and an additional
5 mL of the NH4Cl-solution and 5 mL of Et2O were added and the
layers were separated. After extraction with Et2O (2 ꢃ 5 mL), the
combined organic extracts were dried and carefully concentrated
to a yellow oil. Flash column chromatography (Et2O/pentane
1:99) yielded 16 as a colorless oil.
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time.
4.5.5. (3S,5S)-S-Ethyl 8-(benzyloxy)-3,5-dimethyloctanethioate
22e
This product was purified with flash chromatography (gradient
1:99 to 5:95 Et2O/pentane). [64% yield of a mixture of 94% syn-22e
and 6% of anti-22e, ½a D20
ꢄ
¼ ꢀ2:8 (c 1.0, CH2Cl2), colorless oil]. 1H
NMR d 7.38–7.24 (m, 5H), 4.51 (d, J = 2.1 Hz, 2H), 3.45 (td,
J = 6.7 Hz, 2.3 Hz, 2H), 2.87 (qd, J = 7.4 Hz, 2.5 Hz, 2H), 2.52 (ddd,
J = 14.4 Hz, 5.3 Hz, 2.3 Hz, 1H), 2.28 (ddd, J = 14.4 Hz, 8.5 Hz,
2.5 Hz, 1H), 2.18–2.06 (m, 1H), 1.73–1.63 (m, 1H), 1.63–1.53 (m,
1H), 1.53–1.44 (m, 1H), 1.44–1.34 (m, 1H), 1.31–1.19 (m, 4H),
1.19–1.08 (m, 1H), 1.08–0.98 (m, 1H), 0.93 (dd, J = 6.6 Hz, 2.4 Hz,
3H), 0.89 (dd, J = 6.5 Hz, 2.4 Hz, 3H); 13C NMR d 199.37 (C),
138.77 (C), 128.44 (CH), 127.75 (CH), 127.58 (CH), 73.00 (CH2),
70.87 (CH2), 51.33 (CH2), 44.58 (CH2), 33.08 (CH2), 30.02 (CH),
28.74 (CH), 27.20 (CH2), 23.39 (CH2), 20.31 (CH3), 20.06 (CH3),
14.95 (CH3); MS m/z 322 (M+, 1), 91 (C6H5CH2, 100); HRMS calcd
for C19H30O2S 323.2039, found 323.2036.
4.5.1. (3S,5S)-S-Ethyl 3,5-dimethylnonanethioate is in
accordance with data described in Ref. 4d
[83% yield of a mixture of 96% syn-product 16 and 4% of anti-
product 17, 92% ee, ½a D20
ꢄ
¼ ꢀ1:3 (c 1.0, CHCl3), literature value:4d
[a]D = +2.3 (c 0.5, CHCl3) for (R,R)-enantiomer, colorless oil]. Ratio
of syn- and anti-product and enantiomeric excess were determined
by chiral GC analysis as described previously in Ref. 4d, column:
Chiralsil-Dex-CB, 50–80 °C in 3 min, 80 °C for 90 min, 80–140 °C
in 60 min, retention times (min): 140.2 ((3S,5S)-enantiomer),
142.1 ((3S,5R)-enantiomer), 142.5 ((3R,5S))-enantiomer).
4.5.2. (3R,5S)-S-Ethyl 3,5-dimethylnonanethioate in accordance
with data described in Ref. 4d
Ratio of syn- and anti-product was determined by 13C NMR with
10 s d1-time.
[77% yield of a mixture of 92% anti-product (17) and 8% of syn-
product (16), 85% ee, ½a D20
ꢄ
¼ þ13:9 (c 1.0, CHCl3), literature value:4d
Acknowledgments
We thank T. D. Tiemersma-Wegman (GC, HPLC and MS), M. J.
Smith (GC and HPLC) and A. Kiewiet (MS) for technical support
àààà
This reaction was performed from 0.3 mmol up to 5.0 mmol scale.

1584
T. den Hartog et al. / Tetrahedron: Asymmetry 21 (2010) 1574–1584
Minnaard, A. J. Chem. Commun. 2007, 489–491; Phthioceranic acid: (f) ter
Horst, B.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2007, 9, 3013–3015; PDIM A:
(g) Casas-Arce, E.; ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem. Eur. J. 2008,
14, 4157–4159; Mycolipenic and mycolipanolic acid: (h) ter Horst, B.; Feringa,
B. L.; Minnaard, A. J. Eur. J. Org. Chem. 2010, 38–41; (i) 1-O-TBSA-2-O-palmitoyl-
sn-phosphotidylethanolamine: ter Horst, B.; Seshadri, C.; Sweet, L.; Young, D.
C.; Feringa, B. L.; Moody, D. B.; Minnaard, A. J., J. Lip. Res. 2010, 51, 1017-1022;
(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyldocosane: (j) Zhou, J.; Zhu, Y.; Burgess,
K. Org. Lett. 2007, 9, 1391–1393; C14–C20 fragment of TMC-151A: (k) Lum, T.-
K.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2008, 10, 761–764.
(Stratingh Institute, University of Groningen). Financial support
from the Netherlands Organization for Scientific Research (NWO-
CW) is gratefully acknowledged.
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