Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tet.2010.03.048

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic cente

Full text of DOI:10.1016/j.tet.2010.03.048

Tetrahedron 66 (2010) 3814–3823
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Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction
or enzymatic resolution and their influence on the Sharpless asymmetric
dihydroxylation
Matthias Theurer a, Peter Fischer a, Angelika Baro a, Giang Son Nguyen b, Robert Kourist b,
,
Uwe Bornscheuer b, Sabine Laschat a
*
a
¨
Institut fu¨r Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
b Institut fu¨r Biochemie, Department fu¨r Biotechnologie & Enzymkatalyse, Felix-Hausdorff-Str. 4, D-17487 Greifswald, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol
methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study
asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-pro-
tected derivatives (R)-2b–d were submitted to Sharpless asymmetric dihydroxylation to yield the di-
astereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a–d, revealing that neither the substrate nor
the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-
substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was
favored.
Received 21 December 2009
Received in revised form
8 March 2010
Accepted 15 March 2010
Available online 20 March 2010
Keywords:
Asymmetric synthesis
Homoallylic alcohols
Enzymatic resolution
Lipases
Ó 2010 Published by Elsevier Ltd.
Sharpless asymmetric dihydroxylation
O
OH
*
1. Introduction
OH
*
OH
*
R2
M
SAD
OH
R1
R2
R1
R1
R2
The area of the asymmetric synthesis of compounds with qua-
ternary stereogenic centers is still a challenging task for organic
chemists.1 In particular enantiomerically pure tertiary homoallylic
alcohols 2 constitute valuable building blocks for natural product
synthesis as has been recently demonstrated by Sugai,2 Theodorakis,3
or Tietze.4 A variety of methods deal with the asymmetric allylation
of ketones such as Nozaki–Hiyama–Kishi reactions by Sigman5 and
Guiry,6 allylborations by Brown,7 Shibasaki,8 Chong,9 Schaus,10
Jarvo,11 Batey,12 Goodman and Pellegrinet,13 indium-mediated ally-
lations by Singaram,14 titanocene-catalyzed Barbier-type allylations
by Gansa¨uer,15 BINOL–Ti-catalyzed allylations employing tetraallyl-
stannane by Tagliavini16 and Walsh,17,18 auxiliary-mediated or cata-
lytic allylsilane transfer by Tietze4,19 and Shibasaki,20 respectively,
and addition of allyl(bisoxazoline)zinc by Nakamura.21,22 However,
several of these reagents and catalysts are limited, e.g., with regard to
the ketone substrates, enantioselectivities or use of highly toxic re-
agents. In addition, homoallylic alcohols such as 2 can be further
functionalized to the corresponding 1,2,4-triols 3 by Sharpless
asymmetric dihydroxylation (SAD)23 (Scheme 1).
1
2
3
1a−3a
R1 = Ph, R2 = Me
Scheme 1.
1,2,4-Triols 3 are highly attractive building blocks for natural
product syntheses, such as spongistatine,24 amphidinolide B,25
L
-
methylmycaropyranoside,26 mevalonolactone,27 vitamin E,28 and
anthracycline antibiotics.29 Despite a tremendous amount of work
on matched/mismatched relationships in Sharpless asymmetric
dihydroxylations,30 only a few reports deal with tertiary homoallylic
alcohols as substrates.31–34 For example, Carter observed that shift-
ing of a C]C double bond in the side chain attached to the hetero-
substituted quaternary stereocenter reduced the diastereomeric
ratio from 86:14 to 50:50.31 For acyclic precursors Myles reported
diastereoselectivities up to 75:25.32 Brimble obtained diols from
spiroacetals with only 28% ee.33 In contrast, good selectivities were
determined by Jefford for stericallycongested tricyclic cyclopenteno-
1,2,4-trioxanes, employing an iterative dihydroxylation.34
We therefore explored the double stereodifferentiation of ter-
tiary homoallylic alcohols in more detail. We were particularly
* Corresponding author. Tel.: þ49 711 685 64565; fax: þ49 711 685 64285; e-mail
address: sabine.laschat@oc.uni-stuttgart.de (S. Laschat).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.03.048

M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
3815
interested in the effect of the OH-protecting group on the Sharpless
asymmetric dihydroxylation. As a suitable model substrate, 2-
phenylpent-4-en-2-ol 2a was chosen. Following the method by
Walsh,17a i.e., treatment of ketone 1a with tetraallylstannane in the
presence of (R)-BINOL and Ti(Oi-Pr)4 in i-PrOH/CH2Cl2 at room
temperature, gave (R)-2a in 99% yield and 95% ee (Scheme 2).
addition of acetophenone 1a at ꢀ95 ꢁC and aqueous work-up
yielded a diastereomeric mixture (dr 86:14) from which the ma-
jor diastereomer 6a was easily isolated in 78% by flash chroma-
tography (Scheme 3).
After TBS protection, the chiral auxiliary was reductively cleaved
with LiBH4 (1 M in THF) in MeOH/Et2O at ꢀ10 ꢁC to the primary
alcohol 7 in 60%.37 Dess–Martin periodinane oxidation38 yielded
the aldehyde 8 in 89%, which was then submitted to Wittig
methylenation with Ph3PMeþBrꢀ and KOt-Bu in THF to give the
desired TBS-protected homoallylic alcohol (S)-2c in 84%. Thus, (S)-
2c is available from 1a in five steps with 33% overall yield.
Since the protection experiments were already in progress be-
fore the Evans route was established, homoallylic alcohol (R)-2a
from the allylstannane addition was used (Scheme 4). Methylated
and PMB-protected derivatives 2b,d were isolated after deproto-
nation with NaH and quenching with MeI or PMBCl in 93% and 66%,
respectively. Treatment of (R)-2a with TBSOTf in the presence of
2,6-lutidine provided TBS-ether (R)-2c in 88%.
1) (R)-BINOL, Ti(OiPr)4
iPrOH, CH2Cl2, rt, 1 d
HO
Sn(allyl)4
R
Ph
(R)-2a (99%, 95% ee)
O
2)
, rt, 1 d
Ph
1a
Scheme 2.
However, to avoid the use of stoichiometric amounts of tetraal-
lylstannane we looked for more environmentally benign routes.
Evans aldol methodology was chosen35 because it gives reliable
stereoselectivities even on a large scale and the auxiliary is easily
recovered.
RO
Biocatalysis is an environmentally benign alternative to chem-
ical synthesis. The enzymatic synthesis of quaternary centers such
as tertiary alcohols, however, is hampered by some difficulties. On
one hand, the method of choice for the biocatalytic preparation of
alcohols would be the enantioselective reduction of prochiral ke-
tones and aldehydes to enantiopure alcohols catalyzed by alcohol
dehydrogenases. This is not applicable in the case of tertiary alco-
hols. On the other hand, the hydrolase-catalyzed kinetic resolution
of tertiary alcohols is a difficult task. Very few enzymes are active
for this process, and enantioselectivities are usually low. Never-
theless, considerable progress has been made.36 Tertiary alcohols
have been synthesized in excellent optical purity by using epoxide
hydrolases,2,36b proteases,36c and esterases.36d,e For the enantiose-
lective synthesis of arylaliphatic tertiary alcohols such as 2, several
potentially selective esterases are available now, including variants
of the esterase BS2 from Bacillus subtilis36d and several wild-type
enzymes derived from metagenomic sources.36e
methods A−C
(R)-2a (95% ee)
R
Ph
A: NaH, MeI, THF
(R)-2b R = Me
93%
0°C→rt, 36 h
B: TBSOTf, 2,6-lutidine (R)-2c R = TBS 88%
CH2Cl2, rt, 36 h
C: NaH, PMBCl
DMF, rt, 6 h
(R)-2d R = PMB 66%
Scheme 4.
For analytical purposes and as racemic starting material for the
enzymatic resolution, rac-2a was prepared in 84% by Grignard
addition to acetophenone 1a (Scheme 5). Further treatment with n-
BuLi in THF and acetyl chloride produced the acetate rac-2e in 77%
yield, based on recovered starting material. Next, enzymatic reso-
lutions of racemic acetate rac-2e with esterases were investigated
(Scheme 5, Table 1). Out of 17 esterases with a verified activity
towards tertiary alcohols,36d,e only a few showed activity in the
hydrolysis of rac-2e. Several enzyme variants of esterase BS2 from
B. subtilis were previously shown to be highly enantioselective in
the conversion of several compounds very similar to 2e.36d
Thus the feasibility of Evans aldol versus biocatalysis followed
by SAD for the conversion of acetophenone 1a into 1,2,4-triol 3a
was investigated and the results are reported below.
2. Results and discussion
Surprisingly, the enantioselectivity of the wild-type enzyme
towards 2e was very low; two variants, BS2G105A and BS2 E188W/
M198C, did not convert the substrate at all. Most of the remaining
enzymes had no or low enantioselectivity. The metagenomic es-
terase Est8 converted 2e at room temperature with a moderate E
The Evans route commenced with L-phenylalaninol-derived
oxazolidinone 4,35a which was N-acetylated with n-BuLi, acetyl
chloride in THF at ꢀ78 ꢁC to give the N-acetamide 5 in 82%. Sub-
sequent deprotonation with LiHMDS in THF at ꢀ78 ꢁC, followed by
O
O
O
O
1) LiHMDS, THF
O
RO
−78°C, 2 h
1) BuLi, THF
S
HN
Bn
O
O
O
N
Ph
N
2) AcCl, −78°C
2) 1a, −95°C, 0.5 h;
−78°C, 1 h
0.5 h
Bn
5, 82%
Bn
4
6a R = H, 78%, dr 86:14
6b R = TBS, 95%
TBSOTf
LiBH4, THF, MeOH, Et2O, −10°C, 1 h
KOtBu
TBSO
Ph
TBSO
Ph
TBSO
Ph
DMP, CH2Cl2
rt, 20 min
Ph3PMeBr
S
OH
O
THF, 1 h
(S)-2c, 84%, >99% ee
8, 89%
7, 60%
Scheme 3.

3816
M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
Table 2
HO
Ph
rac-2a, 84%
allylMgBr
Dihydroxylations of homoallylic alcohols (R)-2 under various conditionsa,b
1a
Et2O, rt, 5 h
Entry Alcohol
R
Method Product 3 Yield (%) Diastereomeric
ratio (2R,4R)/(2S,4R)
(R)-2
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2a
H
H
H
A
B
C
A
B
C
A
B
C
A
B
C
D
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
3a
94
79
87
92
92
85
91
80
79
99
85
77
87
46:54c
49:51
55:45
49:51
35:65
60:40
42:58
54:46
41:59
47:53c
51:49
54:46
86:14
1) BuLi, THF, 0°C, 25 min
2) AcCl, 0°C, 10 min
3) reflux, 1 h
Me
Me
Me
TBS
TBS
TBS
PMB
PMB
PMB
H
AcO
Ph
(9)
rac-2e, 77% based on
(10)
(11)
(12)
(13)
recovered 2a
(see Table 1)
esterase
HO
Ph
AcO
a
Reactions conditions: see Scheme 6. Method A: K2OsO4, NMO, acetone/H2O,
+
0
ꢁC/rt, 12 h; method B: AD-mix- , t-BuOH/H2O, 0 ꢁC, 48 h; method C: AD-mix-
a b,
Ph
t-BuOH/H2O, 0 ꢁC, 48 h; method D: OsO4, TMEDA, CH2Cl2, ꢀ78 ꢁC, 1 h.
(S)-2a
(R)-2e
b
Yields refer to isolated yields. Diastereomeric ratios were determined by
1H NMR.
Scheme 5.
c
Diastereomeric ratio was determined by gas chromatography.
Table 1
Selected examples of enzymatic kinetic resolution reactions of rac-2e
Surprisingly, regardless of the protecting group R or the dihy-
droxylation method employed, very poor diastereoselectivities
49:51 up to 35:65 were observed. An illustrative example is the
TBS-protected derivative (R)-2c, which yielded 91% of a (42:58)
mixture of (2R,4R)-3c and (2S,4R)-3c, respectively, via method A
Enzyme
Time (h) Chiral analysis
(S)-2a (ee%)a (R)-2e (ee%)b Conv. (%) E value
BS2
BS2G105A
BS2 E188W/M193C n.d.
CAL-A
PestA
Est8
4
n.d.
37
n.d.
n.d.
28
5
n.d.
n.d.
n.d.
n.d.
n.d.
71
28a
n.c.
n.c.
25a
62
3
n.d.
n.d.
2
n.d.
26d
(entry 7). Treatment of (R)-2c with AD-mix-
80% (dr 54:46) (entry 8). The diastereomeric ratio was reversed by
employing AD-mix- (method C), yielding 79% of 3c (dr 41:59)
(entry 9). A slightly better situation was observed for the methyl-
protected derivative (R)-2b where the use of AD-mix- led to a dr
35:65 of 3b (entry 5) and AD-mix- to dr 60:40 (entry 6) as com-
a (method B) gave 3c in
4
4
1
b
85
46c
n.d. not determined; n.c. no conversion.
a
a
Determined by gas chromatography.
Determined by HPLC.
Calculated from (S)-2a and (R)-2e.
At 4 ꢁC.
b
b
c
pared to the non-selective case via method A (entry 4). The selec-
tivities for the PMB-protected derivative (R)-2d were again very
poor (entries 10–12). We anticipated that the presence of a pro-
tecting group at the tertiary alcohol moiety might interfere with the
Sharpless catalyst. However, even the unprotected derivative (R)-2a
gave disappointing results (entries 1–3).
Thus, the overall steric bulkiness of the tertiary alcohol moiety
in the neighborhood of the C]C double bond seems to minimize
the energetic differences between the diastereomorphic transition
states of the Sharpless asymmetric dihydroxylation. Even the chi-
d
value of E¼23. Lowering the temperature to 4 ꢁC did not sub-
stantially increase the enantioselectivity (E¼26) (Table 1), neither
did cosolvent optimization. The conversion of rac-2e was repeated
on a 120 mg-scale, giving rise to enantiomerically enriched (R)-2e
and (S)-2a with good yields (34% 2e, 39% for 2a) and good optical
purities (71% ee for 2e, 85% ee for 2a).
Est8 was found to be enantioselective in the hydrolysis of some
aliphatic tertiary alcohols while the enantioselectivity of Est8 to-
wards analogues of 2e bearing an ethynyl substituent is very
low.36d The analogous butyric ester of 2e was not converted by Est8.
The remaining enzymes had no or only low enantioselectivity with
this substrate (data not shown).
Next, enantiomerically enriched homoallylic alcohol derivatives
(R)-2a–d were either submitted to dihydroxylation with K2OsO4,
NMO in acetone/H2O (method A), AD-mix-
(method B), AD-mix- in t-BuOH/H2O (method C) or OsO4, TMEDA in
CH2Cl2 (method D) toyield the diastereomeric 1,2-diols 3 (Scheme 6,
rality transfer in the absence of AD-mix-a (or -b) is very poor,
resulting in a slight preference of the (2S,4R)-diastereomer (2S,4R)-
3 regardless of the R group. The results are somewhat surprising
because Carter31 and Eng32 observed at least some kind of stereo-
control with steric bulky substrates. However, as mentioned above,
Carter already noticed that slight side chain modifications such as
a C]C double bond isomerization resulted in complete loss of
diastereoselectivity. Finally, we tested Donohoe’s hydrogen-bond-
directed dihydroxylation using unprotected homoallylic alcohol 2a,
OsO4, and TMEDA (method D),39,40 which has been reported to give
promising diastereoselectivities also for homoallylic alcohols.41
Gratifyingly, the diastereomeric triols 3a were isolated in 87%
yield with a dr of 86:14 (entry 13). Thus, even in this sterically
hindered environment, the tertiary alcohol moiety of 2a is to some
extent able to direct the attack of osmium tetroxide via hydrogen
bonding and chelation by TMEDA.
a in t-BuOH/H2O
b
Table 2).
OH
OH
RO
RO
methods A−D
(R)-2a−d
1
1
OH
OH
+
R
R
R
S
(for details
Ph
(2R,4R)-3a−d
Ph
(2S,4R)-3a−d
see Table 2)
Unfortunately, no single crystals could be grown for di-
astereomeric triols 3a. For assignment of the configuration, com-
pounds3a, whichcould be easilyseparatedbyflashchromatography
were therefore treated with p-anisaldehyde dimethyl acetal in
2, 3
a
R
H
A: K2OsO4, NMO, acetone/H2O, 0°C→rt, 12 h
B: AD-mix-α, tBuOH/H2O, 0°C, 48 h
C: AD-mix-β, tBuOH/H2O, 0°C, 48 h
D: OsO4, TMEDA, CH2Cl2, -78°C, 1 h
b
Me
TBS
PMB
c
42
CH2Cl2 in the presence of camphorsulfonic acid and molecular
d
sieves. The corresponding PMP-acetals (2R,4R,6S)-9 and (2S,4R,6R)-
Scheme 6.
9 were isolated in 52 and 55% yields, respectively (Scheme 7).43

M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
3817
RO
O
RO
PPTS, MeOH,
(2R,4R)-3b
O
R
R
39°C, 12 h, 82%
Ph
(S)-12a R = H, 42%
1) 2,6-lutidine, CH2Cl2
2) TBSOTf, rt, 20 min
11 R = Me
10 R = H
NaH, MeI, THF, 0°C→rt, 36 h, 67%
(S)-12b R = TBS (er 90:10)
tBuOH/H2O (1:1), 0°C, 40 h AD-mix-β
Me2C(OMe)2, CSA, rt, 6 h, 76%
OH
OH
OH
TBSO
TBSO
OH
HO
Ph
HO
4
2
OH
1
OH
+
+
3
1
1
S
R
S
S
OH
OH
R
R
R
S
Ph
(2R,4S)-13, 39%
(2S,4S)-13, 46%
(2R,4R)-3a
(2S,4R)-3a
MeO
OH
OH
TBSO
TBSO
OMe
OH
OH
MeO
R
S
R
R
CSA, mol. sieves 4 Å, CH2Cl2
(2S,4R)-13, 1%
(2R,4R)-13, 14%
0°C→rt, 4 h
Scheme 8.
PMP
PMP
O
6
O5
O
O
3. Conclusion
3
1 OH
OH
4
2
Ph
Ph
The Evans aldol addition to acetophenone 1a was shown to offer
an efficient access to enantiopure homoallylic alcohol 2a by envi-
ronmentally benign protocols as compared to the allylstannane
procedure. Even if some progress has been made, the enzymatic
kinetic resolution of tertiary alcohols is still not always straight-
forward. Taking into account the very low number of hydrolases
with activity towards tertiary alcohols, the identification of some
hydrolases with activity towards 2e was a promising result. With
Est8, one biocatalyst was identified that produces (S)-2a with
moderate optical purity (85% ee). Together with the easy prepara-
tion of the starting compounds, the biocatalytic preparation can be
considered as a straightforward, environmentally benign alterna-
tive. In addition, a series of differently protected homoallylic alco-
hols (R)-2, (S)-12b was submitted to Sharpless asymmetric
dihydroxylation. Regardless of the protecting group, the dihydrox-
ylation catalyst is hardly able to overcome the small chirality
transfer of the quaternary stereogenic center towards the (2S,4R)-
diastereomer (2S,4R)-3 and (2S,4S)-13. This is probably due to the
steric bulkiness of the tertiary alcohol moiety. The observation that
the substrate 2 has little intrinsic bias for formation of the syn or anti
product 3 probably reflects a failure of the alkene 2 to adequately
dock with the Os/ligand assembly due to steric hindrance. However,
this problem can be solved by the use of Donohoe’s hydrogen-bond-
directed dihydroxylation, which yielded preferably the anti-1,2,4-
triol (2R,4R)-3a. Unfortunately, none of the methods shown above is
able to produce the syn-1,2,4-triol with high selectivities. In par-
ticular, alternative routes for the missing 1,3-induction in tertiary
homoallylic alcohols via Sharpless dihydroxylation are highly de-
sirable, and the scope of directed dihydroxylation must be explored
further for acyclic substrates in order to use the current routes to-
wards 1,2,4-triol subunits for natural product synthesis.
(2R,4R,6S)-9, 52%
(2S,4R,6R)-9, 55%
DIBAL, CH2Cl2, 0°C, 3 h
(2R,4R)-3d
(2S,4R)-3d
35%
61%
(based on recovered starting material)
Scheme 7.
PMP-acetals 9 could be reduced to the corresponding PMB-
protected 1,2-diols (2R,4R)-3d and (2S,4R)-3d with DIBAL in
CH2Cl2 at 0 ꢁC (35 and 61% yield, respectively, based on recovered
starting material). The configurational assignment of the PMB-
protected 1,2-diols 3d could be correlated with the unprotected
triols 3a via detailed NMR analysis (Supplementary data). The di-
astereomeric methyl-protected 1,2-diols 3b could not be separated
chromatographically. Therefore, unprotected triol (2R,4R)-3a was
converted in three steps to methyl-protected 1,2-diol (2R,4R)-3b in
42% overall yield by acetalization of the 1,2-diol moiety with 2,2-
dimethoxypropane in the presence of CSA followed by methylation
and subsequent cleavage of the acetal (Scheme 7).
With regard to the Sharpless asymmetric dihydroxylation of
homoallylic alcohol 2a we surmised that the phenyl ring at the
tertiary alcohol stereocenter might interfere with the Sharpless
catalyst through
p–p interactions or steric hindrance, resulting in
a complete loss of the stereoselectivity. In order to test this hy-
pothesis, the known (S)-3-methyl-5-hexen-1-yn-3-ol (S)-12a,7
bearing an almost linear alkynyl moiety at the quaternary stereo-
center, was converted to the TBS-ether (S)-12b (Scheme 8). Due to
the incomplete stereocontrol of the Brown allylation with diisopi-
nocampheylborane,7 the enantiomeric excess of (S)-12b was only
4. Experimental
4.1. General
80%. Treatment of compound (S)-12b with AD-mix-
b under the
above described conditions yielded a mixture of four diastereomers
13 (46:39:1:14). Thus, the (S)-configured homoallylic alcohol (S)-
12b produced a mismatched pair (2S,4S)-13 and (2R,4S)-13 in 46%
and 39%, respectively, whereas the minor enantiomer (R)-12b
yielded a matched pair (2S,4R)-13 and (2R,4R)-13 in 1% and 14%,
respectively. Thus, it seems that neither the type of substituents nor
the OH-protecting group exerts any positive control on the ster-
eoselectivity of the Sharpless asymmetric dihydroxylation.
Melting points (uncorrected) were determined on a Bu¨chi 510
melting point apparatus. Optical rotations were determined with
a Perkin–Elmer 241 LC polarimeter. IR spectra: Bruker Vektor 22 FT-
IR spectrometer. Mass spectra: Finnigan MAT 95, Varian MAT 711,
and Bruker Daltonics micrOTOF_Q spectrometers. NMR spectra:
Bruker ARX 300 and Bruker ARX 500 spectrometers. The spectra

3818
M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
were recorded with TMS as an internal standard. 13C NMR multi-
plicities were determined by DEPT135 experiments. Assignments
were done by using 1H–1H-COSY, 1H–13C-correlation, and NOESY
experiments. Column chromatography: Fluka silica gel 60 (40–
63 mm). All syntheses were performed under nitrogen using stan-
dard Schlenk technique.
Chiralcel OJ-H, hexane/isopropanol (98:2), flow rate 1.0 mL minꢀ1
,
tR,major¼11.26 min and tR,minor¼13.94 min; ee 95%.
4.3.2. (S)-3-Acetyl-4-benzyloxazolidin-2-one (5). Following the
procedure by Evans35b,c compound 5 (2.48 g, 82%) was obtained as
a colorless solid; mp 109 ꢁC; dH (500 MHz, CDCl3) 2.56 (s, 3H, CH3),
2.78 (dd, J¼13.4, 9.5 Hz, 1H, CH2Ph), 3.31 (dd, J¼13.4, 3.5 Hz, 1H,
CH2Ph), 4.15–4.22 (m, 2H, H-5), 4.67 (dddd, J¼10.4, 9.5, 7.1, 3.5 Hz,
1H, H-4), 7.20–7.22 (m, 2H, o-H, Bn), 7.27–7.30 (m, 1H, p-H, Bn),
7.32–7.36 (m, 2H, m-H, Bn).
4.2. Biocatalytic reactions
Recombinant esterases were produced as described.36d,e All
metagenomic esterases were provided by B.R.A.I.N. AG (Zwingen-
berg, Germany) and used as glycerol-stabilized crude cell extracts
or lyophilisate.
4.3.3. (S)-4-Benzyl-3-((S)-3-hydroxy-3-phenylbutanoyl)oxazolidin-
2-one (6a). A solution of 5 (1.00 g, 4.60 mmol) in dry THF (10 mL)
was slowly added at ꢀ78 ꢁC to a solution of LiHMDS (5.7 mL,
4.6 mmol, 0.84 M in THF). After 2 h at ꢀ78 ꢁC, the solution was
4.2.1. General procedure for esterase-catalyzed small-scale reso-
lutions. To a stirred solution of acetate (25 mM) inphosphate buffer
(100 mM, pH 7.5) and the appropriate amount of cosolvent DMSO
[10–20% (v/v)], the appropriate amount of esterase solution was
added to a total volume of 1 mL. The amount of enzyme in crude
extracts was determined according to the activity in hydrolysis of
p-nitrophenyl butyrate. The reaction mixture was stirred in
a thermoshaker (Eppendorf, Hamburg, Germany) at 37 ꢁC for
15 min. Samples were taken every 1, 4, and 24 h. After two times
extraction with CH2Cl2, the organic layer was dried (Na2SO4) and
filtered. Enantioselectivity and conversion were calculated
according to Chen.44 The enantiomeric purityof 2e was analyzed on
a Chiralcel OD-H column by HPLC (hexane/isopropanol 99:1, flow:
0.5 mL minꢀ1) with a retention time of 12.0 min (R)-2e and
cooled to ꢀ95 ꢁC and 1a (365 mg, 360
mL, 3.00 mmol), dissolved in
THF (6 mL) was slowly added. The solution was kept for an addi-
tional 30 min at ꢀ95 ꢁC and then for 45 min at ꢀ78 ꢁC. Sub-
sequently, the reaction was stopped by the addition of aqueous
0.5 M HCl (10 mL). The THF layer was separated and the aqueous
layer was extracted with CH2Cl2 (3ꢂ15 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed in vacuo.
The crude product was purified by column chromatography (silica
gel, hexane/EtOAc 4:1/1:1) to obtain 6a (790 mg, 78%, dr¼84:14
by 1H NMR) as a colorless solid; mp 101–103 ꢁC. Found: C, 70.74; H,
6.28; N, 4.07. C20H21NO4 requires C, 70.78; H, 6.24; N, 4.13%; Rf,major
(hexane/EtOAc 2:1) 0.35; Rf,minor (hexane/EtOAc 2:1) 0.51;
20
[a
]
þ126.2 (c 1.0, CH2Cl2); nmax (neat) 3490 (w, br), 3062 (w), 3029
D
12.8 min (S)-2e. Alcohol 2a was analyzed with an FS-Hydrodex
b
-
(w), 1964 (m), 1779 (vs), 1681 (s), 1380 (s), 1213 (s), 701 (m) cmꢀ1
;
column (Macherey Nagel, Du¨ ren, Germany) on a Shimadzu 2010
gas chromatograph (Shimadzu, Japan) at a constant temperature of
90 ꢁC. Retention times: 22.2 min (R)-2a and 23.5 min (S)-2a.
dH (500 MHz, CDCl3) 1.60 (d, J¼0.9 Hz, 3H, CH3), 2.41 (dd, J¼13.6,
9.3 Hz, 1H, CH2Ph), 2.83 (dd, J¼13.6, 3.4 Hz, 1H, CH2Ph), 3.06 (d,
J¼16.5 Hz, 1H, H-20a), 4.09 (dd, J¼9.1, 2.9 Hz, 1H, H-5a), 4.15 (dd,
J¼9.1, 7.8 Hz, 1H, H-5b), 4.21 (d, J¼16.5 Hz, 1H, H-20b), 4.57 (d,
J¼0.9 Hz, 1H, OH), 4.59 (dddd, J¼9.4, 7.8, 3.4, 2.9 Hz, 1H, CHBn),
6.99–7.01 (m, 2H, o-H, Bn), 7.22–7.30 (m, 4H, m-H, p-H, Bn, p-H, Ph),
7.34–7.39 (m, 2H, m-H, Ph), 7.50–7.53 (m, 2H, o-H, Ph); dC (125 MHz,
CDCl3) 31.1 (CH3), 37.3 (CH2Ph), 45.7 (C-20), 54.8 (C-4), 66.0 (C-5),
73.8 (C-30), 124.6 (2C, C-oPh), 126.9 (C-pPh), 127.4 (C-pBn), 128.3 (2C,
C-mPh), 128.9 (2C, C-mBn), 129.3 (2C, C-oBn), 134.8 (C-iBn), 147.0 (C-
iPh), 153.3 (C]O), 172.9 (COCH2); m/z (ESI) 362 (Mþ), 322, 216, 190;
HRMS (ESI): MNaþ, found 362.1363. C20H21NO4Naþ requires
362.1363.
4.2.2. Preparative scale enzyme hydrolysis of (2e). To a stirred so-
lution of the substrate (120 mg, 0.59 mmol) in DMSO (4 mL) was
added a solution of the enzyme (320 mg,185 U) in phosphate buffer
(7 mL, 100 mM, pH 7.4). The reaction mixture was stirred at 4 ꢁC for
4 h. After extraction with MTBE, the organic layers were combined
and dried (Na2SO4). The organic solvent was removed under re-
duced pressure and the residue chromatographed on silica gel with
n-pentane/EtOAc to give (R)-2-phenylpent-4-en-2-yl-acetate (R)-
2e as white powder (41 mg, 0.2 mmol, 34%, 71% ee) and (S)-2-
phenylpent-4-en-2-ol (S)-2a as white powder (37.5 mg, 0.23 mmol,
39%, 85% ee).
4.3.4. (S)-4-Benzyl-3-((S)-3-(tert-butyldimethylsilyloxy)-3-phenyl-
butanoyl)oxazolidin-2-one (6b). To
0.30 mmol) in CH2Cl2 (2 mL) were added at rt 2,6-lutidine (78
72 mg, 0.52 mmol) and TBSOTf (133 L, 153 mg, 0.45 mmol). After
a
solution of 6a (130 mg,
4.3. Synthesis and characterization
mL,
m
4.3.1. (R)-2-Phenylpent-4-en-2-ol (2a). To a solution of (R)-BINOL
(803 mg, 2.8 mmol) in CH2Cl2 (21 mL) were sequentially added
Ti(Oi-Pr)4 (0.84 mL, 0.80 g, 2.8 mmol), i-PrOH (14.5 mL, 0.19 mol),
and tetraallylstannane (3.36 mL, 3.96 g, 14.0 mmol) and the mix-
ture was stirred at rt for 1 day. Then 1a (1.07 mL, 1.1 g, 9.2 mmol)
was added and the mixture was stirred at rt for a further day. The
reaction mixture was diluted with aqueous NH4Cl solution (10 mL)
and extracted with CH2Cl2 (3ꢂ20 mL). The combined organic layers
were dried (MgSO4) and concentrated. The residue was dissolved in
hexanes, filtered through Celite, and evaporated. The crude oil was
purified by column chromatography (silica gel, hexane/EtOAc
the solution was stirred for an additional 30 min, the reaction
mixture was quenched by the addition of satd aqueous NH4Cl so-
lution (2 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
layers were dried (MgSO4), and the solvent was evaporated. The
crude oil was purified by column chromatography (silica gel, hex-
ane/EtOAc 5:1) to give 6b (129 mg, 95%) as a colorless oil; Rf
20
(hexane/EtOAc 2:1) 0.67; [
a
]
D
þ27.5 (c 1.0, CH2Cl2); nmax (neat)
2954 (s), 2929 (s), 2857 (m), 1962 (w), 1728 (vs), 1698 (s), 1358 (s),
1210 (s), 1002 (m), 835 (s) cmꢀ1
dH (500 MHz, CDCl3) ꢀ0.12 (s, 3H,
;
Si–CH3), 0.10 (s, 3H, Si–CH3), 0.94 (s, 9H, C–CH3), 1.88 (s, 3H, CH3),
2.54 (dd, J¼13.3, 10.2 Hz, 1H, CH2Ph), 3.22 (dd, J¼13.3, 3.4 Hz, 1H,
CH2Ph), 3.51 (d, J¼14.3 Hz, 1H, H-20a), 3.59 (d, J¼14.3 Hz, 1H, H-20b),
3.85 (dd, J¼9.0, 7.8 Hz, 1H, H-5a), 3.97 (dd, J¼9.0, 2.6 Hz, 1H, H-5b),
4.41 (dddd, J¼10.2, 7.8, 3.4, 2.6 Hz, 1H, H-4), 7.14–7.17 (m, 2H, o-H,
Bn), 7.21–7.27 (m, 2H, p-H, Bn, p-H, Ph), 7.29–7.34 (m, 4H, m-H, Bn,
m-H, Ph), 7.51–7.54 (m, 2H, o-H, Ph); dC (125 MHz, CDCl3) ꢀ2.6 (Si–
CH3), ꢀ2.0 (Si–CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.6 (CH3),
37.8 (CH2Ph), 49.1 (C-20), 55.4 (C-4), 65.7 (C-5), 76.2 (C-30), 125.7
15:1/10:1) to give 2a (1.48 g, 99%) as a colorless oil; Rf (hexane/
20
EtOAc 6:1) 0.51; [
a
]
D
þ21.8 (c 0.36, CH2Cl2); dH (300 MHz, CDCl3)
1.55 (s, 3H, CH3), 2.03 (s, 1H, OH), 2.50 (dd, J¼13.7, 8.2 Hz, 1H, H-3a),
2.70 (dd, J¼13.7, 6.5 Hz, 1H, H-3b), 5.10–5.18 (m, 2H, H-5), 5.62
(dddd, J¼17.0, 10.2, 8.3, 6.5 Hz, 1-H, H-4), 7.21–7.27 (m, 1H, p-H, Ph),
7.31–7.38 (m, 2H, m-H, Ph), 7.42–7.47 (m, 2H, o-H, Ph); dC (75 MHz,
CDCl3) 29.9 (CH3), 48.5 (C-3), 73.6 (C-2), 119.5 (C-5), 124.8 (2C, Ph),
126.6 (C-pPh), 128.2 (2C, Ph), 133.7 (C-4), 147.6 (C-iPh); HPLC:

M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
3819
(2C, C-oPh), 127.0 (C-pPh), 127.2 (C-pBn), 127.7 (2C, C-mPh), 128.9 (2C,
773 (s), 699 (s) cmꢀ1
;
dH (500 MHz, CDCl3) 0.07 (s, 3H, Si–CH3), 0.08
C-mBn), 129.4 (2C, C-oBn), 135.5 (C-iBn), 147.0 (C-iPh), 153.2 (C]O),
169.8 (COCH2); m/z (ESI) 476 (MNaþ), 322, 242, 145; HRMS (ESI):
MNaþ, found 476.2221. C26H35NO4SiNaþ requires 476.2228.
(s, 3H, Si–CH3), 0.94 (s, 9H, C–CH3), 1.61 (s, 3H, CH3), 2.46 (dd,
J¼13.9, 7.2 Hz, 1H, H-3a), 2.55 (dd, J¼13.9, 7.0 Hz, 1H, H-3b), 4.90–
4.96 (m, 2H, H-5), 5.64 (dddd, J¼14.2, 10.5, 7.2, 7.0 Hz, 1H, H-4),
7.18–7.22 (m, 1H, p-H, Ph), 7.28–7.31 (m, 2H, m-H, Ph), 7.40–7.43 (m,
2H, o-H, Ph); dC (125 MHz, CDCl3) ꢀ2.3 (Si–CH3), ꢀ1.9 (Si–CH3), 18.5
[SiC(CH3)3], 26.1 [SiC(CH3)3], 28.6 (CH3), 50.6 (C-3), 76.7 (C-2), 117.1
(C-5), 125.4 (2C, C-oPh), 126.3 (C-pPh), 127.7 (2C, C-mPh), 134.8 (C-4),
148.3 (C-iPh); m/z (ESI) 277 (MHþ), 261, 235, 219, 145; HRMS (ESI):
MHþ, found 277.1964. C17H29OSiþ requires 277.1982.
4.3.5. (S)-3-(tert-Butyldimethylsilyloxy)-3-phenylbutan-1-ol (7). To
a solution of 6b (90 mg, 198
mmol) in Et2O (2 mL) and MeOH (9.6
mL,
7.7 mg, 0.24 mmol) was added LiBH4 (119
m
L, 5.17 mg, 238 mol, 2 M
m
in THF) at ꢀ10 ꢁC. After the solution was stirred for 1 h, the mixture
was quenched by the addition of aqueous NaOH solution (1 mL,1 M).
The mixture was warmed to 0 ꢁC and stirred for 15 min, sub-
sequently shaken with brine (10 mL) and the organic layer was
separated. The aqueous layer was extracted with Et2O (3ꢂ10 mL).
The combined organic layers were dried (Na2SO4), and the solvent
was evaporated. The crude oil was purified by column chromatog-
4.3.8. (R)-(2-Methoxypent-4-en-2-yl)benzene (2b). NaH (35 mg,
4.9 mmol, 60% in mineral oil) was washed with dry THF (2ꢂ2.5 mL),
suspended in THF (1 mL), and treated sequentially with a solution of
homoallylic alcohol 2a (94 mg, 0.58 mmol) in THF (1 mL) and MeI
raphy (silica gel, hexane/EtOAc 2:1) to give 7 (34 mg, 60%) as a col-
(108 mL, 247 mg, 1.74 mmol). The ice bath was removed and stirring
20
orless oil; Rf (hexane/EtOAc 1:1) 0.78; [
a
]
ꢀ38.4 (c 1.0, CH2Cl2); nmax
was continued for 36 h at rt. The reaction mixture was quenched by
the addition of satd aqueous Na2S2O3 solution (2 mL). The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers were dried
(MgSO4), and the solvent was evaporated. The crude oil was purified
D
(neat) 3348 (m, br), 2954 (s), 2929 (s), 2856 (m), 1968 (w), 1472 (m),
1255 (s), 1030 (m), 834 (vs), 774 (vs), 700 (s) cmꢀ1
;
dH (500 MHz,
CDCl3) ꢀ0.06 (s, 3H, Si–CH3), 0.12 (s, 3H, Si–CH3), 0.96 (s, 9H, C–CH3),
1.72 (s, 3H, CH3), 1.99 (ddd, J¼14.2, 6.7, 5.5 Hz, 1H, H-2a), 2.06 (ddd,
J¼14.2, 6.7, 5.4 Hz,1H, H-2b), 2.42 (br tr, J¼5.3 Hz, 1H, OH), 3.57–3.67
(m, 2H, H-1), 7.22–7.26 (m, 1H, p-H, Ph), 7.31–7.35 (m, 2H, m-H, Ph),
7.42–7.45 (m, 2H, o-H, Ph); dC (125 MHz, CDCl3) ꢀ2.3 (Si–CH3), ꢀ1.8
(Si-CH3),18.4 [SiC(CH3)3], 26.2 [SiC(CH3)3], 29.6 (CH3), 47.5 (C-2), 59.9
(C-1), 78.4 (C-3), 125.2 (2C, C-oPh), 126.7 (C-pPh), 128.1 (2C, C-mPh),
147.5 (C-iPh); m/z (ESI) 281 (MHþ), 147, 131, 105, 91; HRMS (ESI):
MNaþ, found 303.1761. C16H28O2Si Naþ requires 303.1751.
by column chromatography (silica gel, hexane/EtOAc 20:1) to give
20
2b (95 mg, 93%) as a colorless oil; Rf (hexane/EtOAc 10:1) 0.62; [a]
D
þ13.8 (c 0.42, CH2Cl2); nmax (neat) 2978 (m), 2932 (m), 1640 (w),
1446 (m), 1161 (m), 1073 (vs), 914 (s), 764 (s), 700 (vs) cmꢀ1
;
dH
(500 MHz, CDCl3) 1.52 (s, 3H, CH3), 2.50 (dd, J¼13.9, 7.2 Hz, 1H, H-
3a), 2.56 (dd, J¼13.9, 7.2 Hz, 1H, H-3b), 3.08 (s, 3H, OCH3), 4.98–5.01
(m,1H, H-5a), 5.02–5.03 (m, 1H, H-5b), 5.61–5.70 (m,1H, H-4), 7.23–
7.27 (m, 1H, p-H, Ph), 7.32–7.39 (m, 4H, o-H, m-H, Ph); dC (125 MHz,
CDCl3) 22.8 (CH3), 47.3 (C-3), 50.4 (OCH3), 78.7 (C-2), 117.6 (C-5),
126.3 (2C, C-oPh), 126.9 (C-pPh), 128.1 (2C, C-mPh), 134.1 (C-4), 144.7
(C-iPh); m/z (GC–MS, CI) 177 (3, MHþ), 145 (35), 135 (100), 99 (15%);
HRMS (CI): MHþ, found 177.1263. C12H17Oþ requires 177.1274.
4.3.6. (S)-3-(tert-Butyldimethylsilyloxy)-3-phenylbutanal (8). To a so-
lution of Dess–Martin periodinane (127 mg, 0.3 mmol) in CH2Cl2
(0.6 mL) was added a solution of alcohol 7 (34 mg, 0.12 mmol) in
CH2Cl2 (0.5 mL) at rt. After the solution was stirred for an additional
20 min at rt, the mixture was diluted by the addition of CH2Cl2
(3 mL) and aqueous NaOH solution (1 mL, 1 M) and stirred for an
additional 10 min. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
layers were dried (Na2SO4), and the solvent was evaporated. The
crude oil was purified by column chromatography (silica gel, hex-
4.3.9. (R)-tert-Butyldimethyl(2-phenylpent-4-en-2-yloxy)silane [(R)-
2c]. To a solution of 2a (250 mg, 1.54 mmol) in CH2Cl2 (1.5 mL)
were added at rt 2,6-lutidine (360
mL, 332 mg, 3.10 mmol) and
TBSOTf (530 L, 608 mg, 2.30 mmol). After the solution was stirred
m
for an additional 30 min, the reaction mixture was quenched by the
addition of satd aqueous NH4Cl solution (2 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic layers were dried (MgSO4), and
the solvent was evaporated. The crude oil was purified by column
ane/EtOAc 10:1) to give 8 (30 mg, 89%) as a colorless oil; Rf (hexane/
20
EtOAc 10:1) 0.55; [
a
]
ꢀ37.0 (c 0.5, CH2Cl2); nmax (neat) 2955 (m),
D
2929 (m), 2856 (m), 1723 (vs),1463 (w), 1256 (s), 1126 (m), 832 (vs),
774 (vs), 670 (vs) cmꢀ1
dH (500 MHz, CDCl3) ꢀ0.06 (s, 3H, Si–CH3),
;
0.05 (s, 3H, Si–CH3), 0.88 (s, 9H, C–CH3), 1.65 (s, 3H, CH3), 2.61 (dd,
J¼15.3, 3.5 Hz, 1H, H-2a), 2.79 (dd, J¼15.3, 2.4 Hz, 1H, H-2b), 7.17–
7.21 (m, 1H, p-H, Ph), 7.26–7.30 (m, 2H, m-H, Ph), 7.38–7.41 (m, 2H,
o-H, Ph), 9.52 (dd, J¼3.5, 2.4 Hz, 1H, H-1); dC (125 MHz, CDCl3) ꢀ2.3
(Si–CH3), ꢀ1.9 (Si–CH3), 18.5 [SiC(CH3)3], 26.0 [SiC(CH3)3], 30.2
(CH3), 57.9 (C-2), 75.8 (C-3), 125.0 (2C, C-oPh), 127.1 (C-pPh), 128.3
(2C, C-mPh), 147.0 (C-iPh), 202.8 (C-1); m/z (ESI) 279 (MHþ), 149, 133,
119; HRMS (ESI): MNaþ, found 301.1601. C16H26O2Si Naþ requires
301.1594.
chromatography (silica gel, hexane) to give (R)-2c (440 mg, 88%) as
20
a colorless oil; Rf (hexane) 0.50; [
analytical data: see (S)-2c.
a]
þ8.9 (c 1.0, CH2Cl2); for other
D
4.3.10. (R)-1-Methoxy-4-((2-phenylpent-4-en-2-yloxy)methyl)-
benzene [(R)-2d]. To a stirred suspension of NaH (197 mg, 4.9 mmol,
60% in mineral oil) in DMF under nitrogen was added dropwise 2a
(400 mg, 2.5 mmol) in THF (16 mL) and after 30 min a mixture of
PMBCl (0.50 mL, 579 mg, 3.7 mmol) and TBAI (91 mg, 0.25 mmol) in
6 mL of THF. After 5 h, the reaction mixture was poured into a mix-
ture of ice and satd aqueous NH4Cl solution and extracted with Et2O
(3ꢂ20 mL). The combined extracts were washed with brine, dried
(MgSO4), and concentrated in vacuo. The crude oil was purified by
column chromatography (silica gel, hexane/EtOAc 20:1/10:1) to
4.3.7. (S)-tert-Butyldimethyl(2-phenylpent-4-en-2-yloxy)silane [(S)-
2c]. To a solution of MePPh3Br (31 mg, 86.0
was added KOt-Bu (9.7 mg, 86.0 mol) at rt and the solution was
stirred for 30 min at rt. Subsequently, a solution of 8 (12 mg,
43.0 mol) in THF (1 mL) was added and stirring was continued for
mmol) in THF (0.3 mL)
m
m
give (R)-2d (0.46 g, 66%) as a colorless oil; Rf (hexane/EtOAc 6:1)
20
another 30 min. The reaction was quenched by the addition of
water (2 mL), the organic layer was separated, and the aqueous
layer was extracted with Et2O (3ꢂ10 mL). The combined organic
layers were dried (Na2SO4), and the solvent was removed in vacuo.
The crude oil was purified by column chromatography (silica gel,
0.65; [
a
]
ꢀ25.9 (c 1.0, CH2Cl2); nmax (neat) 2931 (w), 2363 (w),1613
D
(w), 1514 (vs), 1248 (vs), 1036 (m), 701 (s) cmꢀ1
; dH (500 MHz,
CDCl3) 1.61 (s, 3H, CH3), 2.57 (dd, J¼13.8, 7.2 Hz, 1H, H-3a), 2.66 (dd,
J¼13.8, 7.0 Hz, 1H, H-3b), 3.78 (s, 3H, OCH3), 4.12 (d, J¼10.8 Hz, 1H,
OCH2PMP), 4.24 (d, J¼10.8 Hz, 1H, OCH2PMP), 5.00–5.04 (m, 2H, H-
5), 5.66–5.77 (m, 1H, H-4), 6.85–6.88 (m, 2H, m-H, PMP), 7.23–7.28
(m, 3H, o-H, PMP, p-H, Ph), 7.34–7.38 (m, 2H, m-H, Ph), 7.44–7.46 (m,
2H, o-H, Ph); dC (125 MHz, CDCl3) 23.5 (CH3), 47.6 (C-3), 55.3 (OCH3),
hexane) to give (S)-2c (10 mg, 84%) as a colorless oil; Rf (hexane)
20
0.50; [
a
]
D
ꢀ9.8 (c 1.0, CH2Cl2); nmax (neat) 2956 (m), 2929 (m),
2857 (m), 1964 (w, br), 1463 (m), 1255 (s), 1072 (s), 996 (s), 833 (vs),

3820
M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
64.3 (OCH2PMP), 78.8 (C-2), 113.7 (2C, C-mPMB), 117.6 (C-5), 126.3
(2C, C-oPh), 127.0 (C-pPh), 128.2 (2C, C-mPh), 128.8 (2C, C-oPMB), 131.4
(C-iPMB), 134.2 (C-4), 145.0 (C-iPh), 158.9 (C-pPMB); m/z (ESI) 305
(MNaþ), 213, 195, 145, 121; HRMS (ESI): MNaþ, found 305.1508.
C13H16O2Naþ requires 305.1508.
stirred for 45 min and extracted with EtOAc (5ꢂ7 mL). The com-
bined organic layers were washed with satd aqueous NaHCO3 so-
lution, dried (MgSO4), and the solvent was removed in vacuo. The
residue was purified by flash column chromatography (silica gel).
4.3.15. (2R,4R)- and (2S,4R)-4-Phenylpentane-1,2,4-triol [(2R,4R)-
3a] and [(2S,4R)-3a]. Column chromatography (silica gel, hexane/
EtOAc 1:6) gave 3a as colorless oils; 903 mg (4.6 mmol, 94%), dr
46:54 (GC) via method A; 28 mg (0.14 mmol, 79%), dr 49:51 (1H
NMR) via method B; 24 mg (0.12 mmol, 87%), dr 55:45 (1H NMR) via
method C; separation of diastereoisomers: preparative HPLC: Kna-
4.3.11. 2-Phenylpent-4-en-2-ol (rac-2a). In a three-necked flask
equipped with a dropping funnel and a reflux condenser were
placed Mg-turnings (3.89 g, 160 mmol), a crystal of iodine, and
70 mL of anhydrous ether. Within 30 min, a solution of allylbromide
(10.4 ml,14.5 g,120 mmol) in Et2O (50 mL) was added dropwise at rt
in a rate sufficient to maintain a gentle reflux and the solution was
stirred at rt for an additional hour. A solution of 1a (4.68 ml, 4.80 g,
40 mmol) in 40 mL of anhydrous Et2O was added dropwise within
30 min, and then stirring was continued for an additional 2.5 h at rt.
The reaction was quenched with 1 M HCl (70 mL). The organic layer
was separated, and the aqueous layer was extracted with Et2O
(3ꢂ50 mL). The combined organic layers were dried (MgSO4), and
the solvent was removed in vacuo. The crude oil was purified by
column chromatography (silica gel, hexane/EtOAc 15:1/10:1) to
give rac-2a (5.44 g, 84%) as a colorless oil.
uer Eurospher 100-5 Si, hexane/EtOAc (1:6), flow rate 8 mL minꢀ1
.
20
Compound (2R,4R)-3a: Rf (hexane/EtOAc 1:6) 0.38; [
1.0, CH2Cl2); nmax (neat) 3336 (br s), 2928 (m),1444 (s),1073 (s),1054
(s), 700 (vs) cmꢀ1
dH (500 MHz, CDCl3) 1.53 (s, 3H, CH3), 1.89 (dd,
a
]
þ26.2 (c
D
;
J¼14.6, 2.4 Hz, 1H, H-3a), 1.97 (dd, J¼14.6, 10.4 Hz, 1H, H-3b), 3.32
(dd, J¼11.2, 6.8 Hz,1H, H-1a), 3.42 (dd, J¼11.2, 3.2 Hz,1H, H-1b), 3.48
(dddd, J¼10.4, 6.8, 3.2, 2.4 Hz, 1H, H-2), 7.22–7.25 (m, 1H, p-H, Ph),
7.32–7.35 (m, 2H, m-H, Ph), 7.39–7.41 (m, 2H, o-H, Ph); dC (125 MHz,
CDCl3) 32.2 (CH3), 44.1 (C-3), 66.7 (C-1), 70.3 (C-2), 75.5 (C-4), 124.8
(2C, C-oPh), 126.5 (C-pPh), 128.3 (2C, C-mPh), 147.0 (C-iPh); m/z (ESI)
214 (MNHþ4 ), 143, 119; HRMS (ESI): MNaþ, found 219.0991.
4.3.12. 2-Phenylpent-4-en-2-yl-acetate (rac-2e). To a solution of
homoallylic alcohol rac-2a (1.00 g, 6.25 mmol) in THF (16 mL) was
added at 0 ꢁC n-BuLi (4.7 mL, 7.4 mmol, 1.6 M in hexane) over a pe-
riod of 10 min. After the solution was stirred for additional 15 min,
freshly distilled acetyl chloride (0.53 mL, 0.58 g, 7.4 mmol) was
added within 10 min and the mixture was heated under reflux for
1 h. Subsequently, the mixture was cooled down to rt and quenched
by the addition of water (10 mL). The organic layer was separated,
and the aqueous layer was extracted with Et2O (3ꢂ20 mL). The
combined organic layers were washed with brine, dried (MgSO4),
and the solvent was evaporated. The crude oil was purified by col-
umn chromatography (silica gel, hexane/EtOAc 20:1) to give rac-2e
(505 mg, 2.47 mmol, 77% based on recovered starting material) as
a colorless oil. Found: C, 74.4; H, 8.0. C13H16O2 requires C, 74.4; H,
7.9%; Rf (hexane/EtOAc 20:1) 0.30; nmax (neat) 3063 (w), 2981 (w),
C11H16O3Naþ requires 219.0992. Compound (2S,4R)-3a: Rf (hexane/
20
EtOAc 1:6) 0.31; [
a]
þ32.7 (c 1.0, CH2Cl2); nmax (neat) 3334 (br m),
D
2929 (m), 1446 (s), 1026 (s), 764 (s), 699 (vs) cmꢀ1
; dH (500 MHz,
CDCl3) 1.64 (s, 3H, CH3), 1.80 (dd, J¼14.6, 2.7 Hz, 1H, H-3a), 1.99 (dd,
J¼14.6, 9.9 Hz,1H, H-3b), 3.46 (dd, J¼10.9, 6.6 Hz,1H, H-1a), 3.62 (dd,
J¼10.9, 3.6 Hz,1H, H-1b), 4.15 (dddd, J¼9.9, 6.6, 3.6, 2.7 Hz, 1H, H-2),
7.23–7.29 (m,1H, p-H, Ph), 7.32–7.39 (m, 2H, m-H, Ph), 7.44–7.49 (m,
2H, o-H, Ph); dC (125 MHz, CDCl3) 28.5 (CH3), 45.0 (C-3), 66.9 (C-1),
70.0 (C-2), 74.6 (C-4), 124.4 (2C, C-oPh), 126.8 (C-pPh), 128.3 (2C, C-
mPh), 148.6 (C-iPh); m/z (ESI) 214 (MNHþ4 ), 143, 119; HRMS (ESI):
MNaþ, found 219.0984. C11H16O3Naþ requires 219.0992.
4.3.16. (2R,4R)- and (2S,4R)-4-Methoxy-4-phenylpentane-1,2-diol
[(2R,4R)-3b] and [(2S,4R)-3b]. Column chromatography (silica gel,
hexane/EtOAc 1:2) gave 3b as colorless oils. Compound (2S,4R)-3b
was characterized in a mixture of both diastereoisomers; 44 mg
(0.21 mmol, 92%), dr 49:51 (1H NMR) via method A; 70 mg
(0.33 mmol, 92%), dr 35:65 (1H NMR) via method B; 64 mg
2364 (w), 1738 (vs), 1368 (m), 1239 (vs), 1016 (w), 700 (m) cmꢀ1
; dH
(500 MHz, CDCl3) 1.80 (s, 3H, CH3), 2.03 (s, 3H, COCH3), 2.74 (dd,
J¼13.9, 7.6 Hz, 1H, H-3a), 2.83 (dd, J¼13.9, 6.9 Hz, 1H, H-3b), 5.01–
5.07 (m, 2H, H-5), 5.56–5.74 (m, 1H, H-4), 7.21–7.25 (m, 1H, p-Ph),
7.29–7–34 (m, 4H, o-H, m-H, Ph); dC (125 MHz, CDCl3) 22.2 (COCH3),
24.9 (CH3), 46.4 (C-3), 83.0 (C-2), 118.6 (C-5), 124.6 (2C, C-oPh), 126.9
(C-pPh), 128.2 (2C, C-mPh), 132.8 (C-4), 144.7 (C-iPh), 169.5 (COCH3);
m/z (EI, 70 eV) 204 (10, Mþ), 163 (40), 121 (100%); HRMS (ESI):
MNaþ, found 227.1044. C13H16O2Naþ requires 227.1043.
(0.30 mmol, 85%), dr 60:40 (1H NMR) via method C. Compound
20
(2R,4R)-3b: Rf (hexane/EtOAc 1:3) 0.24; [
a
]
þ59.9 (c 0.83, CH2Cl2);
D
nmax (neat) 3394 (br m), 2925 (m), 2364 (w),1445 (m),1165 (m),1065
(vs), 1027 (s), 766 (s), 701 (vs) cmꢀ1
;
dH (500 MHz, CDCl3) 1.62 (dd,
J¼14.5, 2.0 Hz, 1H, H-3a), 1.66 (s, 3H, CH3), 2.11 (dd, J¼14.5, 10.0 Hz,
1H, H-3b), 3.25 (s, 3H, OCH3), 3.33 (dd, J¼11.1, 5.7 Hz, 1H, H-1a), 3.44
(dd, J¼11.1, 3.7 Hz,1H, H-1b) 3.63 (dddd, J¼10.0, 5.7, 3.7, 2.0 Hz,1H, H-
2), 7.25–7.30 (m, 1H, p-H, Ph), 7.34–7.39 (m, 4H, m-H, o-H, Ph); dC
(125 MHz, CDCl3) 24.8 (CH3), 46.3 (C-3), 50.8 (OCH3), 66.8 (C-1), 68.9
(C-2), 80.9 (C-4), 125.9 (2C, C-oPh), 127.1 (C-pPh), 128.5 (2C, C-mPh),
143.1 (C-iPh); m/z (CI, CH4) 211 (10, MHþ), 179 (40), 135 (75), 119
(100%); HRMS (ESI): MNaþ, found 233.1150. C12H18O3Naþ requires
233.1148. Compound (2S,4R)-3b: Rf (hexane/EtOAc 1:3) 0.24; dH
(500 MHz, CDCl3) 1.57 (dd, J¼14.8, 2.0 Hz,1H, H-3a),1.74 (s, 3H, CH3),
2.04 (dd, J¼14.8, 10.5 Hz, 1H, H-3b), 3.10 (s, 3H, OCH3), 3.42 (dd,
J¼11.1, 6.0 Hz,1H, H-1a), 3.55 (dd, J¼11.1, 3.7 Hz,1H, H-1a) 4.09 (dddd,
J¼10.5, 6.0, 3.7, 2.0 Hz,1H, H-2), 7.25–7.30 (m,1H, p-H, Ph), 7.34–7.39
(m, 4H, m-H, o-H, Ph); dC (125 MHz, CDCl3) 20.7 (CH3), 46.9 (C-3),
50.5 (OCH3), 67.0 (C-1), 69.4 (C-2), 80.4 (C-4), 125.7 (2C, C-oPh), 127.3
(C-pPh), 128.5 (2C, C-mPh), 144.8 (C-iPh).
4.3.13. General procedure for the dihydroxylation of olefins 2 with
K2OsO4 and NMO (method A). To a solution of 2 (4.9 mmol) in 50 mL
of acetone/water (8:1) were added at 0 ꢁC NMO (1.67 g, 12.3 mmol)
and K2OsO4$2H2O (67 mg, 0.18 mmol). The ice bath was removed
and the mixture was stirred overnight at rt before the reaction was
quenched by the addition of solid Na2SO3 (9.50 g). The resulting
suspension was stirred for 45 min and extracted with EtOAc
(5ꢂ15 mL). The combined organic layers were washed with satd
aqueous NaHCO3 solution, dried (MgSO4), and the solvent was re-
moved in vacuo. The residue was purified by flash column chro-
matography (silica gel).
4.3.14. General procedure for the Sharpless asymmetric dihydrox-
ylation of olefins 2 (methods B and C). AD-mix-a (method B) or AD-
mix- (method C) (1.44 g, i.e., 0.75 mg, 2 mol K2OsO4$2H2O) was
b
m
4.3.17. (2R,4R)- and (2S,4R)-4-(tert-Butyldimethylsilyloxy)-4-phe-
nylpentane-1,2-diol [(2R,4R)-3c] and [(2S,4R)-3c]. Column chroma-
tography (silica gel, hexane/EtOAc 2:1) gave 3c as colorless oils;
separation of diastereoisomers was not possible; 117 mg (0.38 mmol,
91%), dr 42:58 (1H NMR) via method A; 76 mg (0.24 mmol, 80% based
dissolved in 7 mL of t-BuOH/water (1:1) and cooled to 0 ꢁC. To the
resulting mixture was added 2 (0.72 mmol) and stirring at 0 ꢁC was
continued for 2 days, before the reaction was quenched by the
addition of solid Na2SO3 (1.1 g). The resulting suspension was

M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
3821
on recovered starting material), dr 54:46 (1H NMR) via method B;
95
95
m
m
mol) in CH2Cl2 (1 mL) was added a solution of OsO4 (24 mg,
mol) in CH2Cl2 (0.5 mL). After 1 h, the reaction mixture was
88 mg (0.28 mmol, 79%), dr 41:59 (1H NMR) via method C; Rf (hex-
20
ane/EtOAc 1:1) 0.44; [
a
]
þ30.0 (c 0.58, CH2Cl2); nmax (neat) 3396 (br
warmed to rt and the solvent was removed in vacuo. The brown
residue was dissolved in methanol (2 mL) and two drops of con-
centrated hydrochloric acid were added. The mixture was stirred at
rt for another 1 h before the solvent was removed again. The
remaining crude triol was purified by column chromatography
(silica gel, hexane/EtOAc 1:6) to give 3a (15 mg, 87%, dr 86:14 (GC))
as a colorless oil.
D
m), 2928 (s), 2856 (m), 2360 (w), 1455 (s), 1126 (s), 1061 (s), 1029 (s),
833 (vs), 773 (vs), 699 (vs) cmꢀ1; main isomer following methods A
and C: dH (500 MHz, CDCl3) 0.02 (s, 3H, Si–CH3), 0.18 (s, 3H, Si–CH3),
1.00 (s, 9H, C–CH3), 1.72 (dd, J¼14.3, 2.1 Hz, 1H, H-3a), 1.74 (s, 3H,
CH3), 2.06 (dd, J¼14.3, 10.1 Hz, 1H, H-3b), 2.24 (br s, 1H, OH), 3.26–
3.32 (m, 1H, H-1a), 3.38–3.44 (m, 1H, H-1b), 3.53–3.59 (m, 1H, H-2),
4.12 (s, 1H, OH), 7.22–7.27 (m, 1H, p-H, Ph), 7.31–7.36 (m, 2H, m-H,
Ph), 7.39–7.43 (m, 2H, o-H, Ph); dC (125 MHz, CDCl3) ꢀ2.1 (Si–CH3),
ꢀ1.4 (Si–CH3), 18.4 [SiC(CH3)3], 26.2 [SiC(CH3)3], 31.2 (CH3), 47.7 (C-
3), 66.8 (C-1), 69.3 (C-2), 79.5 (C-4), 125.1 (2C, C-oPh), 126.8 (C-pPh),
128.1 (2C, C-mPh), 146.3 (C-iPh); minor isomer following methods A
and C: dH (500 MHz, CDCl3) ꢀ0.23 (s, 3H, Si–CH3), 0.03 (s, 3H, Si–
CH3), 0.94 (s, 9H, C–CH3), 1.56 (dd, J¼14.7, 1.9 Hz, 1H, H-3a), 1.81 (s,
3H, CH3), 2.10 (dd, J¼14.7,10.0 Hz,1H, H-3b), 2.35 (br s,1H, OH), 3.38–
3.43 (m, 1H, H-1a), 3.49–3.54 (m, 1H, H-1b), 3.75 (s, 1H, OH), 4.05–
4.10 (m, 1H, H-2), 7.22–7.27 (m, 1H, p-H, Ph), 7.31–7.36 (m, 2H, m-H,
Ph), 7.39–7.43 (m, 2H, o-H, Ph); dC (125 MHz, CDCl3) ꢀ2.9 (Si–CH3),
ꢀ2.0 (Si–CH3), 18.3 [SiC(CH3)3], 26.1 [SiC(CH3)3], 26.9 (CH3), 48.6 (C-
3), 67.0 (C-1), 69.5 (C-2), 78.0 (C-4), 125.3 (2C, C-oPh), 127.2 (C-pPh),
128.2 (2C, C-mPh), 147.9 (C-iPh); m/z (EI, 70 eV) 309 (2, MꢀH), 295
(10), 235 (75), 195 (25), 143 (45), 117 (100%); HRMS (ESI): MNaþ,
found 333.1862. C17H30O3Si Naþ requires 333.1856.
4.3.20. PMP-acetals [(2R,4R,6S)-9] and [(2S,4R,6R)-9]. For the cor-
rect IUPAC name see Ref. 43. Triol 3a (106 mg, 0.54 mmol) was dis-
solved in CH2Cl2 (5 mL). Molecular sieves (4 Å, 1 g), p-anisaldehyde
dimethyl acetal (93
acid (6 mg, 26.0
was removed and the reaction mixture was stirred for 4 h. The mo-
lecular sieves were filtered off and washed with EtOAc (20 mL).
Subsequently, the organic layer was washed with satd aqueous
NaHCO3 solution and brine. The aqueous layers were extracted with
EtOAc (2ꢂ20 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The crude oil was purified by column
chromatography (silica gel, hexane/EtOAc 4:1,1% NEt3) to obtain 9 as
colorless oils. Compound (2R,4R,6S)-9: 89 mg, 52%; Rf (hexane/EtOAc
1:1) 0.50; [
(m), 2545 (w, br), 2178 (m), 1974 (m), 1518 (vs), 1249 (vs), 1065 (s),
1033 (s) cmꢀ1; for detailed NMR analysis: see Tables 3 and 4; m/z
(ESI) 337 (MNaþ), 315, 240, 137; HRMS (ESI): MNaþ, found 337.1414.
C19H22O4Naþ requires 337.1410. Compound (2S,4R,6R)-9: 75 mg,
mL, 99 mg, 0.55 mmol), and camphorsulfonic
m
mol) were added at 0 ꢁC. After 10 min, the ice bath
20
a]
þ19.1 (c 1.0, CH2Cl2); nmax (neat) 3416 (br m), 2928
D
4.3.18. (2R,4R)- and (2S,4R)-4-(4-Methoxybenzyloxy)-4-phenyl-
pentane-1,2-diol [(2R,4R)-3d] and [(2S,4R)-3d]. Column chromatog-
raphy (silica gel, hexane/EtOAc 1:3) gave 3d as colorless oils; 457 mg
(1.44 mmol, 99%), dr 47:53 (GC) via method A; 193 mg (0.61 mmol,
85%), dr 51:49 (1H NMR) via method B; 122 mg (0.39 mmol, 77%), dr
54:46 (1H NMR) via method C; separation of diastereoisomers:
preparative HPLC: Knauer Eurospher 100-5 Si, hexane/EtOAc (1:3),
55%. Found: C, 72.24; H, 7.16. C19H22O4 requires C, 72.59; H, 7.05%; Rf
20
(hexane/EtOAc 1:1) 0.42; [
a]
þ44.2 (c 1.0, CH2Cl2); nmax (neat) 3417
D
(br m), 2925 (s), 1615 (s), 1517 (s), 1248 (vs), 1030 (vs), 829 (s) cmꢀ1
;
for detailed NMR analysis: see Tables 3 and 4; m/z (EI, 70 eV) 314 (55,
flow rate 8 mL minꢀ1. Compound (2R,4R)-3d: Rf (hexane/EtOAc 1:2)
Table 3
1H NMR data (500 MHz, C6D6) of compounds (2R,4R,6S)-9 and (2S,4R,6R)-9
20
0.41; [
a]
ꢀ23.4 (c 1.0, CH2Cl2); nmax (neat) 3404 (br m), 2923 (s),
D
1613 (m), 1514 (vs), 1249 (vs), 1033 (vs), 704 (s) cmꢀ1
; dH (500 MHz,
Position
d
(ppm) for (2R,4R,6S)-9
d (ppm) for (2S,4R,6R)-9
CDCl3) 1.66 (dd, J¼14.5, 2.0 Hz, 1H, H-3a), 1.79 (s, 3H, CH3), 2.19 (dd,
J¼14.5, 10.1 Hz, 1H, H-3b), 3.33 (dd, J¼11.2, 5.7 Hz, 1H, H-1a), 3.43
(dd, J¼11.2, 3.5 Hz, 1H, H-1b), 3.68 (dddd, J¼10.1, 5.7, 3.5, 2.0 Hz, 1H,
H-2), 3.81 (s, 3H, OCH3), 4.29 (d, J¼10.5 Hz, 1H, OCH2PMP), 4.45 (d,
J¼10.5 Hz, 1H, OCH2PMP), 6.88–6.92 (m, 2H, m-H, PMB), 7.27–7.32
(m, 3H, o-H, PMB, p-H, Ph), 7.38–7.45 (m, 4H, m-H, Ph, o-H, Ph); dC
(125 MHz, CDCl3) 25.6 (CH3), 46.8 (C-3), 55.3 (OCH3), 65.1
(OCH2PMP), 66.9 (C-1), 68.8 (C-2), 81.2 (C-4), 114.1 (2C, C-mPMB),
126.0 (2C, C-oPh), 127.3 (C-pPh),128.5 (2C, C-mPh),129.0 (2C, C-oPMB),
130.3 (C-iPMB), 143.4 (C-iPh), 159.2 (C-pPMB); m/z (ESI) 339 (MNaþ),
201, 161, 121; HRMS (ESI): MNaþ, found 339,1563. C19H24O4Naþ
CH3
H-3ax
H-3eq
OCH3
1.47 (s, 3H)
1.45 (s, 3H)
1.82 (dd, J¼13.9, 11.9 Hz, 1H)
1.98 (dd, J¼13.9, 2.2 Hz, 1H)
3.31 (s, 3H)
1.77 (dd, J¼13.2,12.1 Hz, 1H)
1.42 (dd, J¼13.2, 2.4 Hz, 1H)
3.34 (s, 3H)
3.46–3.47 (m, 1H)
3.48–3.49 (m, 1H)
3.93 (dddd, J¼12.1 5.6,
4.3, 2.3 Hz, 1H)
CH2OH (H-1)
3.49–3.53 (m, 2H)
H-2
3.76 (dddd, J¼11.8, 5.6,
4.1, 2.1 Hz, 1H)
5.63 (s, 1H)
6.87–6.92 (m, 2H)
7.12–7.16 (m, 1H)
7.21–7.26 (m, 2H)
7.32–7.35 (m, 2H)
7.59–7.62 (m, 2H)
CH-PMP
m-H, PMP
p-H, Ph
m-H, Ph
o-H, Ph
5.92 (s, 1H)
6.89–6.92 (m, 2H)
7.13–7.17 (m, 1H)
7.24–7.28 (m, 2H)
7.50–7.52 (m, 2H)
7.66–7.69 (m, 2H)
o-H, PMP
requires 339,1567. Compound (2S,4R)-3d: Rf (hexane/EtOAc 1:2)
20
0.36; [
a
]
D
ꢀ17.6 (c 1.0, CH2Cl2); nmax (neat) 3416 (br m), 2922 (m),
1613 (m), 1514 (vs), 1249 (vs), 1031 (vs), 703 (s) cmꢀ1
; dH (500 MHz,
Table 4
13C NMR data (125 MHz, C6D6) of compounds (2R,4R,6S)-9 and (2S,4R,6R)-9
CDCl3) 1.60 (dd, J¼14.8, 1.9 Hz, 1H, H-3a), 1.87 (s, 3H, CH3), 2.12 (dd,
J¼14.8,10.6 Hz,1H, H-3b), 3.41 (dd, J¼11.1, 5.9 Hz,1H, H-1a), 3.55 (dd,
J¼11.1, 3.7 Hz, 1H, H-1b), 3.80 (s, 3H, OCH3), 4.10 (d, J¼10.4 Hz, 1H,
OCH2PMP), 4.14 (dddd, J¼10.6, 5.9, 3.7, 1.9 Hz, 1H, H-2), 4.30 (d,
J¼10.4 Hz, 1H, OCH2PMP), 6.86–6.89 (m, 2H, m-H, PMB), 7.20–7.23
(m, 2H, o-H, PMB), 7.28–7.32 (m,1H, p-H, Ph), 7.37–7.41 (m, 2H, m-H,
Ph), 7.45–7.48 (m, 2H, o-H, Ph); dC (125 MHz, CDCl3) 21.4 (CH3), 47.2
(C-3), 55.3 (OCH3), 64.9 (OCH2PMP), 67.0 (C-1), 69.4 (C-2), 80.7 (C-
4), 114.0 (2C, C-mPMB), 125.8 (2C, C-oPh), 127.5 (C-pPh), 128.6 (2C, C-
mPh), 129.1 (2C, C-oPMB), 130.2 (C-iPMB), 145.1 (C-iPh), 159.2 (C-pPMB);
m/z (EI, 70 eV) 316 (20, Mþ), 137 (75), 121 (100%); HRMS (ESI):
MNaþ, found 339,1568. C19H24O4Naþ requires 339,1567.
Position
d
(ppm) for (2R,4R,6S)-9
d (ppm) for (2S,4R,6R)-9
CH3
C-3
OCH3
CH2OH (C-1)
C-2
34.5 (qd, J¼127.8, 3.9 Hz)
23.5 (qdd, J¼126.9, 6.2, 1.9 Hz)
35.2
54.8
65.9
74.3
77.2
96.5
113.8
126.4
127.2
128.1
129.1
132.1
144.5
160.5
37.6
54.8
66.0
74.0
75.2
95.2
113.8
124.3
126.9
128.3
128.4
132.3
149.4
160.5
C-4
C-PMP
C-mPMP
C-oPh
C-pPh
C-mPh
C-oPMP
C-iPMP
C-iPh
4.3.19. (2R,4R)- and (2S,4R)-4-Phenylpentane-1,2,4-triol [(2R,4R)-
3a] and [(2S,4R)-3a]. To a ꢀ78 ꢁC cold solution of (R)-2-phenyl-
C-pPMP
pent-4-en-2-ol (14 mg, 86 mmol) and TMEDA (14 mL, 11 mg,

3822
M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
Mþ),163 (35),143 (60),135 (85),131 (100%); HRMS (ESI): MHþ, found
315.1586. C19H23Oþ4 requires 315.1591.
addition of 1 M aqueous HCl. The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3ꢂ10 mL). The com-
bined organic layers were dried (MgSO4), and the solvent was
evaporated. The crude oil was purified by column chromatography
(silica gel, hexane/EtOAc 1:3) to give (2R,4R)-3b (11 mg, 82%) as
a colorless oil; Rf and dH were identical with those of the diol
(2R,4R)-3b obtained by dihydroxylation of 2b (vide supra).
4.3.21. General procedure for the reductive opening of PMP-acetals
9. To a solution of 9 (33 mg, 0.10 mmol) in CH2Cl2 (2 mL) was
added DIBAL (0.3 mL, 0.3 mmol, 1 M solution in hexane) at 0 ꢁC and
the reaction mixture was stirred for 3 h at 0 ꢁC. The mixture was
cooled down to ꢀ78 ꢁC and quenched by the addition of EtOAc
(5 mL). The mixture was warmed to rt and shaken with Rochelle
salt solution. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were washed with brine, dried (MgSO4), and the solvent was
evaporated. The crude oil was purified by column chromatography
(silica gel, hexane/EtOAc 1:3) to give the diols 3d as colorless oils;
4.3.25. (S)-3-Methylhex-5-en-1-yn-3-ol [(S)-12a]. To a solution of
(ꢀ)-B-allyl-diisopinocampheylborane (7.91 g, 24.2 mmol) in Et2O
(50 mL) was added 3-butyn-2-one (1.9 mL, 1.65 g, 24.2 mmol) at
ꢀ78 ꢁC. After the solution was stirred for an additional 3 h at
ꢀ78 ꢁC, it was warmed to rt. Under nitrogen, the precipitated solid
was filtered off and the filtrate was treated with ethanolamine
(2.2 mL, 2.22 g, 36.6 mmol) at 0 ꢁC. Subsequently, the mixture was
warmed to rt and stirred for another 5 h. The solvent was removed
and the residue was purified by distillation to give (S)-12a (1.12 g,
42%) as a colorless liquid; bp 68–70 ꢁC/110 mbar; dH (500 MHz,
CDCl3) 1.51 (s, 3H, CH3), 2.13 (s, 1H, OH), 2.36 (dddd, J¼13.5, 8.1, 1.0,
1.0 Hz, 1H, H-4a), 2.46 (s, 1H, H-1), 2.52 (dddd, J¼13.5, 6.5, 1.0,
1.0 Hz, 1H, H-4b), 5.18–5.25 (m, 2H, H-6), 5.98 (dddd, J¼16.9, 10.2,
8.1, 6.5 Hz,1H, H-5); dC (125 MHz, CDCl3) 29.2 (CH3), 48.0 (C-4), 66.8
(C-3), 71.5 (C-1), 87.2 (C-2), 119.9 (C-6), 133.0 (C-5).
(2R,4R)-3d (5 mg, 16
mmol, 35%, based on recovered starting ma-
terial); (2S,4R)-3d (9 mg, 28
m
mol, 61%, based on recovered starting
material); Rf and dH were identical with the two diols 3d obtained
by dihydroxylation of 2d (vide supra).
4.3.22. (R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-phenylpropan-
2-ol (10). To a solution of triol 3a (95 mg, 0.48 mmol) in 2,2-dime-
thoxypropane (3 mL) was added camphorsulfonic acid (1.5 mg,
6.5 mmol) at rt. After the solutionwas stirred for 6 h, the reaction was
quenched by the addition of NEt3 (0.3 mL), evaporated, and the
residue was purified by column chromatography (silica gel, hexane/
EtOAc 4:1,1% NEt3) to give 10 (86 mg, 76%) as a colorless oil. Found: C,
4.3.26. (S)-tert-Butyldimethyl(3-methylhex-5-en-1-yn-3-yloxy)-
silane [(S)-12b]. Alcohol 12a (280 mg, 2.53 mmol) was converted
into the corresponding TBS-ether following the procedure reported
for 2c. The crude product was purified by column chromatography
71.03; H, 8.62. C14H20O3 requires C, 71.16; H, 8.53%; Rf (hexane/EtOAc
20
4:1) 0.37; [
a
]
þ47.9 (c 1.0, CH2Cl2); nmax (neat) 3460 (br m), 2983
D
(m), 2934 (m), 1447 (m), 1371 (s), 1217 (s), 1050 (vs), 701 (vs) cmꢀ1
;
(silica gel, pentane) to give 12b (540 mg, 95%) as a colorless oil; Rf
20
NMR-assignment according to the corresponding triol 3a: dH
(500 MHz, C6D6) 1.07 (s, 3H, C-(CH3)2), 1.31 (s, 3H, C-(CH3)2), 1.50 (s,
3H, CH3),1.66 (dd, J¼14.4, 4.5 Hz, 1H, H-3a), 1.86 (dd, J¼14.4, 10.2 Hz,
1H, H-3b), 3.16 (dd, J¼8.2, 6.9 Hz,1H, H-1a), 3.47 (dd, J¼8.2, 6.1 Hz,1H,
H-1b), 3.75–3.81 (m,1H, H-2), 4.01 (s,1H, OH), 7.08–7.12 (m, 1H, p-H,
Ph), 7.20–7.24 (m, 2H, m-H, Ph), 7.43–7.46 (m, 2H, o-H, Ph); dC
(125 MHz, C6D6) 25.7 (C-(CH3)2), 27.0 (C-(CH3)2), 32.2 (CH3), 46.5 (C-
3), 69.7 (C-1), 74.1 (C-2), 74.5 (C-4),109.4 (C-(CH3)2),125.4 (2C, C-oPh),
126.6 (C-pPh),128.4 (2C, C-mPh),148.5 (C-iPh); m/z (EI, 70 eV) 236 (15,
Mþ), 221 (35), 178 (30), 143 (100), 121 (85%); HRMS (ESI): MNaþ,
found 259.1310. C14H20O3Naþ requires 259.1305.
(pentane) 0.86; [
a
]
ꢀ4.4 (c 1.0, CH2Cl2); nmax (neat) 3311 (m), 3080
D
(w), 2930 (s), 2194 (w), 1252 (s), 1067 (s), 832 (vs), 774 (vs) cmꢀ1
; dH
(300 MHz, CDCl3) 0.17 (s, 6H, Si–CH3), 0.87 (s, 9H, C–(CH3)3), 1.42 (s,
3H, CH3), 2.38–2.41 (m, 2H, H-4), 2.43 (s, 1H, H-1), 5.05–5.12 (m, 2H,
H-6), 5.87 (dddd, J¼12.9, 11.0, 7.2, 3.8 Hz, 1H, H-5); dC (75 MHz,
CDCl3) ꢀ2.9 (Si–CH3), ꢀ2.9 (Si–CH3), 18.1 (Si–C(CH3)3), 25.7 (Si–
C(CH3)3), 30.5 (CH3), 49.6 (C-4), 68.5 (C-3), 72.2 (C-1), 88.0 (C-2),
117.8 (C-6), 134.0 (C-5); m/z (CI, CH4) 225 (45, MHþ), 209 (30), 183
(80), 167 (100), 132 (25), 93 (30%); HRMS (CI, CH4): MHþ, found
225.1659. C13H25OSiþ requires 225.1675; GC: HRGC Mega 2, Bondex
un-a-CD column (20 m, 0.4 bar H2, on column), temperature pro-
gram: 40 ꢁC, 3 ꢀm1in isothermal, then 1.5 ꢁC minꢀ1 gradient to 90 ꢁC,
4.3.23. (R)-4-((R)-2-Methoxy-2-phenylpropyl)-2,2-dimethyl-1,3-di-
oxolane (11). Alcohol 10 (29 mg, 0.12 mmol) was converted into the
corresponding methyl ether following the procedure reported for
2b. The crude product was purified by column chromatography
then 10 ꢁC min gradient to 200 ꢁC, tR,minor¼21.727 min and tR,ma-
¼22.127 min; ee 80%.
jor
4.3.27. (2R,4S)- and (2S,4S)-4-(tert-Butyldimethylsilyloxy)-4-meth-
ylhex-5-yne-1,2-diol [(2R,4S)-13] and [(2S,4S)-13]. Following
method C, olefin 12b (0.50 g, 2.22 mmol) was dihydroxylated using
(silica gel, hexane/EtOAc 10:1/4:1) to give 11 (20 mg, 67%) as
20
a colorless oil; Rf (hexane/EtOAc 4:1) 0.66; [
a]
þ5.2 (c 0.33,
D
CH2Cl2); nmax (neat) 2984 (s), 2934 (m), 1377 (s), 1370 (s), 1225 (s),
AD-mix-b (3.15 g). The crude product was purified by column
1161 (s), 1071 (vs), 1054 (vs), 702 (s) cmꢀ1
;
dH (300 MHz, C6D6) 1.36
chromatography (silica gel, hexane/EtOAc 5:2) to give 13 (0.5 g, 88%,
dr 40:60 (1H NMR)) as a colorless oil. Compound (2R,4S)-13: Found:
C, 60.1; H, 10.0. C132H0 26O3Si requires C, 60.4; H, 10.1%; Rf (hexane/
(s, 3H, C–(CH3)2), 1.40 (s, 3H, C–(CH3)2), 1.44 (s, 3H, CH3), 1.90 (dd,
J¼14.4, 6.3 Hz, 1H, H-3a), 2.09 (dd, J¼14.4, 5.4 Hz, 1H, H-3b), 2.88 (s,
3H, OCH3), 3.33 (dd, J¼8.1, 8.1 Hz, 1H, H-1a), 3.83 (dd, J¼8.1, 5.8 Hz,
1H, H-1b), 4.37–4.46 (m, 1H, H-2), 7.04–7.10 (m, 1H, p-H, Ph), 7.12–
7.19 (m, 2H, m-H, Ph), 7.22–7.27 (m, 2H, o-H, Ph); dC (75 MHz, C6D6)
22.8 (CH3), 26.3 (C–(CH3)2), 27.3 (C–(CH3)2), 48.0 (C-3), 50.1 (OCH3),
70.6 (C-1), 73.1 (C-2), 77.9 (C-4), 108.2 (C–(CH3)2), 126.1 (2C, C-oPh),
127.1 (C-pPh), 128.5 (2C, C-mPh), 146.2 (C-iPh); m/z (CI, CH4) 251 (7,
MHþ), 219 (30), 175 (15), 163 (30), 143 (45), 135 (100), 101 (70%);
HRMS (ESI): MNaþ, found 273.1456. C15H22O3Naþ requires 273.1461.
EtOAc 5:2) 0.29; [
a
]
ꢀ1.8 (c 1.0, CH2Cl2); nmax (neat) 3391 (m), 3309
D
(m), 2930 (s), 2858 (s), 2109 (w),1740 (w),1251 (s),1028 (s), 833 (vs),
775 (vs) cmꢀ1
;
dH (300 MHz, CDCl3) 0.23 (s, 3H, Si–CH3), 0.24 (s, 3H,
Si–CH3), 0.87 (s, 9H, C(CH3)3), 1.54 (s, 3H, CH3), 1.68 (dd, J¼14.4,
1.9 Hz, 1H, H-3a), 1.90 (dd, J¼14.4, 9.7 Hz, 1H, H-3b), 2.39 (s, 1H, OH),
2.53 (s, 1H, H-6), 3.45–3.52 (m, 1H, H-1a), 3.60–3.68 (m, 1H, H-1b),
3.84 (s, 1H, OH), 4.25 (dddd, J¼9.7, 5.6, 3.7, 1.9 Hz, 1H, H-2); dC
(75 MHz, CDCl3) ꢀ3.2 (Si–CH3), ꢀ2.7 (Si–CH3),17.9 (Si–C(CH3)3), 25.6
(Si–C(CH3)3), 31.8 (CH3), 47.1 (C-3), 66.7 (C-1), 70.2 (C-2), 70.7 (C-4),
73.6 (C-6), 86.4 (C-5); m/z (CI, CH4) 259 (100, MHþ), 243 (10), 183
4.3.24. (2R,4R)-4-Methoxy-4-phenylpentane-1,2-diol [(2R,4R)-3b]. To
a solution of 11 (16 mg, 64
m
mol) in MeOH (5 mL) was added PPTS
(30), 143 (15), 117 (50%); GC: HRGC Mega 2, Bondex un-b-CD column
(16 mg, 64
m
mol). After the solution was stirred overnight at 39 ꢁC,
(20 m, 0.4 bar H2, split), 100 ꢁC isothermal, tR,minor¼42.692 min and
aqueous NaOH (3 mL, 1 M) was added and stirring was continued
for an additional hour. The mixture was diluted by the addition of
water and EtOAc (2 mL each) and the pH adjusted to 2–3 by the
tR,major¼44.103 min; ee 96%. Compound (2S,4S)-13: Rf (hexane/EtOAc
20
5:2) 0.21; [
a
]
ꢀ9.3 (c 1.0, CH2Cl2); nmax (neat) 3391 (br m), 3309 (m),
D
2930 (s), 2858 (s), 2109 (w),1740 (w),1251 (s), 1028 (s), 833 (vs), 775

M. Theurer et al. / Tetrahedron 66 (2010) 3814–3823
(vs) cmꢀ1
; dH (500 MHz, CDCl3) 0.21 (s, 3H, Si–CH3), 0.21 (s, 3H, Si–
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3823
20. Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2002,
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CH3), 0.85 (s, 9H, C(CH3)3), 1.23 (s, 1H, OH), 1.54 (s, 3H, CH3), 1.72 (dd,
J¼14.4, 2.6 Hz, 1H, H-3a), 1.97 (dd, J¼14.4, 9.3 Hz, 1H, H-3b), 2.55 (s,
1H, H-6), 3.45–3.48 (m,1H, H-1a), 3.58–3.61 (m,1H, H-1b), 3.64 (s,1H,
OH), 4.08–4.11 (m,1H, H-2); dC (125 MHz, CDCl3) ꢀ3.2 (Si–CH3), ꢀ2.8
(Si–CH3), 17.9 (Si–C(CH3)3), 25.7 (Si–C(CH3)3), 30.3 (CH3), 47.2 (C-3),
66.8 (C-1), 68.7 (C-4), 69.1 (C-2), 73.4 (C-6), 87.8 (C-5); m/z (CI, CH4)
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Acknowledgements
Generous financial support by the Deutsche For-
schungsgemeinschaft, the Ministerium fu¨r Wissenschaft, Forschung
und Kunst des Landes Baden-Wu¨rttemberg and the Fonds der
Chemischen Industrie is gratefully acknowledged. We would like to
thank Dennis Wan Hussin, Katharina Lindermayr and Jakob Belka for
skilfull experimental work. The authors are indebted to B.R.A.I.N. AG,
Zwingenberg, Germany, for providing the metagenome-derived es-
terases. R.K. and G.S.N. thank the European Social Funds and the
VentureCup M-V (UG09005) for financial support. G.S.N. also thanks
the Deutscher Akademischer Austauschdienst (DAAD) (Grant A/07/
95194), the Vietnamese Ministry of Education and Training (Grant
3413/QDBGDDT-VP) for financial support.
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