Chiral enolates for highly stereoselective aldol reactionsdScope and limitations

Article abstract of DOI:10.1016/j.tet.2010.10.048

Enantioselective approaches to the formation of a,b-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure b-substituted silyl enol ether

Full text of DOI:10.1016/j.tet.2010.10.048

Tetrahedron 66 (2010) 9954e9963
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral enolates for highly stereoselective aldol reactionsdScope and limitations
*
Matthias Welker, Simon Woodward
University of Nottingham, School of Chemistry, University Park, NG7 2RD Nottingham, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2010
Received in revised form 28 September 2010
Accepted 18 October 2010
Available online 17 November 2010
Enantioselective approaches to the formation of a,b-disubstituted ketones through aldol reactions are
compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving
enantiomerically pure -substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin
provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel
synthesis of functionalized -unsaturated acetals is also described.
Ó 2010 Elsevier Ltd. All rights reserved.
b
b,g
Keywords:
Aldol
Conjugate addition
Tandem
Asymmetric
Copper
1. Introduction
often low, yields.4,5 Among the most interesting synthetic use for
chiral zinc enolates, we were attracted by an elegant conjugate ad-
dition/aldol domino6 and the preparation of chiral silyl enol ethers by
Alexakis and Knopff.7 This study on the use of chiral acetals for the
preparation of trans/syn and trans/anti aldol compounds showed
promising preliminary results. However, this study was limited to the
use of ZnEt2 as a nucleophile, and only two chiral acetals and to the
best of our knowledge no further details have appeared. We have
extended thiswork and defined its scope and limitations with respect
to other nucleophiles, and functionalized chiral acetals.
In the last decade, extensive studies have contributed to the de-
velopment of highly enantioselective copper(I)-catalyzed asym-
metric conjugate addition (ACA) reactions of diorganozinc reagents
using phosphoramidite ligands. These have been recently reviewed.1
However, beyond the possibility of adding sp3 or sp2 carbon nucle-
ophiles with high enantioselectivities, these developments have also
opened the way for use of the chiral enolates resulting from these
reactions. Indeed, the chiral Zn-enolate products are interesting re-
active species in their own right, which can be used for further
functionalization through tandem reactions rather than simple
protonation. Consequently, a number of disperate studies on the
formation of products containing several stereogenic centers with
high enantio- and diastereoselectivities have appeared from such
proceses over the past few years.2 These have been summarized by
Ma and Guo.3 Despite this situation very few systematic comparisons
of the scope and limitations of such enolate trapping protocols have
appeared, which lead us to disclose the results here.
Most chiral acetals required for this scope study were prepared in
good yields from commercially available aldehydes (Table 1). Addi-
tionally, we describe here an unprecedented synthetic pathway to
the preparation of chiral acetals of
b,g-unsaturated aldehydes.
(Scheme 2, see later). Initial investigations indicated difficulties in
extending the literature precedent6 (Table 2, entry 1 vs 2). Although
benzaldehyde reacted under TMSOTf catalysis, simple alkyl acetal
systems proved less reactive and failed to react under conditions
similar to those used by Alexakis et al.6 This could be due to lower
reactivity in the alkyl acetals used, but also due to the lower re-
activity of ZnMe2 compared to ZnEt2. Therefore alternative condi-
tions were tested, and strongly Lewis acidic TiCl4 was found to be an
effective activator of all acetals used, giving the desired products
with excellent diastereomeric ratios (entries 4e10).
2. Results and discussion
2.1. Developments in the ACA/aldol domino reaction
The moderate yields obtained for these domino reactions were
quite limiting and this convinced us to investigate the use of silyl
enol ethers in a Mukaiyama-type reaction9 instead of Zn enolates as
the nucleophiles. A range of aggregated species is likely to be
present in domino aldol reaction and that this might be a cause of
In the late 1990sitwasfoundthatzincenolatesresultingfromACA
reactions could be used for subsequent aldol reactions in variable,
* Corresponding author. E-mail address: Simon.Woodward@nottingham.ac.uk
(S. Woodward).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.048

M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
9955
Table 1
Preparation of chiral acetals
transformations. Other Lewis acids were inefficient when used in
this reaction (entries 2,3).
R
Ph
OH
The reaction did not work with ketals (entry 4). Both cyclo-
propyl and halogenated aryl acetals gave satisfying results (entries
7e10). The products were in most cases isolated as single di-
astereomers. The use of the (S,S)-enantiomer of 6 also produced
a single diastereomer, therefore confirming that the threo/erythro
selectivity of the aldol reaction can be totally controlled by the
configuration of the acetal moiety.
AD-mix α (S,S)
O
or
Ph
Ph
R1
R2
Ph
O
O
R1
R2
R
or
S
AD-mix β (R,R)
Ph
Ph
OH
OH
t-BuOH
3 d.
p-TSA, toluene,
Ph
110 °C, 24 h
1
3-9
Ph
OH
S
2
Indeed, adduct 12 was crystalline and an X-ray structure (Fig. 1)
confirmed the absolute configuration of the compound. It corre-
sponded to the expected results from proposed transition states
and from comparison with literature results.6,11
Entry
Diol config.
Aldehyde
Product
Yielda
O
1
2
S,Sb
R,Rc
3
4
81%
93%
Ph
We then sought to investigate the possibility of constructing and
using more complex and functionalized acetals. Therefore a new
route toward difunctional complex acetals has been developed
(Scheme 2). Satisfyingly, the desymmetrization12 of malonaldehyde
dimethyl acetal was very efficient and 24 was isolated in 66% yield.
We were pleased to see that, whereas a standard WittigeHorner
reaction on aldehyde 26 afforded (E)-27 as a 94:6 mixture, the
StilleGennari modification13 allowed us to completely reverse the
selectivity and afforded (Z)-27 as the only geometrical isomer. Fi-
nally, acetal 10 reacted cleanly with TMS enol ether 21 in good, but
not perfect, selectivity (Table 3, entry 12, d.r. 7:1).
O
O
O
3
4
R,R
R,R
5
6
65%
56%
Ph
O
5
6
R,R
R,R
7
8
85%
80%
2.3. Removal of the chiral auxiliary
O
As the results of Table 3 show, even complex acetals can lead to
good to excellent diastereocontrol of aldol reactions from chiral
enolates, providing either trans/threo or trans/erythro aldol adducts
as required. However, the main limitation of this approach resides
in the fact that the aldol product is not obtained directly, but that
a further step is required for the removal of the chiral auxiliary. In
2001, Alexakis6 used a multistep procedure for the removal of the
auxiliary: treatment with acidic Amberlyst-15 removed the TMS
group and the auxiliary was then removed in a further two steps,
via PDC oxidations and treatment with Zn, and acetic acid.
Alternatively we report here that the auxiliary can be simply
removed in a more user-friendly single step using cerium(IV) am-
monium nitrate (CAN).14 The results of this reaction on some sub-
strates are presented in Table 4. The alcohols can be attained in
good yields using this methodology.
Cl
F
O
7
R,R
9
61%
a
b
c
Isolated yield after column chromatography.
(S,S)-Diol 2 prepared from stilbene diol in 99% ee.8
(R,R)-Diol was purchased from SigmaeAldrich.
the limited yields. Therefore isolating a TMS enol ether after the
ACA reaction should result in an improvement of the efficiency of
the aldol reaction.
3. Conclusion
2.2. Developments of a Mukaiyama asymmetric aldol
reaction using chiral acetals
In conclusion, the scope and limitations of two different methods
to produce rapidly and with high stereoselectivity complex com-
pounds containing three chiral centers were compared. An ACA/al-
dol domino approach while intellectually attractive, has limitations
due to its low yielding nature. A two-step procedure, where a chiral
zinc enolate is first trapped as a silyl enol ether and later subjected to
Mukaiyama conditions, showed significant advantages. Not only the
enol ether can be stored for weeks without degradation, but also this
reaction proceeds in higher yields and with excellent diaster-
eocontrol of the new chiral centers. In this latter case useful
Examples of Mukaiyama aldol reactions where an existing chiral
center
b to the carbonyl is used to also induce a trans stereo-
chemistry are not common (Scheme 1). Our concept is to first install
the stereochemistry on carbon C1 via a highly stereoselective 1,4-
conjugate addition and trap the enolate with TMSOTf in order to
isolate the chiral TMS enol ether.7 These compounds were prepared
in good yields using the known methodology. They are stable and
can easily be stored for weeks in a refrigerator (Scheme 1).
This enol ether will then undergo a Mukaiyama reaction, which
would lead to the introduction of the desired stereochemistry at
centers C1, C2, and C3 with complete control.6,10 It was assumed that
the methyl and alkylchain at centers C1andC2 wouldbe preferentially
in the thermodynamically more stable trans configuration, while the
configuration at center C3 should not depend on the configuration of
center C2, but should be fully controlled by the acetal.6,11 This would
give access to both trans/threo and trans/erythro diastereomers.
A study was performed using the same substrates as for the
domino reaction; the results are reported in Table 3. An appreciable
enhancement in the yields can be noticed when compared with the
domino reaction (Table 2). However, TiCl4 is still needed for these
difunctionalized acetals derived from
b,g-unsaturated aldehydes
react in good yields and selectivities with good functional group
tolerance. The utility of this latter method is also significantly
inproved by single-step oxidative cleavage of the chiral auxiliary.
4. Experimental section
4.1. General methods
Infrared spectra were recorded by using a PerkineElmer 983 G
infrared spectrophotometer and a PerkineElmer 882 infrared

9956
M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
Table 2
ACA/aldol domino reaction with chiral acetals
R1Zn
R2
R1
Ph
O
O
O
L1 4 mol%,
H
Cu(OTf)2 2 mol%
Zn(R1)2, CH2Cl2
Ph
3-8
Ph
P N
Ph
O
O
O
OH
Lewis acid
L1
R1
O
−30 °C, 2 h
Substrates:
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
Ph
Cl
O
O
5
O
O
4
O
8
Ph
Ph
3
7
6
Entry
1
Substr.
R1
Lewis acid
TMSOTfa
Yieldd
Prod. (selectivity)
Products
3
Et
25%
11 (Single diaster.)
Products:
Ph
H
O
Ph Ph
O
Ph
2
3
4
5
6
7
8
9
4
4
4
4
4f
5
6
7
8
Me
Me
Me
Et
Me
Me
Me
Me
Me
TMSOTfb
0%
0%
/
/
H
H
Ti(OiPr)4or BF3$Et2Oc
Ph
Ph
Ph
O
O
O
TiCl4
44%f
32%f
6%f
13 (86:14)e
14 (91:9)e
c
OH
OH
TiCl4
11
12
TiCl4
13 (80:20)e
/
c
c
TiCl4
0%
c
TiCl4
34%
46%
41%
12 (Single diaster.)
15 (Single diaster.)
16 (Single diaster.)
O
Ph
O
Ph
c
H
TiCl4
Ph
Ph
c
10
TiCl4
O
OH
OH
13
14
Cl
O
Ph
O
Ph
H
H
Ph
O
O
OH
OH
15
16
a
Conditions: Lewis acid 1.5 equiv, Acetal 1.5 equiv, ꢀ20 ꢁCe0 ꢁC, 2 h.
b
c
Conditions: Acetal 1.5 equiv, ꢀ20 ꢁC to room temperature, overnight ꢁC, 2 h.
Typical conditions for the ACA/Cu(OTf)2 2 mol %, L1 4 mol %, Zn(Me)2 1.3 equiv, CH2Cl2, ꢀ40 ꢁC, 1 h. Typical conditions for the trapping step: see general procedure B in
Experimental section.
d
Isolated yield.
e
Determined by 1H NMR on the benzylic protons signals.
f
Reaction performed with MeMgBr as the nucleophile, typical conditions for the ACA/MeMgBr 1.15 equiv, CuCl 5 mol %, TaniaPhos 6 mol %, Et2O, 0 ꢁC, 20 min.
100 cm3). GC analyses were performed on a Varian 3380 gas
i) Zn(R1)2
Ph
O
chromatography. Light petroleum refers to that fraction with bp
L1 4 mol%
TMS
R1
R2
O
O
O
R2
40e60 ꢁC.
Cu(OTf)2 2 mol%,
Ph
O
H
−30 oC, 3 h
Ph
3
CO
Ligand L1,5a (S,S)(ꢀ)-hydrobenzoin 28 and silyl enol ethers 21,7
and 237 were obtained by literature procedures.
Ph
C2
Lewis acid, CH2Cl2
ii) CH2Cl2
OH
−78 oC, 4 h
1
C1
R
TMSOTf
n
n
−20 oC to r.t., 2 h
controlled by
trans config.
the acetal config.
21 n = 1, R1 = Me 55%, 96% ee
22 n = 2, R1 = Me 63%, 94% ee
23 n = 1, R1 = Et 71%, 98% ee
4.2. General procedures
Ph
4.2.1. General procedure A. Preparation of chiral acetals: In a 3-neck
flask equipped with a DeaneStark apparatus, (R,R)-(þ)- or (S,S)-
(ꢀ)-hydrobenzoin 2 (1 equiv) and the aldehyde (1 equiv) were
dissolved in toluene (5 mL/mmol). To this solution was added
a catalytic amount of p-TSA (2 mol %) and the resulting solution was
heated at reflux overnight. After 20 h the reaction was monitored
by TLC (Petrol/Et2O 2:1), which showed no trace of diol. The re-
action mixture was then allowed to cool to room temperature. Solid
Na2CO3 was added (200 mg/mmol) and the suspension was filtered.
Solvent was then removed in vacuo and the resulting crude acetal
purified by column chromatography (Petrol/Et2O 2:1), to afford the
desired products.
O
L1 =
P N
O
Ph
Scheme 1. Chiral TMS enol ethers preparation for use in step-wise Mukaiyama protocols.
spectrophotometer. 1H and 13C NMR spectra were recorded on
either Jeol (JNM GX270) or Bruker (DPX400, AV400) spectrometers
(using tetramethylsilane as a standard). All spectra were recorded
at ambient temperature unless otherwise noted. Mass spectra
were obtained on FinniganMAT 1020 or Autospec VG (electron
impact ionisation, EI) Finnigan QMS (electrospray ionisation, ES)
machines. Elemental analyses were performed by using a Fisons
Instrument EA 1108 CHN elemental analyser. Optical rotations
were measured using a Bellingham Stanley ADP440 digital polar-
imeter at ambient temperature in units of 10ꢀ1 cm2 gꢀ1 (c in g/
4.2.2. General procedure B for 1,4-conjugate addition/aldol domino
reaction. A suspension of Cu(OTf)2 (3.6 mg, 2.0 mol %) and (R,S,S)-
Feringa ligand L1 (10.8 mg, 4.00 mol %) in CH2Cl2 (1 mL) was stirred
under argon at room temperature for 15 min. The suspension was

M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
9957
Table 3
Mukaiyama reaction on model chiral acetals
TMS
R1
O
R2 Ph
O
4-10
H
Ph
OH
O
Lewis acid, CH2Cl2
−78 °C, 4 h
R1
n
n
R1 = Me, n = 1, 21
12-20
R1 = Me, n = 2, 22
R
1 = Et, n = 1, 23
Substrates:
F
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
OAc
Cl
O
O
4
O
O
9
Ph
8
5
7
10
6
Run
1
Sub.
R1, n
Lewis acidd
TiCl4
Yielda
72%
Selectivityb (prod.)
Products
96:4b (13)
Products:
4
Me, 1
Ph
O
O
Ph
Ph
O
Ph
H
H
H
2
3
4
5
6
7
8
9
6
6
5
6
Me, 1
Me, 1
Me, 1
Me, 1
Me, 1
Me, 1
Me, 1
Me, 2
Et, 1
TMSOTf
0%c
0%c
0%
47%
58%
60%
62%
65%
68%
66%
61%
d
Ph
Ph
Ph
O
Ti(OiPr)4 or BF3ꢃEt2O
d
O
O
OH
OH
OH
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
d
Single diast.b (12)
Single diast.b (17)
Single diast.b (16)
Single diast.b (15)
Single diast.b (18)
Single diast.b (19)
Single diast.b (14)
7:1.b (20)
12
14
13
(S,S)e6e
Cl
8
7
7
9
4
10
Ph
H
O
Ph
O
H
Ph
O
Ph
H
10
11
12
Ph
Ph
Ph
Ph
O
O
O
Et, 1
Me, 1
OH
OH
OH
16
17
15
F
OAc
Ph
O
H
Ph
O
O
Ph
H
H
Ph
Ph
O
O
O
OH
OH
OH
18
19
20
Typical conditions: see general procedure C in Experimental section.
a
Isolated yield after column chromatography.
b
Determined by 1H NMR spectroscopy using the signals of the benzylic protons.
Starting material was recovered.
c
d
e
1.5 equiv.
The (S,S)-enantiomer of acetal 6 was used.
then cooled to ꢀ40 ꢁC, ZnMe2 (1 M in hexanes, 0.65 mL) was added.
After 20 min cyclohexenone (48 mL, 0.5 mmol) was added to the
reaction mixture. The yellow solution was left to warm to ꢀ20 ꢁC
over 1 h until completion of the reaction. A previously prepared
solution of the acetal (0.75 mmol) and TiCl4 (1 M in CH2Cl2, 0.75 mL)
in 1 mL CH2Cl2 was added at ꢀ50 ꢁC. The resulting dark red/brown
solution was then stirred at ꢀ50 ꢁC for 1 h and left to warm to room
temperature over 1e2 h. The reaction mixture was then treated with
saturated NH4Cl(aq) (10 mL) and then extracted with CH2Cl2
(3ꢂ10 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude material was thenpurified by silica
column chromatography (light petroleum/Et2O 2:1).
4.2.3. General procedure C for the asymmetric Mukaiyama re-
action. A solution of the chiral acetal (1.0 mmol) in freshly distilled
CH2Cl2 (1 mL) was prepared and cooled to ꢀ78 ꢁC. A solution of
TiCl4 (1 M in CH2Cl2, 1.1 mL, 1.1 mmol) was slowly added at ꢀ78 ꢁC.
To the dark red solution was immediately added a solution of the
TMS enol ether in 1 mL CH2Cl2 and the solution was then stirred
at ꢀ78 ꢁC for 4 h. The reaction completion was followed by TLC
(light petroleum/Et2O 2:1). After 4 h at ꢀ78 ꢁC, the reaction mixture
was treated with an aqueous solution saturated with NH4Cl
Fig. 1. Structure of aldol adduct (10R,20R,30R,2R,3R)-12.

9958
M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
Ph
O
P
Ph
F3CH2CO
F3CH2CO
O
Ph
Ph
O
OEt
O
O
Ph
Ph
Oxalic Acid (0.5 equiv.)
Silica gel
O
MeO
OMe
OMe OMe
Ph
Ph
O
O
O
O
O
25
5.5%
85%
OEt
Ph
Ph
OH
OH
1,2 Dichloroethane: THF
+
O
MeO
27
E:Z
Ph
18-crown-6,
THF, −78 oC,
30 mins
HCl 6M (cat.)
CH2Cl2
OMe
O
(1:1)
26
90 °C, 3 days
44%
0:100
24
4 days, r.t
O
66%
(75% based on
recovered Start.
mat.)
2
Ph
DIBAL-H
−78oC to rt
85%
Ac2O, DMAP
NEt3, CH2Cl2
Ph
O
Ph
Ph
O
O
0 °C, 3 h
99%
O
AcO
HO
Ph
28
10
Scheme 2. Synthesis of functionalized acetal 10.
Table 4
Auxiliary removal
was performed with benzaldehyde dimethyl acetal (693
mL,
4.66 mmol) and (S,S)-hydrobenzoin 2 (1.00 g, 4.66 mmol). After
40 h the crude was purified by column chromatography (light
petroleum/Et2O 2:1) to afford the desired product as a light
O
R
O
R
Ph
Ph
H
H
CAN (2 equiv.)
OH
O
MeCN:H2O
6:1
yellow solid (1.13 g, 81% yield); Rf (cyclohexane/EtOAc 2:1) 0.77;
OH
25
r.t., 4 h
[a
]
ꢀ20.1 (c 1.0, CHCl3); nmax (CHCl3, solution) 2887, 1723, 1495,
29-34
D
1454, 1359, 1095, 1067, 1026, 1001 cmꢀ1
; dH (400 MHz, CDCl3)
Entry
R
Isolated yield
Product
7.25e7.80 (15H, m, CHar), 6.44 (1H, s, CH), 5.00 (2H, s, PhCHeCHPh);
dC (100.6 MHz, CDCl3) 138.1,136.2,128.7,128.7 (4C),128.6 (2C),127.0
(2C), 126.8 (2C), 126.5 (2C), 104.8, 87.3, 85.4; m/z (ESþ) 197.1 (23),
325.1 (49, MþNaþ), 341.1 (100), 659.2 (44%); HRMS (ESþ): MNaþ,
found 325.1210. C21H18O2Na requires 325.1199; mp 64e65 ꢁC.
1
2
81%
82%
29
30
4.3.3. (4R,5R)-2-Hexyl-4,5-diphenyl-1,3-dioxolane
(4). Prepared
following general procedure A. The reaction was performed with
heptanal (1.96 mL, 14.0 mmol) and (R,R)-(þ)-hydrobenzoin 2
(3.00 g, 14.0 mmol). After 20 h the crude was purified by column
chromatography (light petroleum/Et2O 2:1) to afford the desired
product as a yellow solid (4.03 g, 93% yield); [found: C, 81.27; H,
3
83%
86%
31
Cl
4
5
32
33
8.48. C21H26O2 requires C, 81.25; H, 8.44%]; Rf (light petroleum/Et2O
88% (ZnEt2 useda)
24
2:1) 0.75; [
a]
þ42.0 (c 1.0, CHCl3); nmax (CHCl3, solution) 3067,
D
3009, 2930, 2860, 1733, 1605, 1497, 1455, 1361, 1288, 1241, 1140,
1118, 1025, 916, 863 cmꢀ1
;
dH (400 MHz, CDCl3) 7.42e7.17 (10H, m,
CHar), 5.55 (1H, t, J 4.6 Hz, CH(OR)2), 4.80 (1H, d, J 7.6 Hz, CHePh),
4.76 (1H, d, J 7.6 Hz, CHePh), 1.94 (2H, m, CH2), 1.67e1.57 (2H, m,
CH2); 1.50e1.40 (2H, m, CH2), 1.40e1.34 (4H, m, CH2CH2), 0.94 (3H,
t, J 7.2 Hz, CH3); dC (100.6 MHz, CDCl3) 138.8, 137.2, 128.7 (2C), 128.6
(2C), 128.5, 128.2, 126.9 (2C), 126.5 (2C), 106.0, 86.9, 85.0, 34.9, 32.0,
29.5, 23.9, 22.7, 14.2; m/z (ESþ) 333.2 (13, MþNaþ), 349.2 (100),
350.2 (20), 675.4 (54), 676.4 (22%); mp: 55 ꢁC.
6b
78%
34
OAc
a
ZnEt2 used in initial ACA reaction.
b: acetal 10 used for aldol reaction-the opposite configuration of the alcohol is
b
obtained in this case.
(10 mL). The product was extracted with CH2Cl2 (3ꢂ10 mL), com-
bined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude material was then purified by silica column
chromatography (light petroleum/Et2O 2:1).
4.3.4. (4R,5R)-2-Methyl-2-pentyl-4,5-diphenyl-1,3-dioxolane
(5). Prepared following general procedure A. The reaction was per-
formed with (R,R)-(þ)-hydrobenzoin 2 (2.20 g, 10.3 mmol) and 2-
heptanone (1.43 mL, 10.3 mmol). Purification by column chroma-
tography (light petroleum/Et2O 2:1) afforded the desired com-
pound as a yellow oil (2.07 g, 65% yield); [found: C, 81.17; H, 8.23.
4.3. Compound preparations and data
4.3.1. (S,S)-Hydrobenzoin (2)8. Prepared using the literature
method;7 Rf (cyclohexane/EtOAc 1:1) 0.57; [
a
]
25 ꢀ93.2 (c 1.0, CHCl3);
C21H26O2 requires C, 81.25; H, 8.44%]; Rf (light petroleum/Et2O 2:1)
D
24
0.72; [
a
]
D
þ46.4 (c 1.0, CHCl3); nmax (CHCl3, solution) 3068, 3009,
nmax (CHCl3, solution) 3612 (OH), 2895, 1454, 1388, 1319, 1046,
913 cmꢀ1
; dH (400 MHz, CDCl3) 7.05e7.35 (10H, m, CHar.), 4.71 (2H, s,
2985, 2935, 2872, 1605, 1497, 1455, 1378, 1308, 1241, 1141, 1099,
1064, 1040, 1026, 907, 867, 649 cmꢀ1
;
dH (400 MHz, CDCl3)
CHeCH), 2.91 (2H, s, OH); dC (100.6 MHz, CDCl3) 139.9 (2C), 128.2
(4C), 128.0 (2C), 127.0 (4C), 79.2 (2C, COH); HRMS (ESþ): MNaþ,
found 237.0886. C14H14O2Narequires 237.0886; mp 142e145 ꢁC. The
spectral data was in accordance with the literature.8
7.38e7.20 (10H, m, CHar), 4.79 (1H, d, J 8.4 Hz, CHePh), 4.74 (1H, d, J
8.4 Hz, CHePh), 1.98e1.92 (2H, m, CH2), 1.72e1.60 (2H, m, CH2), 1.67
(3H, s, CH3), 1.45e1.38 (4H, m, CH2), 0.97 (3H, t, J 7.2 Hz, CH3CH2); dC
(100.6 MHz, CDCl3) 137.2, 136.6, 128.5 (4C), 128.4, 128.3, 126.7 (2C),
126.6 (2C),111.0, 85.9, 85.1, 40.5, 32.1, 25.4, 23.7, 22.7,14.1; m/z (ESþ)
333.2 (63, MþNaþ), 334.2 (15), 415.2 (100), 431.1 (47), 610.2 (18),
4.3.2. (4S,5S)-2,4,5-Triphenyl-1,3-dioxolane (3). Prepared following
general procedure A, using heptane instead of toluene. The reaction

M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
9959
643.4 (45%); HRMS (ESþ): MNaþ, found 333.1817. C21H26O2Na re-
quires 333.1825.
(1H, d, J 8.0 Hz, CHePh); dC (100.6 MHz, CDCl3) 162.8 (d, J 246 Hz),
140.9 (d, J 6.9 Hz), 137.7, 136.1, 130.1 (d, J 7.6 Hz), 128.6 (5C), 128.3,
126.9 (2C), 126.4 (2C), 122.3 (d, J 3.0 Hz), 116.2 (d, J 21.5 Hz), 113.5 (d,
J 22.2 Hz), 103.6, 87.1, 85.2; m/z (ESþ) 304.2 (14), 325.1 (18), 343.1
(100, MþNaþ), 344.1 (22), 413.3 (58), 414.3 (15%); HRMS (ESþ):
MNaþ, found 343.1098. C21H17FO2Na requires 343.1105.
4.3.5. (4R,5R)-2-Benzyl-4,5-diphenyl-1,3-dioxolane
(6). Prepared
following general procedure A. The reaction was performed with
(R,R)-(þ)-hydrobenzoin 2 (3.00 g, 14.0 mmol) and 2-phenyl-
acetaldehyde (1.68 g, 14.0 mmol). Purification by column chroma-
tography (light petroleum/Et2O 2:1) afforded the desired
compound as a white solid (2.48 g, 56% yield); [found: C, 83.40; H,
4.3.9. (2R,3R)-3-ethyl-2-((R)-((1S,2S)-2-hydroxy-1,2-diphenyle-
thoxy)(phenyl)methyl)cyclohexanone (11). In a flame-dried Schlenk
tube was introduced under argon Cu(OTf)2 (3.6 mg, 2.0 mol %) and
(R,S,S)-Feringa ligand L1 (10.8 mg, 4.00 mol %). The suspension was
stirred in CH2Cl2 (1 mL) at room temperature for 15 min. Then the
mixture was cooled to ꢀ20 ꢁC, and diethylzinc (1 M in hexanes,
0.65 mL, 1.3 equiv) was added dropwise. After 30 min at ꢀ20 ꢁC, 2-
6.39. C22H20O2 requires C, 83.51; H, 6.37%]; Rf (light petroleum/Et2O
24
2:1) 0.70; [
a]
þ21.5 (c 0.5, CHCl3); nmax (CHCl3, solution) 3067,
D
3009, 2886, 1604, 1496, 1455, 1406, 1244, 1133, 1080, 1009, 912.
855 cmꢀ1
;
dH (400 MHz, CDCl3) 7.44e7.27 (11H, m, CHar), 7.22e7.13
(4H, m, CHar), 5.74 (1H, t, J 4.2 Hz, CH(OR)2), 4.74 (1H, d, J 8.0 Hz,
PhCHeOR), 4.61 (1H, d, J 8.0 Hz, PhCHeOR), 3.23 (2H, dd, J
4.2, 2.3 Hz, CH2); dC (100.6 MHz, CDCl3) 138.2, 136.7, 135.8,
130.2 (2C), 128.5 (4C), 128.2, 128.2 (2C), 128.1, 126.8 (2C), 126.6,
126.3 (2C), 105.4, 86.8, 85.0, 41.3; m/z (ESþ) 317.2 (6, MþHþ),
334.2 (12, MþNHþ4 ), 339.1 (100, MþNaþ), 340.1 (24), 445.3 (18%);
HRMS (ESþ): MNaþ, found 339.1345. C22H20O2Na requires
339.1356; mp 99 ꢁC.
cyclohexenone (48 mL, 0.50 mmol) dissolved in 0.5 mL of CH2Cl2
was added and the mixture stirred at ꢀ20 ꢁC for 30 min. Monitoring
by TLC (light petroleum/Et2O 4:1; Rf¼0.3) and GC (Lipodex A, iso-
thermal, 60 ꢁC, Flow rate¼2 mL/min, retention times: (þ)-enan-
tioner: 8.45 min, (ꢀ)-enantiomer: 8.65 min, 98% ee), showed
complete conversion and acetal 3 (227 mg, 0.750 mmol) was added
in a single portion at ꢀ20 ꢁC, followed by TMSOTf (0.150 mL,
0.750 mmol). This solution was stirred for 15 min at ꢀ20 ꢁC, and
then heated up to 0 ꢁC and stirred for 2 h, until TLC analysis showed
no starting material. The reaction was then quenched with NH4Cl
saturated, and the aqueous layer extracted with CH2Cl2 and Et2O.
The organic layer was dried over Na2SO4 and solvents evaporated
under vacuum. The crude was dissolved in 10 mL MeOH, a¼with
Amberlyst-15 (100 mg) for 1 h at room temperature. The solution
was then filtered, and poured into water (20 mL). An extractive
work up was performed to afford the crude oil, which was purified
by column chromatography (light petroleum/Et2O 7:3), to afford
the pure desired compound as a colorless oil (48 mg, 25% yield). The
absolute stereochemistry was assigned by analogy with previous
4.3.6. (4R,5R)-2-Cyclopropyl-4,5-diphenyl-1,3-dioxolane
(7). Prepared following general procedure A. The reaction was per-
formed with (R,R)-(þ)-hydrobenzoin 2 (2.10 g, 10.0 mmol) and
cyclopropane carboxaldehyde (0.700 g, 10.0 mmol). Purification by
column chromatography (light petroleum/Et2O 2:1) afforded the
desired compound as a yellow oil (2.25 g, 85% yield); Rf (light pe-
22
troleum/Et2O 2:1) 0.80; [
a]
þ18.7 (c 1.0, CHCl3); nmax (CHCl3, so-
D
lution) 3068, 3011, 2889, 2821, 1699, 1598, 1584, 1453, 1287, 1168,
1097, 1072 cmꢀ1
;
dH (400 MHz, CDCl3) 7.40e7.30 (8H, m, CHar.),
7.28e7.18 (2H, m, CHar.), 5.04 (1H, d, J 6.0 Hz, CH(OR)2), 4.79 (1H, d, J
8.0 Hz, CHePh), 4.75 (1H, d, J 8.0 Hz, CHePh),1.36 (1H, m, CHcyclopr.),
0.69 (2H, m, CH2cyclopr.), 0.62 (2H, m, CH2cyclopr.); dC (100.6 MHz,
CDCl3) 138.4, 136.8, 133.7, 130.2, 128.5 (4C), 126.7 (2C), 126.3 (2C),
108.6, 86.5, 84.9, 14.0, 1.4, 1.3; m/z (ESþ) 213.1 (51), 289.1 (25,
MþNaþ), 303.1 (72), 403.1 (57), 487.2 (100%); HRMS (ESþ): MNaþ,
found 289.1174. C18H18O2Na requires 289.1199.
studies6 and the diastereoselectivity was measured by 1H NMR on
23
the benzylic proton signal; Rf (light petroleum/Et2O 7:3) 0.51; [a]
D
þ39.2 (c 1.0, CHCl3); nmax (CHCl3, solution) 3564 (OH), 2931, 2874,
1704 (C]O), 1455, 1383, 1308, 1051, 909 cmꢀ1
dH (400 MHz, CDCl3)
;
7.25e7.38 (6H, m, CHar), 7.05e7.20 (5H, m, CHar), 6.95 (2H, m, CHar),
6.89 (2H, m, CHar), 4.79 (1H, d, J 8.1 Hz, COCHCHePh), 4.52 (1H, d, J
9.7 Hz, CHePh), 4.09 (1H, d, J 8.1 Hz, CHePh), 3.28 (1H, d, J 1.6 Hz),
2.77 (1H, d, J 9.7 Hz), 2.50 (1H, s, OH), 2.04 (2H, m), 1.50e1.80 (3H,
m), 1.10e1.40 (3H, m), 0.84 (3H, t, J 5.4 Hz, CH3); dC (68 MHz, CDCl3)
211.2, 139.2, 137.1, 128.9, 128.8, 128.5, 128.4, 127.8, 127.7, 127.7, 127.6,
127.2, 83.4, 78.1, 77.6, 63.4, 41.1, 38.9, 25.3, 23.7, 22.2, 12.0; HRMS
(ESþ): MNaþ, found 451.2236. C29H32O3Na requires 451.2249.
4.3.7. (4R,5R)-2-(4-Chlorophenyl)-4,5-diphenyl-1,3-dioxolane
(8). Prepared following general procedure A. The reaction was per-
formed with (R,R)-(þ)-hydrobenzoin 2 (3.00 g, 14.0 mmol) and 4-
chlorobenzaldehyde (2.00 g, 14.0 mmol). Purification by column
chromatography (light petroleum/Et2O 2:1) afforded the desired
compound as a yellow oil (4.05 g, 80% yield); Rf (light petroleum/
Et2O 2:1) 0.75; [
a
]
D
23 þ3.3 (c 1.0, CHCl3); nmax (CHCl3, solution) 3068,
3009, 2891, 1702, 1602, 1494, 1454, 1422, 1363, 1239, 1089, 1015,
824 cmꢀ1; dH (400 MHz, CDCl3) 7.66 (2H, d, J 8.4 Hz, CHar), 7.48 (2H,
d, J 8.4 Hz, CHar), 7.42e7.33 (10H, m, CHar), 6.43 (1H, s, CH(OR)2),
5.02 (1H, d, J 8.0 Hz, CHePh), 4.97 (1H, d, J 8.0 Hz, CHePh); dC
(100.6 MHz, CDCl3) 137.8, 136.8, 136.2, 135.1, 128.7 (2C), 128.6 (4C),
128.3 (2C), 128.0 (2C), 126.8 (2C), 126.4 (2C), 103.9, 87.2, 85.2; m/z
(ESþ) 219.1 (98), 263.1 (100), 359.1 (50, MþNaþ), 410.2 (39), 415.2
4.3.10. (2R,3R)-2-((R)-1-((1R,2R)-2-Hydroxy-1,2-diphenylethoxy)-2-
phenylethyl)-3-methylcyclohexanone (12). Prepared following gen-
eral procedure C, starting from acetal 6 (0.465 g, 1.50 mmol) and
TMS enol ether 21 (184 mg, 1.00 mmol). The crude material was
purified by silica column chromatography (light petroleum/Et2O
2:1), to afford the desired compound as a white solid (201 mg, 47%
yield, single isomer); [found: C, 80.95; H, 7.49. C29H32O32r3equires C,
(61), 695.2 (94%); HRMS (ESþ): MNaþ, found 359.0832.
81.27; H, 7.53%]; Rf (light petroleum/Et2O 2:1) 0.27; [
a
]
ꢀ16.7 (c
D
35
C21
H
ClO2Na requires 359.0809.
1.0, CHCl3); nmax (CHCl3, solution) 3532 (OH), 3066, 3009, 2932,
1703 (C]O), 1603, 1495, 1455, 1383, 1342, 1320, 1264, 1194, 1074,
17
4.3.8. (4R,5R)-2-(3-Fluorophenyl)-4,5-diphenyl-1,3-dioxolane
(9). Prepared following general procedure A. The reaction was per-
formed with (R,R)-(þ)-hydrobenzoin 2 (3.45 g, 16.1 mmol) and 3-
fluorobenzaldehyde (2.00 g, 16.1 mmol). Purification by column
chromatography (light petroleum/Et2O 2:1) afforded the desired
1047, 1023, 915, 852 cmꢀ1
; dH (400 MHz, CDCl3) 7.35e7.30 (2H, m,
CHar), 7.27e7.22 (3H, m, CHar), 7.20e7.14 (3H, m, CHar), 7.11e7.07
(3H, m, CHar), 6.95e6.88 (4H, m, CHar), 4.62 (1H, d, J 8.8 Hz, PheCH),
4.15 (1H, d, J 8.8 Hz, PheCH), 4.08 (1H, td, J 6.6, 1.7 Hz, CHeOR), 3.09
(2H, d, J 6.6 Hz), 2.27 (1H, dt, J 13.6, 4.8 Hz), 2.10 (1H, m), 2.05e1.95
(3H, m), 1.95e1.86 (1H, m), 1.81e1.71 (1H, m), 1.70e1.62 (1H, m),
1.26 (1H, t, J 7.2 Hz), 0.81 (3H, d, J 6.0 Hz, CH3); dC (100.6 MHz,
CDCl3) 211.5, 139.3, 139.2, 138.0, 129.3 (2C), 128.7 (2C), 128.3 (2C),
128.1, 128.0 (2C), 127.7 (2C), 127.5, 127.2 (2C), 126.5, 86.0, 78.2, 77.6,
59.0, 42.1, 37.7, 35.1, 33.3, 24.9, 20.4; m/z (ESþ) 429.24 (2, MþHþ),
compound as a yellow oil (3.13 g, 61% yield); Rf (light petroleum/
25
Et2O 2:1) 0.76; [
a
]
D
þ11.8 (c 1.0, CHCl3); nmax (CHCl3, solution)
3068, 3009, 2896, 1596, 1495, 1454, 1402, 1361, 1268, 1166,
1046 cmꢀ1
dH (400 MHz, CDCl3) 7.50e7.35 (13H, m, CHar), 7.17 (1H,
m, CHar), 6.44 (1H, s, CH(OR)2), 5.02 (1H, d, J 8.0 Hz, CHePh), 4.97
;

9960
M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
446.27 (3; MþNHþ4 ), 451.22 (76, MþNaþ), 452.23 (23), 879.46 (100,
2MþNaþ), 880.46 (63%); HRMS (ESþ): MNaþ, found 451.2231.
C29H32O3Na requires 451.2244; mp 142e144 ꢁC.
(1H, m), 1.87 (1H, dd, J 13.4, 3.2 Hz), 1.76 (1H, m), 1.43 (2H, m), 0.86
(3H, d, J 6.2 Hz, CH3), 0.80 (1H, m), 0.44 (1H, m), 0.16 (1H, sext, J
4.8 Hz, CHcyclopr.), ꢀ0.15 (1H, sext, J 4.8 Hz, CHcyclopr.); dC (100.6 MHz,
CDCl3) 211.4, 139.5, 137.9, 127.9 (2C), 127.8 (2C), 127.7, 127.6 (2C),
127.4, 127.3 (2C), 82.7, 78.7, 78.4, 61.8, 42.7, 35.5, 33.5, 25.4, 20.1,
11.9, 7.2, 0.5; m/z (ESþ) 401.2 (21, MþNaþ), 402.2 (5), 779.4 (100),
780.4 (55%); HRMS (ESþ): MNaþ, found 401.2089. C25H30O3Na re-
quires 401.2087.
4.3.11. (2R,3R)-2-((R)-1-((1R,2R)-2-Hydroxy-1,2-diphenylethoxy)
heptyl)-3-methylcyclohexanone (13). Prepared following general
procedure C, starting from acetal 4 (0.310 g, 1.00 mmol) and TMS
enol ether 21. The crude material was purified by silica column
chromatography (light petroleum/Et2O 2:1), to afford the desired
compound as a colorless oil (303 mg, 72% yield, 96:4 mixture of
4.3.14. (2R,3R)-2-((S)-(4-chlorophenyl)((1R,2R)-2-hydroxy-1,2-di-
phenylethoxy)methyl)-3-methylcyclohexanone (16). Prepared fol-
lowing general procedure C, starting from acetal 8 (0.50 g,
1.50 mmol) and enol ether 21 (275 mg, 1.50 mmol). The crude
material was purified by silica column chromatography (light pe-
isomers, d.r. measured by 1H NMR on the benzylic protons signal);
25
Rf (light petroleum/Et2O 2:1) 0.38; [
a
]
ꢀ13.0 (c 1.0, CHCl3); nmax
D
(CHCl3, solution) 3559 (OH), 3065, 3009, 2958, 2930, 2872, 1704
(C]O), 1454, 1383, 1194, 1074, 1047, 1023 cmꢀ1
;
dH (400 MHz,
CDCl3) data for the mixture: 7.22e7.17 (3H, m, CHar), 7.15e7.11 (3H,
m, CHar), 7.04e6.98 (4H, m, CHar), 4.72 (1H, d, J 8.3 Hz, CHePh,
minor isomer), 4.67 (1H, d, J 8.3 Hz, CHePh, Major isomer), 4.27
(1H, d, J 8.3 Hz, CHePh), 4.20 (1H, d, J 8.3 Hz, CHePh, minor isomer),
3.74 (1H, q, J 5.5 Hz, CHeOR), 2.15 (1H, t, J 5.5 Hz, CHeCO), 2.08 (2H,
t, J 6.8 Hz), 1.89e1.62 (4H, m), 1.36e1.23 (10H, m), 0.93e0.81 (8H,
m); dC (100.6 MHz, CDCl3), major isomer: 212.0, 139.4, 138.0, 128.4
(2C), 128.2, 128.1 (2C), 127.8 (2C), 127.6, 127.2 (2C), 85.0, 78.0, 75.5,
59.9, 41.1, 34.2, 31.7, 31.2, 30.2, 29.5, 25.1, 23.9, 22.6, 20.1, 14.1, minor
isomer: 213.7, 139.8, 138.7, 128.5 (2C), 128.1, 128.0 (2C), 127.9 (2C),
127.7, 127.5 (2C), 86.1, 78.5, 76.7, 57.8, 41.6, 34.6, 31.9, 29.1, 27.8, 26.4,
23.9, 22.7, 21.3, 20.7, 14.5; m/z (ESþ) 423.29 (2, MþHþ), 440.31 (1,
MþNHþ4 ), 445.27 (100, MþNaþ), 446.27 (28), 867.55 (31, 2MþNaþ),
868.56 (19%); HRMS (ESþ): MNaþ, found 445.2697. C28H38O3Na
requires 445.2713.
troleum/Et2O 2:1), to afford the desired compound as a colorless oil
23
(404 mg, 60% yield); Rf (light petroleum/Et2O 2:1) 0.30; [a]
D
ꢀ126.3 (c 1.0, CHCl3); nmax (CHCl3, solution) 3572 (OH), 3064, 3009,
2963, 1710 (C]O), 1490, 1454, 1363, 1239, 1091, 1047 cmꢀ1
dH
;
(400 MHz, CDCl3) 7.36 (2H, d, J 8.8 Hz, CHar), 7.28e7.20 (3H, m,
CHar), 7.15 (2H, d, J 8.8 Hz, CHar), 7.12e7.05 (3H, m, CHar), 6.92 (2H,
dd, J 7.6, 1.8 Hz, CHar), 6.87 (2H, dd, J 7.6, 1.8 Hz, CHar), 4.70 (1H, d, J
8.0 Hz, CHePh), 4.51 (1H, d, J 10.0 Hz, CHeAr), 3.95 (1H, d, J 8.0 Hz,
CHePh), 3.34 (1H, br s, OH), 2.51 (1H, d, J 10.0 Hz), 2.23e2.08 (2H,
m), 1.88e1.55 (4H, m), 1.26 (1H, m), 0.82 (3H, d, J 7.2 Hz, CH3); dC
(100.6 MHz, CDCl3) 211.8, 139.1, 136.9, 134.4, 129.2 (2C), 129.1 (2C),
128.5, 128.3 (2C), 128.2 (2C), 128.1, 127.8 (2C), 127.5, 126.9 (2C), 83.6,
78.0, 77.7, 64.3, 39.3, 32.8, 27.1, 22.6, 19.0; m/z (ESþ) 471.2 (51,
MþNaþ), 472.2 (15), 473.2 (18), 919.4 (100), 920.4 (61), 921.4 (83%);
35
HRMS (ESþ): MNaþ, found 471.1708. C28
471.1697.
H ClO3Na requires
29
4.3.12. (2R,3R)-3-Ethyl-2-((R)-1-((1R,2R)-2-hydroxy-1,2-diphenyl-
ethoxy)heptyl)cyclohexanone (14). Prepared following general
4.3.15. (2R,3R)-3-Ethyl-2-((S)-(3-fluorophenyl)((1R,2R)-2-hydroxy-
1,2-diphenylethoxy)methyl)cyclohexanone (19). Prepared following
general procedure C, starting from acetal 9 (0.256 mg, 0.8 mmol) and
enol ether 23. The crude material was purified by silica column
chromatography (light petroleum/Et2O 2:1), to afford the desired
procedure B, starting from acetal
4 (232 mg, 0.750 mmol),
2-cyclohexenone (48 L, 0.50 mmol), and ZnEt2 (1.0 M in hexanes,
m
0.65 mL). The crude material was purified by silica column chro-
matography (light petroleum/Et2O 2:1), to afford the desired
compound as a colorless oil (70 mg, 32% yield, 91:9 mixture of
compound as a colorless oil (242 mg, 68% yield); Rf (light petro-
23
diastereomers, d.r. ratio measured on the benzylic proton signal);
leum/Et2O 2:1) 0.28; [
a
]
D
ꢀ74.4 (c 1.0, CHCl3); nmax (CHCl3, solu-
24
[
a]
ꢀ6.8 (c 0.5, CHCl3); nmax (CHCl3, solution) 3493 (OH), 3066,
tion) 3574 (OH), 3066, 3011, 2964, 2938, 1706 (C]O), 1592, 1488,
D
3006, 2933, 2874, 1703 (C]O), 1601, 1494, 1452, 1408, 1342,
1453, 1385, 1253, 1050 cmꢀ1
;
dH (400 MHz, CDCl3) 7.40 (1H, m,
1049 cmꢀ1
;
dH (400 MHz, CDCl3) data for the mixture: 7.23e7.18
CHar), 7.30e7.23 (3H, m, CHar), 7.13e7.02 (5H, m, CHar), 6.98e6.92
(3H, m, CHar), 6.89 (2H, dd, J 7.4, 1.6 Hz, CHar), 4.73 (1H, d, J 7.8 Hz,
CHePh), 4.55 (1H, d, J 10.5 Hz, CHeAr), 3.99 (1H, d, J 7.8 Hz, CHePh),
3.10 (1H, br s, OH), 2.70 (1H, d, J 10.5 Hz, C(O)eCHeCHeAr),
2.25e2.08 (2H, m), 1.76 (2H, m), 1.62 (1H, m), 1.41 (1H, m),1.35e1.15
(3H, m), 0.69 (3H, t, J 7.3 Hz, CH3); dC (100.6 MHz, CDCl3) 212.0,163.1
(d, J 248 Hz), 141.0 (d, J 6.4 Hz), 139.1, 137.0, 130.6 (d, J 8.4 Hz), 128.5,
128.3 (4C), 127.7 (2C), 127.5, 126.9 (2C), 123.3 (d, J 3.0 Hz), 115.8 (d, J
21.5 Hz), 114.6 (d, J 21.5 Hz), 83.8, 78.3, 77.6, 62.3, 39.6, 39.2, 24.9,
24.4, 22.5, 11.3; m/z (ESþ) 469.2 (52, MþNaþ), 470.2 (16), 915.4
(100), 916.4 (64%); HRMS (ESþ): MNaþ, found 469.2145.
C29H31FO3Na requires 469.2149.
(3H, m, CHar), 7.15e7.11 (3H, m, CHar), 7.03e6.98 (4H, m, CHar), 4.73
(1H, d, J 8.4 Hz, CHOH, minor isomer), 4.68 (1H, d, J 8.4 Hz, CHOH,
major isomer), 4.28 (1H, d, J 8.4 Hz, CHCHOH, major isomer), 4.21
(1H, d, J 8.4 Hz, CHCHOH, minor isomer), 3.75 (1H, ddd, J 7.6, 5.2,
3.6, CHeOR), 3.65 (1H, s, OH), 2.37 (1H, dd, J 6.8, 5.2 Hz, C(O)CHR2),
2.08e1.95 (2H, m), 1.85e1.60 (5H, m), 1.40e1.10 (12H, m), 0.91 (3H,
t, J 7.2 Hz, CH3), 0.83 (3H, t, J 7.6 Hz, CH3); dC (100.6 MHz, CDCl3)
212.8, 139.3, 137.7, 128.4 (2C), 128.2, 128.0 (2C), 127.7 (2C), 127.5
(2C), 127.0, 84.4, 77.9, 75.1, 58.1, 40.2, 40.1, 31.7, 29.6, 29.3, 26.1, 25.6,
23.7, 23.0, 22.6, 14.0, 11.4; m/z (ESþ) 226.1 (33), 451.2 (55), 459.3
(100, MþNaþ), 460.3 (31%); HRMS (ESþ): MNaþ, found 459.2865.
C29H40O3Na requires 459.2870.
4.3.16. (R)-Trimethyl(3-methylcyclohex-1-enyloxy)silane (21).7. In
a flame-dried Schlenk tube flushed with argon, we dissolved Cu
(OTf)2 (72 mg, 2.0 mol %) and (R,S,S)-Feringa phosphoramidite li-
gand L1 (216 mg, 4.00 mol %) in dry CH2Cl2 (8 mL). The resulting
suspension was stirred at room temperature for 30 min before
cooling to ꢀ40 ꢁC. Dimethylzinc in toluene (13 mmol of a 1.81 M
solution) was then added and the mixture stirred 2 min at ꢀ40 ꢁC,
after which time 2-cyclohexenone (0.96 mL, 10 mmol) was added.
The mixture was stirred at ꢀ40 ꢁC for 1 h, until TLC indicated
complete conversion. To the zinc enolate a previously prepared
solution of TMSOTf (2.18 mL, 12.0 mmol) and dimethylzinc (0.5 mL)
was added at ꢀ20 ꢁC. The resulting solution was then allowed to
warm to room temperature and stirred for 2 h. The reaction was
4.3.13. (2R,3R)-2-((R)-Cyclopropyl((1R,2R)-2-hydroxy-1,2-dipheny-
lethoxy)methyl)-3-methylcyclohexanone (15). Prepared following
general procedure C, starting from acetal 7 (400 mg, 1.50 mmol) and
TMS enol ether 21 (275 mg, 1.50 mmol). The crude material was
purified by silica column chromatography (light petroleum/Et2O
2:1), to afford the desired compound as a colorless oil (351 mg, 62%
yield); Rf (light petroleum/Et2O 2:1) 0.22; [
a]
22 þ21.1 (c 2.5, CHCl3);
D
nmax (CHCl3, solution) 3465 (OH), 3066, 3009, 2932, 2872, 1704 (C]
O), 1494, 1429, 1321, 1264, 1192, 1081, 1022 cmꢀ1
; dH (400 MHz,
CDCl3) 7.22e7.12 (6H, m, CHar.), 7.05 (2H, m, CHar), 6.96 (2H, m,
CHar), 4.92 (1H, d, J 8.8 Hz, CHePh), 4.61 (1H, d, J 8.8 Hz, CHePh), 4.5
(1H, br s, OH), 2.75 (1H, dd, J 9.6, 2.0 Hz), 2.40e2.23 (4H, m), 2.00

M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
9961
then diluted with Et2O (20 mL) and filtered through deactivated
silica gel using (previously deactivated by addition of 2.5 mL trie-
thylamine to the top of the silica before the addition of the silyl enol
ether) using Et2O. The solvent was removed in vacuo. Impurities
were separated by a fast column filtration on similar NEt3 deacti-
vated silica gel using pentane to afford the desired compound as
a colorless liquid (1.01 g, 55% yield).; GC: performed on 3-methyl-
cyclohexanone, ee¼96% (Lipodex A, isothermal, 75 ꢁC, flow
rate¼1 mL/min, retention times: (þ)-enantioner: 11.3 min,
(ꢀ)-enantiomer: 10.9 min); nmax (CHCl3, solution) 3009, 2957, 2928,
2867, 1663, 1455, 1364, 1324, 1253, 1181, 1131, 1046, 1015, 989, 960,
128.8 (2C), 128.1 (2C), 128.0 (3C), 127.7 (2C), 127.5, 127.3 (2C), 126.7,
87.5, 78.7, 78.5, 60.6, 42.0, 37.7, 35.2, 32.4, 24.9, 20.1; mp 136e138 ꢁC.
4.3.20. (2R,3R)-2-((R)-Cyclopropyl((1R,2R)-2-hydroxy-1,2-dipheny-
lethoxy)methyl)-3-methylcycloheptanone (18). Prepared following
general procedure C, starting from acetal 7 (400 mg, 1.50 mmol) and
TMS enol ether 22 (198 mg, 1.00 mmol). The crude material was
purified by silica column chromatography (light petroleum/Et2O
2:1), to afford the desired compound as a colorless oil (252 mg, 65%
yield); Rf (light petroleum/Et2O 2:1) 0.28; [
a
]
22 þ67.5 (c 0.8, CHCl3);
D
nmax (CHCl3, solution) 3535 (OH), 3066, 3008, 2962, 2939, 1691 (C]
887, 849 cmꢀ1
;
dH (400 MHz, CDCl3) 4.73 (1H, dd, CH]C, J 1.7,
O), 1454, 1382, 1321, 1192, 1054, 1026 cmꢀ1
; dH (400 MHz, CDCl3)
1.1 Hz), 2.22 (1H, m), 2.02e1.92 (2H, m, CH2), 1.80e1.65 (2H, m,
CH2),1.60e1.50 (1H, m, CH); 1.06e1.00 (1H, m, CH), 0.93 (3H, d, CH3,
J 6.8 Hz), 0.16 (9H, s, SiCH3); dC (100.6 MHz, CDCl3) 150.0, 111.2, 31.1,
29.8, 29.5, 22.5, 21.8, 0.3 (3C); HRMS (EI): Mþ, found 184.1256.
C10H20OSi requires 184.1283. The spectral data was in accordance
with the literature.7
7.25e7.21 (3H, m, CHar.), 7.20e7.15 (3H, m, CHar.), 7.04 (4H, m, CHar),
4.89 (1H, d, J 8.4 Hz, CHePh), 4.74 (1H, d, J 8.4 Hz, CHePh), 2.97 (1H,
td, J 12.0, 3.0 Hz), 2.73 (1H, dd, J 9.6, 2.5 Hz), 2.51 (1H, m), 2.22 (1H, dd,
J 10.5, 2.5 Hz), 2.03e0.80 (9H, m), 0.81 (1H, m, CHcyclopr.), 0.74 (3H, d, J
6.8 Hz, CH3), 0.58 (1H, m, CHcyclopr.), 0.24 (1H, sext., J 4.8 Hz,
CHcyclopr.), ꢀ0.12 (1H, sext, J 4.8 Hz, CHcyclopr.); dC (100.6 MHz, CDCl3)
215.6,139.2,137.1,128.3,128.1 (2C),128.0 (2C),127.8 (2C),127.6,127.2
(2C), 83.4, 80.3, 78.6, 65.7, 44.2, 37.0, 31.4, 29.4, 27.3, 21.5, 12.9, 7.5,
0.6; m/z (ESþ) 259.2 (11), 415.2 (100, MþNaþ), 416.2 (28%); HRMS
(ESþ): MNaþ, found 415.2250. C26H32O3Na requires 415.2244.
4.3.17. (R)-Trimethyl(3-methylcyclohept-1-enyloxy)silane
(22). Prepared following the procedure described for silyl enol
ether 21, using 2-cycloheptanone (668 mL, 6.00 mmol) as the Mi-
chael acceptor. The desired product was obtained as a colorless
liquid (747 mg, 63% yield); [
a
]
23 þ3.0 (c 1.0, CHCl3); GC: performed
4.3.21. (2R,3R)-2-((R)-1-Hydroxyheptyl)-3-methylcyclohexanone
(29). Cerium(IV) ammonium nitrate (CAN, 328 mg, 0.600 mmol)
was added in a single portion to a solution of 13 (125 mg,
0.300 mmol) in MeCN (3 mL) and water (0.5 mL). The resulting
yellow mixture was then stirred at room temperature under an air
atmosphere for 4 h. After that time K2CO3 (400 mg) was added, the
suspension stirred for 10 more minutes and filtered. Diethyl ether
was added and the mixture was dried over MgSO4. Solvent was
then removed under vacuum and the crude oil purified by column
D
on 3-methylcycloheptanone, ee¼94% (Lipodex A, isothermal, 60 ꢁC,
Flow rate¼1 mL/min, retention times: (þ)-enantiomer: 10.4 min,
(ꢀ)-enantiomer: 10.0 min); nmax (CHCl3, solution) 3008, 2958,
2924, 2850, 1658, 1456, 1366, 1252, 1182, 1130, 874 cmꢀ1
; dH
(400 MHz, CDCl3) 4.74 (1H, d, J 4.0 Hz, CH]C), 2.40e2.20 (2H, m),
2.10 (1H, m), 1.83 (1H, m), 1.70e1.20 (5H, m), 0.98 (3H, d, CH3, J
7.0 Hz), 0.17 (9H, s, SiCH3); dC (100.6 MHz, CDCl3) 154.1, 116.1, 36.3,
35.3, 31.0, 30.0, 25.1, 23.8, 0.3 (3C); m/z (EI): 73, 75, 169, 183, 198
(Mþ); HRMS (EI): Mþ, found 198.1438. C11H22OSi requires 198.1440.
chromatography (light petroleum/Et2O 1:1) to afford the desired
25
product as a yellow oil (55 mg, 81% yield); [
a]
þ90.0 (c 0.5,
D
4.3.18. (R)-Trimethyl(3-ethylcyclohex-1-enyloxy)silane
CHCl3); nmax (CHCl3, solution) 3541 (OH), 3007, 2930, 2857, 1695
(23).7. Prepared following the procedure described for silyl enol
(C]O), 1457, 1406, 1380, 1362, 1240, 1125, 1063 cmꢀ1
;
dH (400 MHz,
ether 21, using 2-cyclohexanone (960
acceptor and diethylzinc (13.0 mmol, 1.1 M solution). The desired
product was obtained as a colorless liquid (1.39 g, 71% yield); [a]
D
m
L, 10.0 mmol) as the Michael
CDCl3) 3.71 (1H, br s, OH), 2.82 (1H, d, J 10.0 Hz), 2.36 (2H, m),
2.20e2.00 (3H, m), 1.92 (1H, m), 1.79e1.65 (2H, m), 1.52e1.40 (3H,
m), 1.31 (7H, m), 1.13 (3H, d, J 6.4 Hz, CH3), 0.91 (3H, t, J 6.8 Hz, CH3);
dC (100.6 MHz, CDCl3) 215.9, 70.1, 61.2, 43.2, 37.3, 36.4, 34.0, 31.8,
29.2, 26.7, 26.6, 22.6, 20.4, 14.0; m/z (ESþ): 249.2 (39, MþNaþ),
475.4 (100), 476.4 (32%); HRMS (ESþ): MNaþ, found 249.1779.
C14H26O2Na requires 249.1825.
23
þ5.2 (c 1.0, CHCl3); GC: performed on 3-ethylcyclohexanone,
ee¼98% (Lipodex A, isothermal, 60 ꢁC, Flow rate¼2 mL/min, re-
tention times: (þ)-enantioner: 8.45 min, (ꢀ)-enantiomer:
8.65 min); nmax (CHCl3, solution) 3008, 2961, 2933, 2858, 1663,
1456, 1366, 1252, 1180, 1130, 848 cmꢀ1
; dH (400 MHz, CDCl3) 4.80
(1H, d, J 1.4 Hz, CH]C), 2.05e1.92 (3H, m), 1.80e1.62 (2H, m),
1.58e1.48 (1H, m), 1.33e1.23 (2H, m), 1.07 (1H, m), 0.88 (3H, t, CH3, J
7.4 Hz), 0.17 (9H, s, SiCH3); dC (100.6 MHz, CDCl3) 150.3, 109.5, 36.3,
30.0, 29.6, 28.4, 21.8, 11.4, 0.3 (3C); m/z (EI): 73.0 (71), 75.0 (20),
169.1 (100), 170.1 (10), 198 (Mþ, 7%); HRMS (EI): Mþ, found
198.1433. C11H22OSi requires 198.1440. The spectral data was in
accordance with the literature.7
4.3.22. (2R,3R)-2-(R)-(1-Hydroxy-2-phenylethyl)-3-methyl cyclohex-
anone(30). Preparedasdescribedfor29, using12 (98mg, 0.23mmol)
and cerium(IV) ammonium nitrate (CAN, 252 mg, 0.460 mmol) and
yielding the desired product as a yellow oil after column chroma-
tography (44 mg, 82% yield); [
a
]
23 þ11.8 (c 2.0, CHCl3); nmax (CHCl3,
D
solution) 3537 (OH), 3064, 3009, 2933, 2871,1695 (C]O),1495,1454,
1239, 1080, 1024, 909 cmꢀ1
; dH (400 MHz, CDCl3) 7.35e7.15 (5H, m,
CHar), 4.01 (1H, s, OH), 3.15 (1H, dd, J 18.6, 7.2 Hz), 2.93 (1H, dd, J 13.4,
7.2 Hz), 2.43e2.32 (2H, m), 2.20e2.00 (3H, m), 1.89 (1H, ddd, J 13.4,
3.6, 1.2 Hz), 1.74 (2H, m), 1.42 (1H, m), 1.05 (3H, d, J 6.4 Hz, CH3); dC
(100.6 MHz, CDCl3) 215.9, 139.0, 129.0 (2C), 128.6 (2C), 126.3, 71.2,
59.3, 43.1, 42.5, 37.2, 33.9, 26.6, 20.1; m/z (ESþ) 255.1 (39, MþNaþ),
451.2 (87), 487.3 (64), 683.4 (42) 879.5 (100%); HRMS (ESþ): MNaþ,
found 255.1357. C15H20O2Na requires 255.1356.
4.3.19. (2R,3R)-2-((S)-1-((1S,2S)-2-Hydroxy-1,2-diphenylethoxy)-2-
phenylethyl)-3-methylcyclohexanone (17). Prepared following gen-
eral procedure C, starting from (S,S)-6 (310 mg, 1.00 mmol) and TMS
enol ether 21 (184 mg, 1.00 mmol). The crude material was purified
by silica column chromatography (light petroleum/Et2O 2:1), to af-
ford the desired compound as a white solid (248 mg, 58% yield); Rf
24
(light petroleum/Et2O 2:1) 0.30; [
a
]
ꢀ1.3 (c 1.0, CHCl3); dH
D
(400 MHz, CDCl3) 7.43e7.27 (5H, m, CHar), 7.22e7.17 (3H, m, CHar),
7.14e7.07 (3H, m, CHar), 6.95e6.85 (4H, m, CHar), 4.60 (1H, d, J 8.8 Hz,
CHePh), 4.08 (1H, d, J 8.8 Hz, CHePh), 4.04 (1H, td, J 4.8, 0.7 Hz,
CHeOR), 3.44 (1H, dd, J 14.2, 8.7 Hz), 2.87 (1H, dd, J 14.2, 4.0 Hz), 2.21
(1H, dd, J 8.8, 4.8 Hz), 2.10e1.97 (2H, m),1.87e1.77 (2H, m),1.65e1.53
(2H, m), 1.25e1.18 (1H, m), 1.04 (3H, t, J 6.6 Hz, CH3), 0.91 (1H, d, J
6.6 Hz); dC (100.6 MHz, CDCl3) 211.1, 139.5, 139.0, 138.6, 129.5 (2C),
4.3.23. (2R,3R)-2-((S)-(4-Chlorophenyl)(hydroxy)methyl)-3-methyl
cyclohexanone (31). Prepared as described for 29 using 16 (300 mg,
0.670 mmol) and cerium(IV) ammonium nitrate (CAN, 734 mg,
1.33 mmol) and yielding the desired product as a yellow oil after
22
column chromatography (140 mg, 83% yield); [
a
]
D
ꢀ18.2 (c 1.0,
CHCl3); nmax (CHCl3, solution) 3523 (OH), 3008, 2933, 2871, 1697
(C]O),1599,1492,1454,1413,1239,1092,1079,1049,1014 cmꢀ1
;
dH

9962
M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
(400 MHz, CDCl3) 7.28 (4H, s, CHar), 4.8 (1H, d, J 3.6 Hz, CHeOH),
3.74 (1H, br s, OH), 2.51 (1H, dd, J 9.5, 3.6 Hz, CHeCHeOH), 2.31 (2H,
m), 2.18e1.90 (3H, m),1.75 (1H, m),1.50 (1H, m),1.13 (3H, d, J 6.6 Hz,
CH3); dC (100.6 MHz, CDCl3) 215.0, 142.2, 132.6, 128.3 (2C), 127.1
(2C), 71.2, 63.1, 42.5, 36.9, 33.1, 26.1, 20.4; m/z (ESþ) 275.1 (100,
(light petroleum/Et2O 2:1) to afford the desired product as a yellow
25
oil (120 mg, 61% yield); [
lution) 3564 (OH), 3070, 3009, 2942, 1730 (C]O), 1454, 1385, 1240,
1070, 1046, 1024, 909 cmꢀ1
dH (400 MHz, CDCl3) 7.10e6.85 (10H, m,
a]
D
þ12.9 (c 1.0, CHCl3); nmax (CHCl3, so-
;
CHar), 5.52 (1H, t, J 7.2 Hz, CH]C), 4.66 (2H, dd, J 15.3, 9.0 Hz), 4.64
(1H, d, J 8.0 Hz, CHePh), 4.31 (1H, d, J 8.0 Hz, CHePh), 3.80 (1H, m),
3.16 (1H, s, OH), 2.60 (1H, m), 2.40 (1H, m), 2.20 (1H, m), 2.15e2.02
(2H, m), 2.08 (3H, s, CH3), 1.81 (3H, d, CH3, J 1.2 Hz), 1.60e1.25 (3H,
m), 1.15 (1H, m), 0.93 (3H, d, J 6.4 Hz, CH3), 0.84 (1H, m); dC
(100.6 MHz, CDCl3) 211.5, 171.0, 140.0, 139.0, 138.0, 133.2, 128.1, 127.9
(2C), 127.7 (2C), 127.1 (2C), 127.0 (2C), 126.0, 86.5, 79.0, 78.4, 75.6,
63.1, 60.6, 41.4, 33.8, 30.3, 29.3, 23.9, 22.6, 21.6, 20.9, 19.8; m/z (ESþ)
355.0 (22), 369.0 (10), 473.2 (99), 487.2 (100, MþNaþ), 951.5 (19%);
HRMS (ESþ): MNaþ, found 487.2241. C29H36O5Na requires 487.2460.
MþNaþ), 277.1 (33), 471.2 (66), 473.2 (24), 919.3 (15%); HRMS (ESþ):
35
MNaþ, found 275.0800. C14
H ClO2Na requires 275.0809.
17
4.3.24. (2R,3R)-2-((R)-Cyclopropyl(hydroxy)methyl)-3-methyl cyclo-
hexanone (32). Prepared as described for 29, using 15 (264 mg,
0.700 mmol) and cerium(IV) ammonium nitrate (CAN, 767 mg,
1.40 mmol) and yielding the desired product as a yellow oil after
21
column chromatography (110 mg, 86% yield); [
a
]
þ 42.0 (c 0.5,
d
CHCl3); nmax (CHCl3, solution) 3547 (OH), 3081, 3008, 2932, 1695
(C]O), 1454, 1431, 1379, 1239, 1091, 1075, 1023 cmꢀ1
;
dH (400 MHz,
CDCl3) 2.77 (1H, dd, J 9.4, 2.3 Hz, CHeOH), 2.37 (2H, m), 2.25 (1H,
m), 2.15e2.01 (2H, m), 1.86 (1H, m), 1.71 (1H, m), 1.53e1.40 (1H, m),
1.30e1.20 (2H, m), 1.05 (3H, d, J 6.4 Hz, CH3), 0.61e0.55 (1H, m,
CH2cyclopr.), 0.50e0.36 (2H, m, CH2cyclopr.), 0.05 (1H, m, CH2cyclopr.);
dC (100.6 MHz, CDCl3) 215.7, 75.5, 61.8, 43.0, 36.8, 33.8, 26.4, 20.3,
16.5, 4.2, 3.3; m/z (ESþ) 205.1 (17, MþNaþ), 387.2 (100), 388.2 (24);
HRMS (ESþ): MNaþ, found 205.1182. C11H18O2Na requires 205.1199.
4.3.28. (4S,5S)-2-(2,2-Dimethoxyethyl)-4,5-diphenyl-1,3-dioxolane
(24). To a flame-dried flask flushed with argon was added (S,S)-
hydrobenzoin 2 (2.00 g, 9.31 mmol) in CH2Cl2 (25 mL). To this
stirred solution at room temperature was added (1,1,3,3)-tetrame-
thoxypropane (1.53 mL, 9.31 mmol) and HCl 6 M (0.08 mL). The
resulting solution was left to stir at room temperature for 4 days.
After that period almost all the starting material has been con-
sumed, and Na2CO3 was added (1 g). The resulting suspension was
filtered and the crude mixture of mono- and diacetal (12:1) was
purified by flash chromatography (light petroleum/Et2O 2:1) to give
the desired product as an air stable colorless oil (1.93 g, 66% yield);
4.3.25. (2R,3R)-3-Ethyl-2-((R)-1-hydroxyheptyl)cyclohexanone
(33). Prepared as described for 29, using 14 (145 mg, 0.33 mmol)
and cerium(IV) ammonium nitrate (CAN, 395 mg, 0.72 mmol) and
yielding the desired product as a yellow oil after column chroma-
[found: C, 72.79; H, 7.10. C19H22O4 requires C, 72.59; H, 7.05%]; Rf
25
tography (70 mg, 88% yield); [
a
]
21 þ58.2 (c 0.5, CHCl3); nmax (CHCl3,
(light petroleum/Et2O 2:1) 0.75; [
a]
ꢀ37.7 (c 1.0, CHCl3); nmax
D
D
solution) 3538 (OH), 3008, 2931, 2859, 1694 (C]O), 1461, 1408,
(CHCl3, solution) 2901, 2835, 2357,1455,1367,1119,1072, 899 cmꢀ1
;
1365, 1239, 1183, 1065 cmꢀ1
;
dH (400 MHz, CDCl3) 3.70 (1H, t, J
dH (400 MHz, CDCl3) 7.39e7.25 (10H, m, CHar), 5.62 (1H, t, J 5.2 Hz,
CHCH2CH(OMe)2), 4.82 (1H, t, J 5.6 Hz, CH(OMe)2), 4.80 (2H, s), 3.42
(6H, d, J 3.2 Hz, CH3OR), 2.28 (2H, t, J 5.6 Hz, CH2CH(OMe)2); dC
(100.6 MHz, CDCl3) 138.2, 136.7, 128.5 (2C), 128.5 (2C), 127.8 (2C),
126.8 (2C), 126.3 (2C), 102.9, 101.3, 86.9, 84.8, 53.1, 52.8, 38.2; HRMS
(ESþ): MNaþ, found 337.1395. C19H22O4Na requires 337.1416.
9.2 Hz), 2.66 (1H, d, J 10.5 Hz, CHeOH), 2.34 (2H, m), 2.18 (1H, m),
2.06e1.85 (3H, m), 1.74e1.58 (3H, m), 1.52e1.25 (11H, m), 0.92 (3H,
t, J 7.4 Hz, CH3), 0.87 (3H, t, J 7.0 Hz, CH3); dC (100.6 MHz, CDCl3)
216.2, 70.0, 59.2, 42.8, 42.5, 36.5, 31.8, 29.2, 29.1, 26.4, 26.0, 25.8,
22.6, 14.1, 10.3; m/z (ESþ) 263.2 (73, MþNaþ), 459.3 (100), 503.4
(26), 895.6 (29%); HRMS (ESþ): MNaþ, found 263.1971. C15H28O2Na
requires 263.1982.
4.3.29. 2-((4S,5S)-4,5-Diphenyl-1,3-dioxolan-2-yl)acetaldehyde
(26). To a flame-dried flask equipped with a condenser and flushed
with argon was added 24 (2.14 g, 6.79 mmol) in a THF/1,2-di-
chloroethane 1:1 mixture (50 mL). To this stirred solution was
added silica gel (0.340 g) and oxalic acid (0.340 g, 3.78 mmol). The
resulting suspension was heated to 90 ꢁC for 3 days. After that
period some starting material remained but the reaction was
stopped as some side products began to appear (monitored by TLC
light petroleum/Et2O 2:1). The reaction mixture was cooled down
to room temperature, and NaCO3 was added (1 g). The resulting
suspension was filtered and the crude mixture was purified by flash
chromatography (light petroleum/Et2O 2:1) to give the desired
product in a 44% yield as an air stable colorless oil and a fraction of
4.3.26. (Z)-4-((4S,5S)-4,5-Diphenyl-1,3-dioxolan-2-yl)-2-methylbut-
2-enyl acetate (10). A solution of alcohol 28 (0.81 g, 2.6 mmol) in
dry CH2Cl2 (25 mL) was cooled to 0 ꢁC. To the solution was added
successively DMAP (10 mg), NEt3 (1.1 mL, 7.9 mmol) and acetic
anhydride (0.52 mL, 5.5 mmol). The reaction was then allowed to
warm and stirred at room temperature for 3 h. After that time
a saturated solution of NH4Cl was added (10 mL) and the product
extracted with CH2Cl2 (10 mL), and Et2O (2ꢂ10 mL). The combined
organic fractions were dried over MgSO4, filtered and concentrated
in vacuo. The crude product was then purified by column chro-
matography (light petroleum/Et2O 2:1) to afford the desired
product as a colorless oil. (99% yield, 915 mg); Rf (light petroleum/
recovered starting material as a colorless oil (0.750 g, 41%); Rf (light
25
25
Et2O 2:1) 0.45; [
a
]
ꢀ26.4 (c 1.0, CHCl3); nmax (CHCl3, solution)
petroleum/Et2O 2:1) 0.37; [
a]
ꢀ34.3 (c 1.0, CHCl3); nmax (CHCl3,
D
D
3067, 3011, 2888, 1731 (C]O), 1496, 1454, 1368, 1241, 1135,
solution) 2901, 2834, 2356, 1455, 1367, 1119, 1072, 899 cmꢀ1
; dH
1024 cmꢀ1
;
dH (400 MHz, CDCl3) 7.40e7.22 (10H, m, CHar.), 5.70 (1H,
(400 MHz, CDCl3) 10.03 (1H, t, J 2.4 Hz, CHO) 7.41e7.24 (10H, m,
CHar), 5.95 (1H, t, J 4.4 Hz, CHCH2CHO), 4.84 (2H, dd, J 11.2, 8.0 Hz,
CHePh), 3.05 (2H, m, CH2CHO); dC (100.6 MHz, CDCl3) 199.0, 137.7,
136.0, 128.7 (5C), 128.5, 126.7 (2C), 126.2 (2C), 101.3, 87.0, 85.2, 48.1;
HRMS (ESþ): MNaþ, found 291.0757. C17H16O3Na requires 291.0997.
t, J 7.6 Hz, CH]C) 5.59 (1H, t, J 4.4 Hz, CH(OR)2), 4.79 (2H, s, CHePh),
4.73 (2H, s, CH2OH), 2.78 (2H, dd, J 7.6, 4.4 Hz, CH2CH]C), 2.07 (3H,
s, CH3), 1.93 (3H, d, J 1.2 Hz, CH3); dC (100.6 MHz, CDCl3) 170.7, 138.0,
136.5, 133.5, 128.3 (4C), 128.2, 128.0, 126.6 (2C), 126.2 (2C), 123.3,
104.6, 86.6, 85.9, 63.0, 33.3, 21.5, 20.7; m/z (ESþ) 370.0 (20,
MþNHþ4 ), 375.2 (100, MþNaþ), 376.2 (22); 633.3 (18%); HRMS
(ESþ): MNH4þ, found 370.2013. C22H28O4N requires 370.2013.
4.3.30. (Z)-Ethyl-4-((4S,5S)-4,5-diphenyl-1,3-dioxolan-2-yl)-2-
methylbut-2-enoate (27). To a solution of 18-crown-6 (15.9 g,
60.2 mmol) and ethyl 2-(bis(2,2,2-trifluoroethoxy) phosphoryl)
propanoate (415 mg, 12.0 mmol) in THF (150 mL) a solution of
KHMDS (15% in toluene, 18.2 mL, 12.0 mmol) was added under
argon at ꢀ78 ꢁC. The resulting slightly green mixture was stirred for
20 min at ꢀ78 ꢁC. After that time a solution of 26 (3.22 g,
12.0 mmol) in 10 mL THF was added at ꢀ78 ꢁC. The resulting yellow
4.3.27. (S,Z)-5-((1S,2S)-2-Hydroxy-1,2-diphenylethoxy)-2-methyl-5-
((1R,2R)-2-methyl-6-oxocyclohexenyl)pent-2-enyl
acetate
(20).
Prepared following general procedure C. The reaction was performed
with enol ether 21 (82 mg, 0.44 mmol) and acetal 10 (150 mg,
0.44 mmol). The crude was purified by column chromatography

M. Welker, S. Woodward / Tetrahedron 66 (2010) 9954e9963
9963
solution was then stirred for 2 h at ꢀ78 ꢁC. The reaction mixture
was treated with an aqueous solution saturated with NH4Cl and
then extracted with CH2Cl2 (3ꢂ60 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The crude
mixture was purified by column chromatography (2:1 light petro-
leum/Et2O) to give the pure compound as a yellow oil (3.59 g, 85%
yield); [found: C, 74.68; H, 6.80. C22H24O4 requires C, 74.98; H,
291.2 (86, MþNaþ), 292.2 (14), 559.3 (100), 671.3 (15%); HRMS
(ESþ): MNaþ, found 291.1567. C15H24O4Na requires 291.1567.
5. Supplementary data
Crystallographic data for compound 12 is available from the
Cambridge Crystallographic Data Centre (reference number:
783764). This data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
6.86%]; Rf (light petroleum/Et2O 2:1) 0.68; [
a]
25 ꢀ16.5 (c 1.0, CHCl3);
D
nmax (CHCl3, solution) 3011, 2897, 1706 (C]O), 1497, 1455, 1374,
1240, 1131,1020, 898 cmꢀ1
; dH (400 MHz, CDCl3) 7.40e7.23 (10H, m,
CHar), 6.23 (1H, td, J 7.2, 1.5 Hz, CH]C), 5.63 (1H, t, J 4.6 Hz, CH
(OR)2), 4.80 (2H, d, J 1.5 Hz, CHePh,), 4.25 (2H, q, J 7.2 Hz, CH2CH3),
3.17 (2H, m, CH2CH]C), 2.00 (3H, d, J 1.5 Hz, CH3); 1.34 (3H, t, J
7.2 Hz, CH3); dC (100.6 MHz, CDCl3) 167.8, 138.2, 136.7, 135.2, 130.1,
128.6 (2C), 128.5 (2C), 128.5, 128.2, 126.8 (2C), 126.4 (2C), 104.7,
86.8, 85.1, 60.3, 35.2, 20.8,14.3; m/z (EIþ) 375.1 (100, MþNaþ), 376.1
(17%); HRMS (ESþ): MNaþ, found 375.1248. C22H24O4Na requires
375.15668.
Acknowledgements
We are grateful to the FP6 Programme for providing a Marie
Curie Early Stage Fellowship under Contract MEST-CT-2005-019780
(INDACCHEM). We thank Prof. A.J. Blake and Dr. W. Lewis for their
input into the crystallographic studies.
References and notes
4.3.31. (Z)-4-((4S,5S)-4,5-Diphenyl-1,3-dioxolan-2-yl)-2-methylbut-
2-en-1-ol (28). A solution of ester 27 (1.00 g, 2.83 mmol) in dry THF
(50 mL) was cooled to ꢀ78 ꢁC. DIBAL-H (1.7 M in toluene, 5.00 mL,
8.51 mmol) was then added slowly and the reaction was allowed to
warm to room temperature over 2 h. After complete disappearance
of the starting material, hydrolysis was effected by addition of
20 mL of wet diethyl ether, followed by 2 mL of water, 2 mL of 10%
aqueous NaOH solution and 3 g of Na2SO4. The resulting suspension
was stirred for 30 min, filtered through Celite and washed with
diethyl ether. The filtrate was dried with Na2SO4, filtered, and the
solvent was evaporated in vacuo. Purification by column chroma-
tography (light petroleum/Et2O 1:1) afforded the allylic alcohol as
1. For recent developments in Cu-catalyzed conjugate addition reactions, see (a)
Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008,
108, 2796e2823; (b) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L.
Chem. Soc. Rev. 2009, 38, 1039e1075; (c) Christoffers, J.; Koripelly, G.; Rosiak, A.;
€
Roessle, M. Synthesis 2007, 1279e1300; (d) Krause, N.; Hoffmann-Roder, A.
Synthesis 2001, 2, 171e196; (e) Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A.
Chem. Commun. 2004, 1779e1785; (f) Lopez, F.; Minnarrd, A. J.; Feringa, B. L. Acc.
Chem. Res. 2007, 40, 179e188; (g) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A.
In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 224e258; (h) Karlstrom, A. S. E.; Backvall, J. E. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, Germany,
2002; pp 258e289; (i) Mori, S.; Nakamura, E. In Modern Organocopper Chem-
istry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; pp 315e346.
2. (a) Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. Tetrahedron Lett. 2008, 49,
2343e2447; (b) Xu, Y.-J.; Liu, Q.-Z.; Dong, L. Synlett 2007, 2, 273e277; (c)
Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528e4529;
(d) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,
755e756; (e) Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Chem.
Commun. 2001, 735e736; (f) Dijk, E. W.; Panella, L.; Pinho, P.; Naasz, R.;
Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2004, 60, 9687e9693;
(g) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006, 71, 5737e5742; (h)
Vuagnoux-d’Augustin, M.; Alexakis, A. Tetrahedron Lett. 2007, 48, 7408e7412;
(i) Welker, M.; Woodward, S.; Alexakis, A. Org. Lett. 2010, 12, 576e579 See also
Refs. 4e7.
3. Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354e366.
4. Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett. 1996, 37,
5141e5144.
5. (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H. M. Angew.
Chem., Int. Ed. 1997, 36, 2620e2623; (b) Howell, G. P.; Fletcher, S. P.; Geurts, K.;
ter Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 14977e14985.
6. Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001,123, 4358e4359.
7. Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835e3837.
a colorless oil (770 mg, 88% yield); Rf (light petroleum/Et2O 2:1)
25
0.10; [
a
]
ꢀ29.4 (c 1.0, CHCl3); nmax (CHCl3, solution) 3504 (OH),
D
3068, 3007, 2886, 1605, 1496, 1454, 1407, 1306, 1288, 1240, 1131,
1003, 943, 861 cmꢀ1
;
dH (400 MHz, CDCl3) 7.40e7.20 (10H, m, CHar),
5.58 (1H, dt, J 8.0, 1.3 Hz, CH]C) 5.56 (1H, t, J 4.2 Hz, CH(OR)2), 4.80
(2H, s, CHePh), 4.17 (2H, s, CH2OH), 2.76 (2H, dd, J 8.0, 4.2 Hz,
CH2CH]C), 1.94 (3H, d, J 1.3 Hz, CH3); dC (100.6 MHz, CDCl3) 139.8,
138.0, 136.3, 128.7 (2C), 128.6 (2C), 128.2, 126.9 (2C), 126.3 (2C),
120.7, 104.5, 86.9, 85.1, 61.6, 33.1, 22.3; m/z (ESþ) 333.1 (100,
MþNaþ), 334.1 (19); 412.7 (12%); HRMS (ESþ): MNaþ, found
333.1162. C20H22O3Na requires 333.1461.
4.3.32. (S,Z)-5-Hydroxy-2-methyl-5-((1R,2R)-2-methyl-6-ox-
ocyclohexyl)pent-2-enyl acetate (34). Prepared following the pro-
cedure described for compound 29. The reaction was performed
using 20 (235 mg, 0.500 mmol) and cerium(IV) ammonium nitrate
8. Developments in the asymmetric Sharpless dihydroxylation enabled a rapid
access to both enantiomers of stilbene diol in large scale using the method-
ology described in Wang, Z. M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994,
59, 5104e5105.
9. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 2, 1011e1014; (b)
Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503e7509.
10. For examples of the use of chiral acetals for asymmetric aldol reactions, see (a)
McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371e7372; (b) Sekizaki,
H.; Jung, M.; McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7372e7374.
11. Stereoselectivity of the opening of chiral acetals is developed in (a) Alexakis, A.;
Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477e511; (b) Bartlett, P. A.;
Johnson, W. S.; Elliott, J. D. J. Am. Chem. Soc. 1983, 105, 2088e2089.
12. Shi-Qi, P.; Winterfeldt, E. Liebigs Ann. Chem. 1989, 1045e1047.
13. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405e4408.
14. Fujioka, H.; Hirose, H.; Ohba, Y.; Murai, K.; Nakahara, K.; Kita, Y. Tetrahedron
2007, 63, 625e637.
(CAN, 548 mg, 1.00 mmol). This afforded the allylic acetate after
22
column chromatography (105 mg, 78% yield); [
a
]
ꢀ18.2 (c 1.00,
D
CHCl3); nmax (CHCl3, solution) 3530 (OH), 3009, 2937, 1729 (C]O),
1695 (C]O), 1454, 1368, 1240, 1130, 1026, 909 cmꢀ1
;
dH (400 MHz,
CDCl3) 5.53 (1H, t, J 7.8 Hz, CH]C), 4.56 (2H, d, J 5.7 Hz, CH2OAc),
3.78 (1H, s, OH), 2.51e2.20 (5H, m), 2.11e1.85 (4H, m), 2.03 (3H, s,
CH3), 1.75 (3H, d, J 1.2 Hz, CH3), 1.75e1.65 (1H, m), 1.46 (1H, m), 1.01
(3H, d, J 7.6 Hz, CH3); dC (100.6 MHz, CDCl3) 214.4, 171.1, 132.0, 127.5,
70.4, 63.3, 61.5, 41.9, 35.0, 32.7, 31.0, 24.4, 21.5, 21.0, 19.9; m/z (ESþ)