Chiral linker. Part 4: Diastereoselective addition of RZnX to α-keto esters using m-hydrobenzoin derived chiral auxiliaries in solution and on solid support and their application in the stereoselective synthesis of frontalin

Article abstract of DOI:10.1016/j.tetasy.2006.08.016

Two recently reported, m-hydrobenzoin derived open chain chiral auxiliaries, which were developed for application in either solution or immobilized on a solid support, were tested in the diastereoselective addition of RZnX to their corresponding phenylglyoxylates and pyruvates, respectively, resulting in diastereoisomeric excesses of up to >98% de. The optimized procedure was applied in the stereoselective synthesis of frontalin, the aggregation pheromone of pine bark beetles of the Dendroctonus family, by the use of both the solution phase and the polymer supported chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2006.08.016

Tetrahedron: Asymmetry 17 (2006) 2430–2441
Chiral linker. Part 4: Diastereoselective addition of RZnX to
a-keto esters using m-hydrobenzoin derived chiral auxiliaries
in solution and on solid support and their application in
the stereoselective synthesis of frontalin
Christian Schuster, Max Knollmueller and Peter Gaertner*
Department of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
Received 18 August 2006; accepted 22 August 2006
Available online 26 September 2006
Abstract—Two recently reported, m-hydrobenzoin derived open chain chiral auxiliaries, which were developed for application in either
solution or immobilized on a solid support, were tested in the diastereoselective addition of RZnX to their corresponding phenylglyoxy-
lates and pyruvates, respectively, resulting in diastereoisomeric excesses of up to >98% de. The optimized procedure was applied in the
stereoselective synthesis of frontalin, the aggregation pheromone of pine bark beetles of the Dendroctonus family, by the use of both the
solution phase and the polymer supported chiral auxiliary.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently reported a novel class of m-hydrobenzoin
derived chiral auxiliaries 6 for the L-Selectrideꢁ mediated
stereoselective reduction of phenylglyoxylates.8 These aux-
iliaries were developed for the application in either solution
or immobilized on a solid support and could easily be syn-
thesized by desymmetrization of m-hydrobenzoin 1 using
Noe’s anhydro lactols9 and subsequent derivatization
steps.8 Therefore, by utilizing each one of Noe’s lactols,
either stereoisomer of the resulting auxiliary could possibly
be obtained, thus being a simple application of the
so-called ‘meso trick’10 (Scheme 2).
Chiral tertiary a-hydroxy carboxylic acids are important
building blocks and intermediates in the synthesis of com-
plex, biologically active molecules. For example, (S)-(+)-1-
(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-
phenylpropan-2-ol A, a potential cocaine abuse therapeu-
tic,1 (S)-oxybutynin (ditropan) B, a muscaronic receptor
antagonist for the treatment of urinary incontinence2 and
even a-tocopherol3 C, which is derived from the corre-
sponding a-hydroxycarboxylic acid derivatives (Scheme 1).
Diastereoselective addition of organometallic reagents to
a-keto carboxylic acids by means of a chiral auxiliary is a
proper methodology to obtain tertiary a-hydroxy carbox-
ylic acids with high enantiomeric purities, with cyclohexyl
based auxiliaries like menthol, Corey’s 8-phenylmenthol4
and Whitesell’s trans-2-phenylcyclohexan-1-ol5 being the
gold standards6 in the field. As these auxiliaries have to
be isolated or synthesized expensively, a number of alterna-
tive auxiliaries have successfully been developed, in recent
years for this type of reaction.7
In our previous work, it became evident that the introduc-
tion of a second oxygen in the ether moieties of hydrobenz-
oin mono-ether auxiliaries 6a and 6b8b resulted in
substantially improved diastereoselectivities in the L-
Selectrideꢁ mediated reduction of their phenylglyoxylates
7a and 7b, especially when the Lewis acid ZnCl2 was used
as an additive, whereas this additive had no effect, when the
analogous tert-butyl ether auxiliary 6c8a was used in the
same reduction of phenylglyoxylate 7c. Therefore, based
on the works of Rosini et al.,11 we had proposed a confor-
mational rationale for the stereochemical outcome of this
reaction. Therein, we had supposed that the ether moiety
had effectively shielded one face of the keto carbonyl from
the hydride attack by chelation of the Zn2+ cation, which
itself had forced the two carbonyls of the keto carboxylic
*
Corresponding author. Tel.: +43 15880155421; fax: +43 15880115492;
e-mail: peter.gaertner@tuwien.ac.at
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.08.016

C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2431
F
O
OH
COOH
N
OH
N
A
F
OH
OH
COOH
N
O
O
B
OMe
OH
O
OR
HO
O
OMe
C
Scheme 1.
OH
OH
1
i
ii
HO
O
HO
O
O
O
v, vi
O
O
iii, iv
O
O
O
OH
OH
OH
O
O
6a
vii, viii
2b
2a
4
HO
O
HO
O
O
O
Noe´s anhydro lactols:
O
O
O
O
O
O
6b
endo-anhydro lactol
... Wang resin
exo-anhydro lactol
Scheme 2. Reagents and conditions: (i) Noe’s exo-anhydro lactol, p-TsOH, CH2Cl2; (ii) Noe’s endo-anhydro lactol, p-TsOH, CH2Cl2; (iii) NaH;
BrCH2COO–t-Bu, HMPA, THF; (iv) LiAlH4, THF; (v) NaH; CH3I, DMF; (vi) p-TsOH, MeOH, CH2Cl2; (vii) NaH; NaI, Wang-Cl, DMF; NaI, acetone;
Å
Bu3SnH, THF; (viii) PPh3 HBr, MeOH, CH2Cl2.
si-attack
ester into a syn-conformation by chelation8 (Scheme 3).
This in consequence resulted in an improved diastereoselec-
tion of 91% de compared to 77% de without ZnCl2 in the
L-Selectrideꢁ mediated reduction of phenylglyoxylate 7a.
-
Nu
H
H
re-attack
OH
Nu
O
O
H
H
O
O
O
O
O
O
O
Zn
Based on this model, we suggested that the addition of
organozinc reagents to a-keto carboxylic esters might pro-
ceed in a similar manner with auxiliaries 6a and 6b, espe-
cially since there have been numerous examples of
X
Scheme 3. Proposed model for Zn2+ enhanced diastereoselection with
auxiliary 6a.

2432
C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
auxiliary mediated stereoselective organozinc additions to
a-keto esters reported in the literature,6,7 even with im-
proved stereoselections by using zinc instead of magnesium
as the metal cation.7d
product diastereomers 9a, as well as after ester saponifica-
tion and further derivatization with L-valine methyl ester12
by 1H and 13C NMR analysis of resulting 15a, as described
in our previous work,8 resulting in consistent de values.
The absolute configuration was approved by means of
the specific rotation of the cleaved hydroxy acid 14a.
Herein, we report the stereoselective addition of several
organozinc reagents to a-keto esters using m-hydrobenzoin
derived chiral auxiliaries 6a and 6b in solution as well as on
solid support, and the application of this type of reaction
as the key step in the stereoselective synthesis of (+)-
frontalin.
Similarly, 94% de could be achieved in the analogous addi-
tion reaction of i-PrZnCl to phenylglyoxylate 7a (Table 1,
entry 5), whereas the reaction with the small nucleophile
MeZnCl resulted in only 45% de (Table 1, entry 6), thus
revealing the limitation of auxiliary 6a in this type of reac-
tion. Furthermore, the application of tert-butyl auxiliary
6c8a in the addition of n-BuZnCl to phenylglyoxylate 7c
resulted in a diminished diastereoisomeric excess of only
89% de (Table 1, entry 9). This was in accordance with
our previous results from the L-Selectrideꢁ/ZnCl2 medi-
ated reduction of phenylglyoxylates 7a and 7c,8 respec-
tively (Table 1, entries 2 and 8) and obviously underlined
the benefit of the additional Lewis basic O-atom in the
ether moiety of auxiliary 6a.
2. Results and discussion
2.1. RZnX addition in solution
We chose the addition of n-BuZnCl, which had simply been
prepared in situ by reaction of n-BuMgCl with dry ZnCl2,
to phenylglyoxylate 7a8b at ꢀ78 ꢂC in THF, according to
the procedure described by Boireau et al.,6e for the evalua-
tion of the stereoinducing ability of our chiral auxiliary 6a
in this type of reaction. Thereby, we initially found that all
of the ZnCl2 had to be consumed by using an equal amount
of Grignard reagent for the formation of the organozinc re-
agent, otherwise only incomplete addition would result as a
matter of competing coordination of unreacted ZnCl2 by
the ketoester6e (Table 1, entries 3 and 4). On the other
hand, we were pleased to find that a diastereomeric excess
of >98% de resulted in this experiment (Table 1, entries 3
and 4), with the absolute configuration at the new stereo-
center being (S), as correctly predicted by our model
(Scheme 3). The stereochemical outcome of this reaction
2.2. RZnX addition on solid support
Polymer supported chiral auxiliary 6b8b was tested analo-
gously in the addition of several organozinc reagents to
a-keto esters. Thus, by employing identical reaction condi-
tions, we obtained results very similar to the ones men-
tioned above, with the larger nucleophiles added to
phenylglyoxylate 7b yielding good to excellent diastereo-
selectivities (Table 2, entries 1–3), whereas the small ones
MeZnCl and EtZnCl, respectively, gave only poor results
(Table 2, entries 4–5). Furthermore, it could be shown that
even the addition to enolizable keto esters such as pyruvate
1
was analyzed by H NMR integration on the mixture of
Table 1. Diastereoisomeric ratio of 8a–11a from addition of H- and C-nucleophiles, respectively, to a-keto esters 7a,ca
O
OH
O
R'
i
ii
HO
R
O
R
O
R
O
O
O
O
8-11
6a-c
7a-c
Entry
Ester
R
Nucleophile R0
ZnCl2 (equiv)
Ratiod (S,R,S)/(S,R,R)
Product (yield, %)e
1
2
3
4
5
6
7ab
7ab
7a
H/1 equiv L-Selectrideꢁ
H/1 equiv L-Selectrideꢁ
4.5 equiv n-BuMgCl
8 equiv n-BuMgCl
8 equiv i-PrMgBr
—
2
9
7.5
7.5
7.5
88.5:11.5b
95.5:4.5b
>99:1
>99:1
97:3
8a (80)
8a (99)
9a (20)
9a (98)
10a (97)
11a (82)
O
7a
7a
7a
8 equiv MeMgBr
72.5:27.5
7
8
9
7cc
7cc
7c
t-Bu
H/1 equiv L-Selectrideꢁ
H/1 equiv L-Selectrideꢁ
8 equiv n-BuMgCl
—
2
7.5
92:8c
8c (87)
8c (88)
9c (92)
92:8c
94.5:5.5
a Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2; (ii) nucleophile R0, ꢀ78 ꢂC, THF.
b Data from Ref. 8b.
c Data from Ref. 8a.
d Diastereoisomeric ratios determined by 1H NMR integration on crude reaction mixtures 8–11 and L-valine methyl ester derivatives 15 of cleaved hydroxy
acids 14; absolute configuration of major diastereoisomers approved by optical rotation of 14.
e Isolated yields by vacuum flash chromatography.

C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2433
Table 2. Stereoisomeric ratio of 14a–e from addition of R0ZnX to polymer supported a-keto esters 7b,ea
O
OH
R
O
i
O
HO
O
O
O
R
ii
O
O
O
6b
7b, e
iii
R'
R
OH
OH
O
14a-e
R'
OH
O
O
R
O
O
iv
... Wang resin
O
R'
R
9b-13b
OH
H
N
O
O
15a-e
Entry
Ester
R
Run
Nucleophile R0
Ratiob (S)/(R)
Product (yield, %)c
1
2
3
4
5
6
7b
7b
7b
7b
7b
7e
Ph
Ph
Ph
Ph
Ph
1a
1b
2a
2b
3a
3b
n-BuZnCl
i-PrZnCl
c-HexZnCl
EtZnCl
MeZnCl
PhZnCl
95:5
92:8
93:7
75:25
65:35
11:89
14a (76)
14b (95)
14c (90)
14d (95)
14e (90)
14f (75)
Me
a Reagents and conditions: (i) RCOCOOH, DIC, DMAP, CH2Cl2; (ii) R0ZnX, ꢀ78 ꢂC, THF; (iii) LiOH, THF/MeOH/H2O; (iv) L-valine methyl ester,
DIC, HOBt, CH2Cl2.
b Stereoisomeric ratios determined by 1H and 13C NMR analysis of L-valine methyl ester derivatives 15a–e of cleaved hydroxy acids 14a–e; absolute
configuration of major enantiomers approved by optical rotation of 14a–e.
c Yields over two steps, based on gravimetrically estimated amount of ketoacid bound in the esterification step.
7e could result in acceptable yields and stereoselectivities as
well—a small amount of dry methanol had been added to
the PhZnCl solution in the pyruvate experiment, as was
recommended by Dosa and Fu for achieving higher yields
and selectivities in the addition of Ph2Zn to enolizable
ketones.13 Thus, the addition of PhZnCl to pyruvate 7e
yielded hydroxy acid 14c with a much more satisfying
enantiomeric purity than the addition of MeZnCl to
phenylglyoxylate 7b had achieved, and, certainly,
with the inverse absolute configuration (R) (Table 2, entry
6).
ester saponification, both resins were recovered, recom-
bined, and introduced in the next reaction cycle (run 2),
as far as IR spectroscopic analysis had indicated quantita-
tive ester cleavage by the complete disappearance of the
CO band at 1740 cmꢀ1. The third run finally started with
the esterification of the recovered, recombined and then di-
vided resin 6b from run 2 with phenyl glyoxylic acid and
pyruvic acid, respectively (run 3).
All reactions on solid support were monitored qualitatively
by FT-IR spectroscopy, employing KBr disks, as well as
yields, which were estimated gravimetrically.8b The stereo-
chemical outcomes were analyzed after cleavage of hydr-
oxy esters 9b–13b from the resin and further derivatization
of recovered hydroxy acids 14a–e with L-valine methyl
ester.12 While the absolute configurations of 14a–e were
determined by their specific rotations and comparison with
literature values, their stereoisomeric ratios were quantified
It had been shown in our previous phenylglyoxylate reduc-
tion series that auxiliary 6b could be reused several times,
without any loss of its stereoinducing ability.8b Conse-
quently, the current set of experiments was also carried
out in three runs, starting with a freshly prepared sample
of auxiliary 6b,8b which was first esterified with phenyl gly-
oxylic acid, then divided into two parts and used in the first
two RZnX addition experiments (run 1). After cleavage of
the resulting hydroxy esters 9b and 10b by LiOH mediated
1
by H and 13C NMR integration on the mixtures of prod-
uct diastereoisomers of L-valine methyl ester derivatives
15a–e.

2434
C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2.3. Preparation of frontalin
about 98% ee as indicated by chiral GC. On the other
hand, the analogous synthesis using polymer supported
chiral auxiliary 6b yielded 1,2-diol 23 with an isolated yield
of 50% over two steps, which resulted in (+)-frontalin 24
with 86% ee analyzed by GC (Scheme 4).
1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane, frontalin, is
part of the aggregation pheromone of pine beetles of the
Dendroctonus family, with the (1S,5R)-(ꢀ) enantiomer
being the much more active stereoisomer.14 Frontalin has
also been isolated from the temporal gland secretion of
male Asian elephant bulls during the period of musth,15
as well as from the bark of several angiosperm trees.16 As
the molecule consists of only two stereocenters, of which
the one at C5 is dictated by that at C1 through the forma-
tion of the bicyclic, ketal structure, it has frequently been
used from the 1970s on17 as a valuable simple target to test
diverse stereoselective synthetic methods.18 In 1986, White-
sell published the diastereoselective addition of Grignard
reagents to keto esters by the use of 8-phenylmenthol as
the key step in the syntheses of each of the enantiomers
of frontalin with high enantiomeric purities.19
3. Conclusion
In conclusion, we have demonstrated the applicability of
m-hydrobenzoin derived, open chain chiral auxiliaries 6a
and 6b in the diastereoselective addition of RZnX to a-keto
esters such as phenylglyoxylates 7a and 7b and pyruvates,
respectively. Thereby, good to excellent diastereoisomeric
excesses of up to >98% de could be achieved using solution
phase auxiliary 6a, provided that the nucleophiles were not
too small. Similarly good results were achieved with poly-
mer supported auxiliary 6b, whereas diastereoisomeric ex-
cesses were diminished to some extent in all solid phase
experiments compared to the ones employing solution
phase auxiliary 6a. In summary, it can be said that the reus-
able auxiliaries 6a and 6b, of which both enantiomers are
easily accessible from m-hydrobenzoin by desymmetriza-
tion with Noe’s anhydro lactols,8,9 are within the best aux-
iliaries in their class6,7 and therefore seem to be a viable
alternative to cyclohexyl based chiral auxiliaries for access-
ing tertiary a-hydroxy acids from their corresponding keto
acids by addition of RZnX with good yields and high enan-
tiomeric purities. The applicability of this method was
demonstrated in the stereoselective synthesis of 1,2-diol
23, which is the key intermediate in the 8-phenylmenthol
mediated stereoselective synthesis of frontalin reported by
Whitesell and Buchanan.19 Therein auxiliary 6a proved to
be equally useful resulting in (+)-frontalin 24 with high
enantiomeric purities of 92–98% ee, whereas the result with
polymer supported auxiliary 6b was again slightly inferior.
Nevertheless, to the best of our knowledge, the latter is the
first reported application of a polymer supported chiral
auxiliary in a stereoselective synthesis of frontalin. We
were, therefore, encouraged to carry on our investigations
on further auxiliary improvements, as well as to look out
for other applications of our novel hydrobenzoin derived,
reusable open chain chiral auxiliaries.
Based on Whitesell’s findings, we suggested our m-hydro-
benzoin derived chiral auxiliaries 6a and 6b to be equally
applicable in this synthetic pathway, especially since we
had supposed organozinc reagent 21 to be big enough for
achieving good diastereoisomeric selectivities in addition
to pyruvates 7d and 7e with regards to the above men-
tioned results. Therefore, 7d and 7e were reacted with 21,
which had been prepared from the corresponding Grignard
reagent 20 and ZnCl2, according to the procedure used in
our preceding experiments. Compound 20 had been syn-
thesized directly before from bromide 19, which had been
prepared from ethyl laevulinate 16 in three steps by a mod-
ification of known procedures.20,21
Thus, according to the above mentioned solution phase
series, the diastereoselective addition reaction of 21 to
pyruvate 7d yielded hydroxy ester 22a with 81% yield. It
is noteworthy that in contrast to Whitesell’s findings with
RMgBr, in our hands, no Grignard reduction based lactate
could be detected at all. The diastereoisomeric ratio of a-
hydroxy ester 22a was again directly evaluated by 1H
NMR analysis of the crude reaction mixture by integration
of the sufficiently resolved benzylic protons Ha in the two
diastereoisomers,8a which indicated a high enantiomeric
excess of 92% de. The absolute configuration of the major
diastereoisomer was determined after the reduction of
22a with LiAlH4 to be (R) by comparing the specific rota-
tion of liberated 1,2-diol 23 with the value reported by
Whitesell and Buchanan.19 For test purposes, 23 was final-
ly converted by ozonolysis, as described by Whitesell and
Buchanan,19 to frontalin 24, which proved to be the
expected (+)-enantiomer with an enantiomeric excess of
4. Experimental
4.1. General
Commercially available reagents and solvents were used
as received from the supplier unless otherwise specified.
ZnCl
21
O
OH
OH
O
O
O
O
O
OH
O
R
O
R
O
O
O
23
24
7d, e R ... Me, Wang resin
22a, b
Scheme 4. Stereoselective preparation of frontalin by the application of hydrobenzoin mono-ether auxiliaries 6a,b.

C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2435
Diethyl ether (E), petroleum ether (PE, 60–80 ꢂC fraction),
ethyl acetate (EE) and dichloromethane were distilled prior
to use. Dry ether and THF were pre-dried over KOH and
distilled from Na/benzophenone. Dry dichloromethane
was distilled from P2O5. ZnCl2 was dried by heating to
150–300 ꢂC in high vacuo for 30 min prior to use. All mois-
ture sensitive reactions were carried out under a nitrogen
atmosphere. Reactions on solid support were shaken on a
laboratory shaker unless otherwise stated. For TLC-analy-
matic), 6.01/4.71 (2d, 2H, Ph–CH–O, J = 6.3 Hz), 3.60–
3.37 (m, 4H, O–CH2–CH2–O), 3.23 (s, 3H, O–CH3), 2.30
(s, 3H, CH3–CO). 13C NMR (50 MHz, CDCl3):
dC = 191.2 (s, CO), 159.2 (s, O–CO), 137.3/136.2 (2s, Ph–
C-1), 128.4/128.2/128.0/127.9/127.8/127.7 (6d, Ph–C),
83.9/79.5 (2d, Ph–CH–O), 71.8/68.8 (2t, O–CH2–CH2–O),
58.8 (q, O–CH3), 26.6 (q, CH3–CO). Anal. Calcd for
C20H22O5 · 0.1H2O: C, 69.79; H, 6.50. Found: C, 69.91;
H, 6.44.
sis, precoated aluminum-backed plates (Silica gel 60 F254
,
Merck) were used. Compounds were visualized by spraying
with 5% phosphomolybdic acid hydrate in ethanol and
heating. Vacuum flash chromatography was carried out
with silica gel Merck 60. Melting points were determined
with a Kofler hot-stage apparatus and are uncorrected.
Specific rotations were measured on a Perkin–Elmer 241
4.3. Preparation of polymer bound keto carboxylic acid
esters, 7b and 7e
4.3.1. General procedure. DIC (10 equiv) was added drop-
wise to a mixture of resin 6b (1 equiv/ꢂ1.5 g), keto carbox-
ylic acid (10 equiv), and DMAP (1 equiv) in dry
dichloromethane (15 mL) while cooling on an ice bath.
The resulting mixture, which had turned from pale yellow
to orange and brown, was shaken for 48 h at room temper-
ature. The resin was filtered off and thoroughly washed
successively with dichloromethane, methanol, dichloro-
methane, methanol, dichloromethane, methanol, and dried
in vacuo overnight at 40 ꢂC.
1
polarimeter. H and 13C NMR spectra were recorded on
a Bruker AC 200 in CDCl3 at 200 and 50 MHz, respec-
tively, using TMS or the solvent peak as the reference.
IR spectra were recorded on a BioRad FTS 135 FT-IR-
spectrometer, using KBr disks. Elemental analysis was car-
ried out at Vienna University, Department of Physico-
chemistry—Laboratory for Microanalysis, Wa¨hringer Str.
42, A-1090 Vienna.
4.3.2. Polymer bound phenylglyoxylate, 7b. 1.542 g pale
yellow resin (mass increase: 0.090 g = 0.681 mmol). IR m
(KBr) = 3576 cmꢀ1 (OH: vanished), 1739 cmꢀ1 (COOR),
1689 cmꢀ1 (CO); no further changes.
4.2. Preparation of ketocarboxylic acid esters, 7a and 7d
4.2.1. General procedure. Diisopropylcarbodiimide (DIC)
(1.1 equiv) was added dropwise to a solution of auxiliary 6a
(1.0 equiv), keto carboxylic acid (1.1 equiv), and 4-(N,N-
dimethylamino)pyridine (DMAP) (0.2 equiv) in dry dichlo-
romethane, while cooling on an ice bath. The mixture was
stirred for 1–20 h at room temperature until TLC control
indicated total conversion. The white precipitate was fil-
tered off and the filtrate was diluted with dichloromethane
and washed successively with a saturated aqueous NaH-
CO3 solution, 5% KHSO4 solution, and brine. The organic
layer was dried over Na2SO4, filtered, and evaporated.
4.3.3. Polymer bound pyruvate, 7e. 1.641 g light brown
resin (mass increase: 0.053 g = 0.754 mmol). IR
m
(KBr) = 3576 cmꢀ1 (OH: vanished), 1730 cmꢀ1 (CO–
COOR); no further changes.
4.4. Addition of RZnX to a-keto esters
4.4.1. General procedure. A freshly prepared and ti-
trated22 solution of RMgX (8 equiv) in THF was slowly
added to a thoroughly stirred solution of pre-dried ZnCl2
(7.5 equiv) in dry THF (5 mL) while cooling on an ice bath,
and stirring was continued for 2 h at 0 ꢂC. The supernatant
solution of the prepared RZnX reagent was slowly added
over 15 min to a solution of ester 7a,c (1 equiv/ꢂ100 mg)
in dry THF (10 mL), precooled to ꢀ90 ꢂC, by means of a
syringe, and the resulting mixture stirred for 2 h at
ꢀ78 ꢂC. The temperature was raised up to ꢀ20 ꢂC over a
period of 1 h, and finally a 10% aqueous NH4Cl solution
was added and stirring continued for 15 min at room tem-
perature. The mixture was taken up with a saturated aque-
ous NH4Cl solution and extracted three times with ether.
The combined ether extracts were successively washed with
aqueous NH4Cl and brine, dried over Na2SO4, filtered, and
evaporated. The crude product was purified by vacuum
flash chromatography on silica gel, eluting with petroleum
ether/ether (10/1 ! 2/1).
4.2.2. Oxophenylacetic acid, (1R,2S)-2-(2-methoxyethoxy)-
1,2-diphenylethyl ester, 7a. The crude product was puri-
fied by vacuum flash chromatography on silica gel, eluting
with petroleum ether/ether (20/1 ! 5/1). White solid (yield
20
91%), mp 79–81 ꢂC, Rf = 0.65 (PE/E 4/1), ½aꢁD ¼ þ18:6 (c
0.71 CH2Cl2). 1H NMR (200 MHz, CDCl3, TMS):
dH = 7.67–7.26 (m, 15H, aromatic), 6.29/4.70 (2d, 2H,
Ph–CH–O, J = 6.7 Hz), 3.59–3.38 (m, 4H, O–CH2–CH2–
O), 3.23 (s, 3H, O–CH3). 13C NMR (50 MHz, CDCl3):
dC = 186.1 (s, CO), 162.7 (s, O–CO), 137.4/136.3/132.2
(3s, Ph–C-1), 134.7/129.9–127.7 (m, Ph–C), 84.0/78.9 (2d,
Ph–CH–O), 71.8/68.7 (2t, O–CH2–CH2–O), 58.8 (q, O–
CH3). Anal. Calcd for C25H24O5 · 0.4H2O: C, 72.94; H,
6.07. Found: C, 72.99; H, 5.87.
4.2.3. 2-Oxopropionic acid, (1R,2S)-2-(2-methoxyethoxy)-
1,2-diphenylethyl ester, 7d. The crude product was puri-
fied by vacuum flash chromatography on silica gel, eluting
with dichloromethane/methanol (100/1).
4.4.2. (S)-2-Hydroxy-2-phenylhexanoic acid, (1R,2S)-2-(2-
methoxyethoxy)-1,2-diphenylethyl ester, 9a. White solid
(yield 98%), Rf = 0.51 (PE/E 1:1). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.38–6.76 (m, 15H, aromatic), 5.78/
4.43 (2d, 2H, Ph–CH–O, J = 6.4 Hz), 3.66 (s, 1H, OH),
3.42–3.18 (m, 4H, O–CH2–CH2–O), 3.11 (s, 3H, O–CH3),
0.355 g (yield 82%) white solid, mp 40–43 ꢂC, Rf = 0.43
20
(PE/E 1/1), ½aꢁD ¼ ꢀ2:4 (c 0.99, CH2Cl2). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.32–7.30 (m, 10H, aro-

2436
C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
1.99–0.67 (m, 9H, –CH2–CH2–CH2–CH3). 13C NMR
(50 MHz, CDCl3): dC = 174.1 (s, O–CO), 141.4/137.6/
136.8 (3s, Ph–C-1), 128.2–125.8 (m, Ph–C), 84.4/79.7 (2d,
Ph–CH–O), 77.9 (s, O–CO–C(OH)(Ph)–CH2), 71.7/68.6
(2t, O–CH2–CH2–O), 58.8 (q, O–CH3), 38.5 (t, CH2–
CH2–CH2–CH3), 25.3 (t, CH2–CH2–CH2–CH3), 22.8 (t,
CH2–CH2–CH2–CH3), 13.9 (q, CH2–CH2–CH2–CH3).
Anal. Calcd for C29H34O5 · 0.3H2O: C, 74.43; H, 7.45.
Found: C, 74.53; H, 7.73.
bath; stirring was continued for 2 h at 0 ꢂC. In the case
of enolizable pyruvate 7e, dry methanol (1.5 equiv) was
then added and stirring was continued for 10 min at 0 ꢂC.
The supernatant solution of the as prepared RZnX reagent
was slowly added over 15 min to a suspension of esters 7b
and 7e (0.5–1.2 mmol/1 equiv/ꢂ1.2–1.8 g) in dry THF
(20 mL) precooled to ꢀ90 ꢂC, by means of a syringe, and
the resulting mixture was stirred for 2 h at ꢀ78 ꢂC. The
temperature was then increased to ꢀ20 ꢂC over a period
of 1 h, and finally a 10% aqueous NH4Cl solution
(10 mL) was added and stirring continued for 15 min at
room temperature. The resin was filtered off and thor-
oughly washed successively with aqueous NH4Cl, NH4Cl/
THF (1/1), water, water/THF (1/1), THF, methanol,
dichloromethane, methanol, dichloromethane, methanol
and dried in vacuo overnight at 40 ꢂC.
4.4.3. (S)-2-Hydroxy-2-phenylhexanoic acid, (1R,2S)-2-(1,1-
dimethylethoxy)-1,2-diphenylethyl ester, 9c. White solid
1
(yield 92%), Rf = 0.77 (PE/E 1:1). H NMR (200 MHz,
CDCl3, TMS): dH = 7.40–6.72 (m, 15H, aromatic), 5.53/
4.47 (2d, 2H, Ph–CH–O, J = 7.1 Hz), 3.63 (s, 1H, OH),
1.92–0.68 [m, 18H, therein 0.77 (s, 9H, O–C(CH3)3),
–CH2–CH2–CH2–CH3]. 13C NMR (50 MHz, CDCl3):
dC = 174.3 (s, O–CO), 141.7/141.4/137.6 (3s, Ph–C-1),
128.0–126.0 (m, Ph–C), 81.1/76.7 (2d, Ph–CH–O), 77.8
(s, O–CO–C(OH)(Ph)–CH2), 74.9 (s, O–C(CH3)3), 38.3 (t,
CH2–CH2–CH2–CH3), 28.1 (q, O–C(CH3)3), 25.3 (t,
CH2–CH2–CH2–CH3), 22.8 (t, CH2–CH2–CH2–CH3),
13.9 (q, CH2–CH2–CH2–CH3). Anal. Calcd for
C30H36O4 · 0.1H2O: C, 77.92; H, 7.89. Found: C, 77.97;
H, 8.17.
4.5.2. Polymer bound (S)-2-hydroxy-2-phenylhexanoic acid
ester, 9b. Addition of n-BuZnCl to phenylglyoxylate 7b (run
1).
4.5.3. Polymer bound (S)-2-hydroxy-3-methyl-2-phenyl-
butyric acid ester, 10b. Addition of i-PrZnCl to phenylgly-
oxylate 7b (run 1).
4.5.4. Polymer bound (S)-2-hydroxy-2-phenylpropanoic acid
ester, 11b. Addition of MeZnCl to phenylglyoxylate 7b (run
3).
4.4.4. (S)-2-Hydroxy-3-methyl-2-phenylbutyric acid, (1R,
2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl
ester,
10a.
1
White solid (yield 86%), Rf = 0.53 (PE/E 1:1). H NMR
(200 MHz, CDCl3, TMS): dH = 7.46–6.70 (m, 15H, aro-
matic), 5.77/4.47 (2d, 2H, Ph–CH–O, J = 6.2 Hz), 3.55 (s,
1H, OH), 3.45–3.21 (m, 4H, O–CH2–CH2–O), 3.13 (s,
3H, O–CH3), 2.42 (m, 1H, CH(CH3)2, J = 6.7 Hz), 0.62/
0.59 (2d, 6H, CH(CH3)2, J = 6.7 Hz). 13C NMR
(50 MHz, CDCl3): dC = 174.4 (s, O–CO), 140.5/137.5/
136.7 (3s, Ph–C-1), 128.2–126.3 (m, Ph–C), 84.4/80.0 (2d,
2Ph–CH–O), 80.7 (s, O–CO–C(OH)(Ph)–CH(CH3)2),
71.8/68.7 (2t, O–CH2–CH2–O), 58.8 (q, O–CH3), 34.8 (d,
CH(CH3)2), 16.5/15.8 (2q, CH(CH3)2). Anal. Calcd for
C28H32O5 · 1.0H2O: C, 72.08; H, 7.35. Found: C, 72.17;
H, 7.22.
4.5.5. Polymer bound (S)-2-cyclohexyl-2-hydroxyphenylace-
tic acid ester, 12b. Addition of c-HexZnCl to phenylglyoxy-
late 7b (run 2).
4.5.6. Polymer bound (S)-2-hydroxy-2-phenylbutyric acid
ester, 13b. Addition of EtZnCl to phenylglyoxylate 7b (run
2). All
reactions:
pale
yellow
resin.
IR
(COOR),
m
(KBr) = ꢂ3500 cmꢀ1(OH),
ꢂ1740 cmꢀ1
1689 cmꢀ1 (CO: vanished); no further changes.
4.5.7. Polymer bound (R)-2-hydroxy-2-phenylpropanoic acid
ester, 11c. Addition of PhZnCl to pyruvate 7e (run 3). Pale
yellow resin. IR m (KBr) = ꢂ3500 cmꢀ1(OH), ꢂ1740 cmꢀ1
(COOR); no further changes.
4.4.5. (S)-2-Hydroxy-2-phenylpropanoic acid, (1R,2S)-2-(2-
methoxyethoxy)-1,2-diphenylethyl ester, 11a. White solid
1
(yield 82%), Rf = 0.33 (PE/E 1:1). H NMR (200 MHz,
4.6. Saponification of hydroxy ester 9a
CDCl3, TMS): dH = 7.35–6.83 (m, 15H, aromatic), 5.83/
4.45 (2d, 2H, Ph–CH–O, J = 6.5 Hz), 3.62 (s, 1H, OH),
3.44–3.20 (m, 4H, O–CH2–CH2–O), 3.14 (s, 3H, O–CH3),
1.49 (s, 3H, –CH3). 13C NMR (50 MHz, CDCl3):
dC = 174.3 (s, O–CO), 142.2/137.6/136.7 (3s, Ph–C-1),
128.2–125.5 (m, Ph–C), 84.4/79.3 (2d, Ph–CH–O), 75.5
(s, O–CO–C(OH)(Ph)–CH3), 71.8/68.7 (2t, O–CH2–CH2–
O), 58.8 (q, O–CH3), 25.8 (t, –CH3). Anal. Calcd for
C26H28O5 · 0.4H2O: C, 73.01; H, 6.79. Found: C, 73.10;
H, 7.09.
4.6.1. (S)-2-Hydroxy-2-phenylhexanoic acid, 14a. A solu-
tion of ester 9a (1 equiv/ꢂ100 mg) and LiOH (5.0 equiv)
in THF/methanol/water (5/4/1) (10 mL) was stirred over-
night at room temperature. After TLC analysis had indi-
cated a total conversion, an equal amount of a saturated
aqueous NaHCO3 solution was added and THF and meth-
anol were evaporated. The aqueous remaining was ex-
tracted three times with ether. For the recovery of
auxiliary 6a, the combined ether extracts were washed with
brine, dried over Na2SO4, filtered, evaporated, and the res-
idue was purified by vacuum flash chromatography. The
combined aqueous phases were carefully acidified with
HCl concd while cooling on an ice bath and extracted three
times with ethyl acetate. The combined ethyl acetate ex-
tracts were washed with brine, dried over Na2SO4, filtered,
and evaporated yielding the free hydroxy acid.
4.5. Addition of RZnX to polymer bound a-keto esters
4.5.1. General procedure.
A
freshly prepared and
titrated22 solution of RMgX (8 equiv) in THF was slowly
added to a thoroughly stirred solution of pre-dried ZnCl2
(7.5 equiv) in dry THF (5 mL), while cooling on an ice

C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2437
20
White solid (yield 99%), ½aꢁD ¼ þ36:7 (c 0.98, CHCl3)
4.7.4. (S)-2-Cyclohexyl-2-hydroxyphenylacetic acid, 14c.
Addition of c-HexZnCl to phenylglyoxylate 7b. White
20
{Lit.: ½aꢁD ¼ ꢀ37:2 (c 11.3 CHCl3) [R]23}. 1H NMR
22
(200 MHz, acetone-d6, TMS): dH = 7.71–7.67 (m, 2H,
aromatic), 7.40–7.23 (m, 4H, aromatic), 2.31–1.94 (m,
2H, CH2–CH2–CH2–CH3), 1.47–1.24 (m, 4H, CH2–
CH2–CH2–CH3), 0.88 (t, 3H, CH2–CH2–CH2–CH3,
J = 7.1 Hz).
solid (yield 90%), ½aꢁD ¼ þ14:4 (c 0.55, EtOH) {Lit.:
22
1
½aꢁD ¼ 25:8 (c 1.0, EtOH) [S]2}. H NMR (200 MHz, ace-
tone-d6, TMS): dH = 7.60–7.56 (m, 2H, aromatic), 7.24–
7.08 (m, 3H, aromatic), 2.21–0.64 (m, 11H, aliphatic).
13C NMR (50 MHz, acetone-d6): dC = 177.0 (s, O–CO),
142.6 (s, Ph–C-1), 128.6/127.9/126.9 (3d, Ph–C), 81.4 (s,
Ph–C(OH)(c-Hex)–COOH), 46.5 (d, c-Hex–CH), 30.3/
28.1/27.0/26.9/26.4 (5t, c-Hex–CH2).
4.7. Saponification of polymer bound hydroxy esters 9b–13b
4.7.1. General procedure. A mixture of resins 9b–13b and
LiOH (5 equiv) in THF/methanol/water (10/4/1) was re-
fluxed overnight. After complete conversion had been indi-
cated by IR spectroscopy, the resin was filtered off and
thoroughly washed successively with saturated aqueous
NaHCO3, water, water/THF (1/1), methanol, THF, water,
methanol, THF, methanol, THF, methanol, and dried in
vacuo overnight at 40 ꢂC. Recovered resin 6b could be
introduced in the next reaction cycle without any further
purification.
4.7.5. (S)-2-Hydroxy-2-phenylbutyric acid, 14d. Addition of
EtZnCl to phenylglyoxylate 7b. White solid (yield 95%),
25
25
½aꢁD ¼ þ14:4 (c 1.34, EtOH) {Lit.: ½aꢁD ¼ ꢀ32:6 (c 1.0,
EtOH) [R]25}. 1H NMR (200 MHz, acetone-d6, TMS):
dH = 7.69–7.65 (m, 2H, aromatic), 7.39–7.23 (m, 3H, aro-
matic), 2.35–1.93 (m, 2H, CH2–CH3), 0.92 (t, 3H, CH2–
CH3, J = 7.3 Hz).
4.7.6. (S)-2-Hydroxy-2-phenylpropanoic acid, 14e. Addition
of MeZnCl to phenylglyoxylate 7b. White solid (yield
Pale yellow resin. IR m (KBr) = 3528 cmꢀ1(OH), ꢂ1740
20
20
90%), ½aꢁD ¼ þ12:9 (c 0.62, EtOH) {Lit.: ½aꢁD ¼ þ35:1 (c
1.01, EtOH) [S]26}. 1H NMR (200 MHz, acetone-d6,
TMS): dH = 7.52–7.48 (m, 2H, aromatic), 7.26–7.13 (m,
3H, aromatic), 1.62 (s, 3H, CH3).
cmꢀ1 (COOR: vanished); no further changes.
The combined filtrates were diluted with saturated aqueous
NaHCO3, and THF and methanol were evaporated. The
aqueous remaining was extracted three times with ether,
acidified carefully with HCl concd while cooling on an
ice bath, and then extracted three times with ethyl acetate.
The combined ethyl acetate extracts were washed with
brine, dried over Na2SO4, filtered, and evaporated. To ob-
tain hydroxy acids 14a–f with appropriate purities, the
extractive purification step was repeated once or twice if
necessary. The resulting hydroxy acids 14a–f were dried
in high vacuo and characterized by 1H NMR spectroscopy
and [a]D-values, respectively.
4.7.7. (R)-2-Hydroxy-2-phenylpropanoic acid, 14f. Addition
of PhZnCl to pyruvate 7e. White solid (yield 75%),
20
20
½aꢁD ¼ ꢀ26:8 (c 0.76, EtOH) {Lit.: ½aꢁD ¼ þ35:1 (c 1.01,
EtOH) [S]26}. 1H NMR (200 MHz, acetone-d6, TMS):
dH = 7.52–7.48 (m, 2H, aromatic), 7.26–7.13 (m, 3H,
aromatic), 1.62 (s, 3H, CH3).
4.8. Derivatization of hydroxy acids 14a–f and diastereo-
1
isomeric H and 13C NMR analysis of L-valine methyl ester
derivatives 15a–f12
In the following, yields are given over two steps, based on
the gravimetrically estimated amount of keto acid bound in
the esterification step.
4.8.1. General procedure. A solution of L-valine methyl
ester (10–30 mg) in dry dichloromethane (ꢂ1 mL) was
added to a solution of hydroxy acid 14a–f (10–30 mg)
and HOBt (10–30 mg) in dry dichloromethane (3 mL),
and the resulting mixture cooled to ꢀ30 ꢂC. Then a solu-
tion of DIC (10–30 mg) in dry dichloromethane (ꢂ1 mL)
was added and stirring was continued for 1 h at ꢀ30 ꢂC
and then overnight at ambient temperature. Finally, the
reaction mixture was diluted with dichloromethane,
filtered, successively washed with 10% aqueous KHSO4,
saturated aqueous NaHCO3, and brine, dried over
Na2SO4, filtered, and evaporated. For the removal of diiso-
propyl urea, the crude product was taken up with ꢂ1 mL
of acetone, cooled for 10 min on an ice bath, filtered, and
evaporated. The crude product was purified by vacuum
flash chromatography on silica gel, eluting with petroleum
ether/ether (5/1 ! 2/1).
4.7.2. (S)-2-Hydroxy-2-phenylhexanoic acid, 14a. Addition
of n-BuZnCl to phenylglyoxylate 7b. White solid (yield
20
20
76%), ½aꢁD ¼ þ36:6 (c 0.98, CHCl3) {Lit.: ½aꢁD ¼ ꢀ37:2 (c
11.3, CHCl3) [R]23}. 1H NMR (200 MHz, acetone-d6,
TMS): dH = 7.71–7.67 (m, 2H, aromatic), 7.40–7.23 (m,
3H, aromatic), 2.31–1.94 (m, 2H, CH2–CH2–CH2–CH3),
1.47–1.24 (m, 4H, CH2–CH2–CH2–CH3), 0.88 (t, 3H,
CH2–CH2–CH2–CH3, J = 7.1 Hz).
4.7.3. (S)-2-Hydroxy-3-methyl-2-phenylbutyric acid, 14b.
Addition of i-PrZnCl to phenylglyoxylate 7b. White solid
25
(yield 98%), ½aꢁD ¼ þ22:3 (c 1.55, EtOH) {Lit.:
25
1
½aꢁD ¼ þ32:5 (c 2.0, EtOH) [S]24}. H NMR (200 MHz,
acetone-d6, TMS): dH = 7.71–7.56 (m, 2H, aromatic),
7.26–7.08 (m, 3H, aromatic), 2.53 (m, 1H, CH–(CH3)2,
J = 6.8 Hz), 0.90/0.54 (2d, 6H, CH–(CH3)2, J = 6.7 Hz).
13C NMR (50 MHz, acetone-d6): dC = 176.9 (s, O–CO),
143.0 (s, Ph–C-1), 128.6/128.0/126.8 (3d, Ph–C), 81.3 (s,
Ph–C(OH)(i-Pr)–COOH), 36.4 (d, CH–(CH3)2), 17.6/16.2
(2q, CH–(CH3)2).
The diastereoisomeric ratios were determined by integra-
tion of the sufficiently resolved OMe signals at ꢂ3.6 ppm
1
in the H NMR spectra and, if necessary, additionally by
integration of several signals in the 13C NMR spectra. In
the following, NMR-values are given only for the main
diastereoisomers.

2438
C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
4.8.2.
(S)-2-((S)-2-Hydroxy-2-phenylhexanoylamino)-3-
NH–CO), 142.2 (s, Ph–C-1), 128.3/127.6/125.3 (3d, Ph–
C), 79.4 (s, Ph–C(CH2CH3)(OH)–CO–NH), 56.9 (d, NH–
CH(CH(CH3)2)COO), 52.1 (q, OCH3), 32.1 (t, CH2–
CH3), 31.2 (d, NH–CH(CH(CH3)2)COO), 18.8/17.6 (2q,
NH–CH(CH(CH3)2)COO), 7.6 (q, CH2–CH3).
methylbutyric acid, methyl ester, 15a. Colorless oil. 1H
NMR (200 MHz, CDCl3, TMS): dH = 7.54–7.50 (m, 2H,
aromatic), 7.33–7.19 (m, 3H, aromatic), 7.02 (d, 1H, NH,
J = 8.7 Hz), 4.38 (dd, 1H, NH–CH(CH(CH3)2)COO,
J1 = 8.9 Hz, J2 = 4.9 Hz), 3.64 (s, 3H, OCH3), 2.99 (s,
1H, OH), 2.26–1.94 (m, 3H, NH–CH(CH(CH3)2)COO,
CH2CH2CH2CH3), 1.35–1.14 (m, 4H, CH2CH2CH2CH3),
0.82 (t, 3H, CH2CH2CH2CH3, J = 6.8 Hz), 0.74/0.73 (2d,
6H, NH–CH(CH(CH3)2)COO, J = 6.9 Hz). 13C NMR
(50 MHz, CDCl3): dC = 174.1/172.3 (2s, O–CO, NH–
CO), 142.4 (s, Ph–C-1), 128.4/127.6/125.2 (3d, Ph–C),
79.1 (s, Ph–C(CH2CH2CH2CH3)(OH)–CO–NH), 57.0 (d,
NH–CH(CH(CH3)2)COO), 52.1 (q, OCH3), 39.1 (t,
CH2CH2CH2CH3), 31.2 (d, NH–CH(CH(CH3)2)COO),
25.5/22.8 (2t, CH2CH2CH2CH3), 18.8/17.6 (2q, NH–
CH(CH(CH3)2)COO), 13.9 (q, CH2CH2CH2CH3).
4.8.6.
(S)-2-((S)-2-Hydroxy-2-phenylpropionylamino)-3-
methylbutyric acid, methyl ester, 15e. Colorless oil. 1H
NMR (200 MHz, CDCl3, TMS): dH = 7.53–7.47 (m, 2H,
aromatic), 7.32–7.19 (m, 3H, aromatic), 7.07 (d, 1H, NH,
J = 8.7 Hz), 4.38 (dd, 1H, NH–CH(CH(CH3)2)COO,
J1 = 8.8 Hz, J2 = 4.8 Hz), 3.64 (s, 3H, OCH3), 2.16–1.96
(m, 1H, NH–CH(CH(CH3)2)COO), 1.74 (s, 3H, CH3),
0.74/0.73 (2d, 6H, NH–CH(CH(CH3)2)COO, J = 6.9 Hz).
13C NMR (50 MHz, CDCl3): dC = 174.7/172.3 (2s, O–
CO, NH–CO), 143.2 (s, Ph–C-1), 128.3/127.7/125.1 (3d,
Ph–C), 76.5 (s, Ph–C(CH3)(OH)–CO–NH), 57.0 (d, NH–
CH(CH(CH3)2)COO), 52.1 (q, OCH3), 31.3 (q, CH3),
27.1 (d, NH–CH(CH(CH3)2)COO), 18.8/17.5 (2q, NH–
CH(CH(CH3)2)COO).
4.8.3.
(S)-2-((S)-2-Hydroxy-3-methyl-2-phenylbutyryl-
amino)-3-methylbutyric acid, methyl ester, 15b. White so-
lid. 1H NMR (200 MHz, CDCl3, TMS): dH = 7.58–7.54
(m, 2H, aromatic), 7.30–7.10 (m, 4H, aromatic, NH),
4.32 (dd, 1H, NH–CH(CH(CH3)2)COO, J1 = 8.8 Hz,
J2 = 4.9 Hz), 3.62 (s, 3H, OCH3), 3.14 (s, 1H, OH), 2.77
(m, 1H, CH(CH3)2, J = 6.8 Hz), 2.10–1.89 (m, 1H, NH–
CH(CH(CH3)2)COO), 0.94/0.73 (2d, 6H, CH(CH3)2,
J = 6.8 Hz), 0.68/0.64 (2d, 6H, NH–CH(CH(CH3)2)COO,
J = 7.0 Hz). 13C NMR (50 MHz, CDCl3): dC = 174.0/
172.2 (2s, O–CO, NH–CO), 141.8 (s, Ph–C-1), 128.1/
127.2/125.2 (3d, Ph–C), 81.8 (s, Ph–C(i-Pr)(OH)–CO–
NH), 56.9 (d, NH–CH(CH(CH3)2)COO), 51.9 (q, OCH3),
34.6 (d, CH(CH3)2), 31.0 (d, NH–CH(CH(CH3)2)COO),
4.8.7.
(S)-2-((R)-2-Hydroxy-2-phenylpropionylamino)-3-
methylbutyric acid, methyl ester, 15f. Colorless oil. 1H
NMR (200 MHz, CDCl3, TMS): dH = 7.52–7.46 (m, 2H,
aromatic), 7.34–7.19 (m, 3H, aromatic), 6.77 (d, 1H, NH,
J = 8.6 Hz), 4.40 (dd, 1H, NH–CH(CH(CH3)2)COO,
J1 = 8.8 Hz, J2 = 4.8 Hz), 3.62 (s, 3H, OCH3), 2.20–1.96
(m, 1H, NH–CH(CH(CH3)2)COO), 1.77 (s, 3H, CH3),
0.79/0.73 (2d, 6H, NH–CH(CH(CH3)2)COO, J = 6.9 Hz).
13C NMR (50 MHz, CDCl3): dC = 174.7/172.1 (2s, O–
CO, NH–CO), 142.9 (s, Ph–C-1), 128.5/128.0/125.5 (3d,
Ph–C), 76.2 (s, Ph–C(CH3)(OH)–CO–NH), 57.1 (d, NH–
CH(CH(CH3)2)COO), 52.1 (q, OCH3), 31.2 (q, CH3),
26.8 (d, NH–CH(CH(CH3)2)COO), 18.9/17.5 (2q, NH–
CH(CH(CH3)2)COO).
18.7/17.6/16.8/15.7
CH(CH3)2).
(4q,
NH–CH(CH(CH3)2)COO,
4.8.4.
(S)-2-((S)-2-Cyclohexyl-2-hydroxy-2-phenylacetyl-
amino)-3-methylbutyric acid, methyl ester, 15c. White
solid. H NMR (200 MHz, CDCl3, TMS): dH = 7.58–7.53
4.9. Preparation of 5-bromo-2-methylpent-1-ene, 19
1
(m, 2H, aromatic), 7.31–7.13 (m, 4H, aromatic, NH),
4.33 (dd, 1H, NH–CH(CH(CH3)2)COO, J1 = 8.9 Hz,
J2 = 5.0 Hz), 3.64 (s, 3H, OCH3), 2.87 (s, 1H, OH), 2.45–
2.30 (m, 1H, c-Hex–CH), 2.12–1.94 (m, 1H, NH–
CH(CH(CH3)2)COO), 1.77–0.67 [m, 16H, c-Hex–CH2;
therein 0.73/0.69 (2d, 6H, NH–CH(CH(CH3)2)COO,
J = 7.0 Hz)]. 13C NMR (50 MHz, CDCl3): dC = 173.7/
172.2 (2s, O–CO, NH–CO), 141.4 (s, Ph–C-1), 128.2/
127.2/125.3 (3d, Ph–C), 81.8 (s, Ph–C(c-Hex)(OH)–CO–
NH), 56.9 (d, NH–CH(CH(CH3)2)COO), 52.0 (q, OCH3),
44.7 (d, c-Hex–CH), 31.2 (d, NH–CH(CH(CH3)2)COO),
29.7/27.2/26.3/26.3/25.9 (5t, c-Hex–CH2), 18.7/17.7 (2q,
NH–CH(CH(CH3)2)COO).
4.9.1. 4-Methylpent-4-enoic acid, ethyl ester,20 17.
A
mechanically stirred suspension of methyltriphenylphos-
phonium bromide (369 mmol/132 g) in dry THF
(500 mL) was cooled to ꢀ85 ꢂC. Then a 2.5 M solution
of n-BuLi (410 mmol/164 mL) was slowly added by main-
taining the temperature below ꢀ70 ꢂC and stirring was
continued for 1.5 h while cooling on an ice bath. After
the mixture had been cooled again to ꢀ60 ꢂC, a solution
of ethyl laevulinate 16 (289 mmol/41 mL) in dry THF
(150 mL) was slowly added by maintaining the temperature
below ꢀ60 ꢂC and stirring was continued overnight at
room temperature. Water (200 mL) was then added while
cooling on an ice bath. The organic layer was separated
and the aqueous layer extracted three times with ether.
The combined organic extracts were dried over Na2SO4, fil-
tered, and the solvents were evaporated under reduced
pressure (1013–380 mbar). The residue was taken up with
pentane (250 mL) and stirred for 1 h while cooling on an
ice bath. The remaining precipitate was filtered off, washed
with a little portion of cold pentane, and the solvent was
evaporated from the combined filtrates. The crude oil
was fractionated in vacuo. 23.9 g (yield 58%) colorless
oil, bp 75 ꢂC (35 mbar). 1H NMR (200 MHz, CDCl3,
TMS): dH = 4.76/4.71 (2s, 2H, CH3–C(@CH2)–CH2),
4.8.5. (S)-2-((S)-2-Hydroxy-2-phenylbutyrylamino)-3-meth-
1
ylbutyric acid, methyl ester, 15d. Colorless oil. H NMR
(200 MHz, CDCl3, TMS): dH = 7.54–7.49 (m, 2H, aro-
matic), 7.32–7.19 (m, 3H, aromatic), 7.08 (d, 1H, NH,
J = 8.7 Hz), 4.37 (dd, 1H, NH–CH(CH(CH3)2)COO,
J1 = 8.9 Hz, J2 = 5.0 Hz), 3.63 (s, 3H, OCH3), 2.36–2.13
(m, 1H, NH–CH(CH(CH3)2)COO), 2.13–1.92 (m, 2H,
CH2–CH3), 0.85 (t, 3H, CH2–CH3, J = 6.9 Hz), 0.74/0.73
(2d, 6H, NH–CH(CH(CH3)2)COO, J = 6.9 Hz). 13C
NMR (50 MHz, CDCl3): dC = 174.0/172.3 (2s, O–CO,

C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
2439
4.14 (q, 2H, O–CH2–CH3, J = 7.1 Hz), 2.51–2.30 (m, 4H,
CH2–CH2–CO), 1.75 (s, 3H, CH3–C(@CH2)–CH2), 1.26
(t, 3H, O–CH2–CH3, J = 7.1 Hz).
another 10 min and then cooled to ambient temperature.
The concentration of the resulting Grignard solution 20
was determined to be 0.58 M by titration.22
4.9.2. 4-Methylpent-4-en-1-ol,20 18. A solution of ester 17
(168 mmol/23.92 g) in dry THF (300 mL) was slowly added
to a suspension of LiAlH4 (337 mmol/12.77 g) in dry THF
(200 mL), while cooling on an ice bath, with the resulting
mixture stirred for 1 h at room temperature. After TLC
analysis had indicated total conversion, water (40 mL)
and a 2 M NaOH solution (20 mL) were slowly added
while cooling on an ice bath, and stirring continued at
room temperature until a white precipitate had formed.
A small portion of Na2SO4 was added, and stirring contin-
ued for another 5 min at room temperature. Finally the
mixture was filtered through a pad of Hyfloꢁ and evapo-
rated, yielding crude alcohol 18, which was introduced in
the next reaction step without any further purification.
The freshly prepared Grignard solution 20 (9.344 mmol/
16.1 mL) was slowly added to a thoroughly stirred solution
of pre-dried ZnCl2 (7.528 mmol/1.206 g) in dry THF
(5 mL) while cooling on an ice bath, and the stirring con-
tinued for 2.5 h at 0 ꢂC. Then dry methanol (1.752 mmol/
0.07 mL) was added13 and stirring was continued for
10 min at 0 ꢂC. The supernatant solution of the as prepared
organozinc reagent 21 was slowly added over 20 min to a
solution of ester 7d (0.818 mmol/0.28 g) in dry THF
(20 mL), pre-cooled to ꢀ90 ꢂC, by means of a syringe,
and the resulting mixture stirred for 2 h at ꢀ78 ꢂC. The
temperature was then raised up to ꢀ20 ꢂC over a period
of 1 h, and finally a 10% aqueous NH4Cl solution
(10 mL) was added and stirring continued for 15 min at
room temperature. The mixture was taken up with satu-
rated aqueous NH4Cl solution and extracted three times
with ether. The combined ether extracts were successively
washed with aqueous NH4Cl and brine, dried over
Na2SO4, filtered, and evaporated. The crude product was
purified by vacuum flash chromatography on silica gel,
eluting with petroleum ether/ether (10/1 ! 5/1). 0.284 g
15.1 g (yield 90%) colorless oil. 1H NMR (200 MHz,
CDCl3, TMS): dH = 4.72 (s, 2H, CH3–C(@CH2)–CH2),
3.65 (q, 2H, CH2–OH, J = 6.5 Hz), 2.10 (q, 2H, CH3–
C(@CH2)–CH2, J = 7.7 Hz), 1.78–1.64 (m, 3H, CH2–
CH2–CH2–OH), 1.74 (s, 3H, CH3–C(@CH2)–CH2).
1
4.9.3. 5-Bromo-2-methylpent-1-ene,21 19. NEt3 (161
mmol/22.4 mL) and methanesulfonyl chloride (80 mmol/
6.2 mL) were successively added to a solution of alcohol
18 (54 mmol/5.38 g) in dry dichloromethane (25 mL) while
cooling on an ice bath, and stirring continued for 1 h at
0 ꢂC and 1 h at room temperature. Then 1 M HCl
(25 mL) was added while cooling on an ice bath and the
resulting mixture extracted three times with dichlorometh-
ane. The combined organic extracts were successively
washed with a saturated aqueous NaHCO3 solution and
brine, dried over Na2SO4, filtered, and evaporated. The res-
idue was dissolved in dry acetone (200 mL), LiBr
(108 mmol/9.4 g) was added and the resulting mixture re-
fluxed for 2 h. The solids were filtered off, washed with
small portions of acetone, and the combined filtrates evap-
orated. Unreacted alcohol 18 was removed by vacuum
flash chromatography on silica gel, eluting with petroleum
ether/ether (20/1), and the resulting bromide 19 was dis-
tilled in vacuo to remove residual solvents. 8.47 g (yield
97%) colorless oil, bp 84–89 ꢂC (110 mbar). 1H NMR
(200 MHz, CDCl3, TMS): dH = 4.77/4.73 (2s, 2H, CH3–
C(@CH2)–CH2), 3.42 (q, 2H, CH2–Br, J = 6.6 Hz), 2.21–
1.93 (m, 4H, CH2–CH2–CH2–Br), 1.74 (s, 3H, CH3–
C(@CH2)–CH2).
(yield 81%) white solid, Rf = 0.51 (PE/E 1/1). H NMR
(200 MHz, CDCl3, TMS): dH = 7.25–7.11 (m, 10H, aro-
matic), 5.84/4.50 (2d, 2H, Ph–CH–O, J = 6.7 Hz), 4.57
(d, 2H, CH3–C(CH2)–CH2–CH2–CH2, J = 13.7 Hz),
3.45–3.21 (m, 4H, O–CH2–CH2–O), 3.11 (s, 3H, O–CH3),
2.98 (s, 1H, OH), 1.80–1.73 (m, 2H, CH3–C(CH2)–CH2–
CH2–CH2), 1.58 (s, 3H, CH3–C(CH2)–CH2–CH2–CH2),
1.44–1.10 (m, 7H, CH3–C(CH2)–CH2–CH2–CH2), therein
1.20 (s, 3H, CH3–C(OH)–CO)]. 13C NMR (50 MHz,
CDCl3): dC = 175.6 (s, O–CO), 145.2 (s, CH3–C(CH2)–
CH2–CH2–CH2), 137.7/137.3 (2s, Ph–C-1), 128.2–127.2
(m, Ph–C), 109.9 (t, CH3–C(CH2)–CH2–CH2–CH2), 84.3/
78.8 (2d, Ph–CH–O), 74.1 (s, O–CO–C(OH)(CH3)–CH2),
71.7/68.6 (2t, O–CH2–CH2–O), 58.7 (q, O–CH3), 39.4 (t,
CH3–C(CH2)–CH2–CH2–CH2), 37.5 (t, CH3–C(CH2)–
CH2–CH2–CH2), 25.7 (q, CH3–C(CH2)–CH2–CH2–CH2),
22.2 (q, O–CO–C(OH)(CH3)–CH2), 21.0 (t, CH3–
C(CH2)–CH2–CH2–CH2). Anal. Calcd for C26H34O5 ·
0.3H2O: C, 72.30; H, 8.07. Found: C, 72.39; H, 8.39.
4.10.2. (R)-2,6-Dimethylhept-6-ene-1,2-diol, 23. A solu-
tion of ester 22a (0.609 mmol/0.259 g) in dry THF
(10 mL) was slowly added to a suspension of LiAlH4
(1.218 mmol/0.046 g) in dry THF (10 mL) while cooling
on an ice bath, and the resulting mixture was stirred for
24 h at room temperature. After TLC analysis had indi-
cated total conversion, a 10% aqueous KHSO4 solution
was added while cooling on an ice bath and the mixture
was immediately extracted three times with ethyl acetate.
The combined organic extracts were washed with brine,
dried over Na2SO4, filtered, and evaporated. The crude
product was purified by vacuum flash chromatography
on silica gel, eluting with petroleum ether/ethyl acetate
(5/1 ! 0/1).
4.10. Solution phase synthesis of (R)-2,6-dimethylhept-6-ene-
1,2-diol, 23
4.10.1. (R)-2-Hydroxy-2,6-dimethylhept-6-enoic acid, (1R,
2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl
ester,
22a.
Magnesium turnings (50.0 mmol/1.2 g) were suspended in
dry THF (5 mL). Then 1/10 of a solution of bromide 19
(25.0 mmol/4.1 g) in dry THF (30 mL) was added where-
upon the reaction started immediately. Then the whole
amount of the bromide solution was added in such a way
that a gentle reflux was maintained. After complete bro-
mide addition, the resulting mixture was refluxed for
0.077 g (yield 80%) colorless oil, Rf = 0.28 (PE/EE 1/1),
25
25
½aꢁD ¼ þ2:4 (c 1.29, CH2Cl2) {Lit.: ½aꢁD ¼ þ2:4 (R)19}.

2440
C. Schuster et al. / Tetrahedron: Asymmetry 17 (2006) 2430–2441
1H NMR (200 MHz, CDCl3, TMS): dH = 4.56 (d, 2H,
CH3–C(CH2)–CH2–CH2–CH2, J = 6.0 Hz), 3.33/3.25 (2d,
2H, C(OH)–CH2–OH, JAB = 11.0 Hz), 2.81 (s, 2H, OH),
1.88 (m, 2H, CH3–C(CH2)–CH2–CH2–CH2), 1.58 (s, 3H,
CH3–C(CH2)–CH2–CH2–CH2), 1.36 (m, 4H, CH3–
C(CH2)–CH2–CH2–CH2), 1.02 (s, 3H, CH3–C(OH)). 13C
NMR (50 MHz, CDCl3): dC = 145.5 (s, CH3–C(CH2)–
CH2–CH2–CH2), 110.0 (t, CH3–C(CH2)–CH2–CH2–CH2),
73.0 (s, HO–CH2–C(OH)(CH3)–CH2), 69.6 (t, CH2–OH),
38.1 (2t, CH3–C(CH2)–CH2–CH2–CH2), 23.0 (q, CH3–
C(CH2)–CH2–CH2–CH2), 22.2 (q, HO–CH2–C(OH)-
(CH3)–CH2), 21.6 (t, CH3–C(CH2)–CH2–CH2–CH2).
by vacuum flash chromatography on silica gel, eluting with
petroleum ether/ether (20/1). The as isolated product was
assigned as (+)-frontalin by 1H NMR analysis and determi-
nation of its specific rotation. It was used for additional
enantiomeric analysis by GC without total removal of the
1
residual amounts of the solvent. Rf = 0.51 (PE/E 4/1). H
NMR (200 MHz, CDCl3, TMS): dH = 3.92 (d, 1H, O–
CH2–CO, J = 7.4 Hz), 3.46 (dd, 1H, O–CH2–CO, J1 =
7.4 Hz, J2 = 1.8 Hz), 1.90–1.33 [m, 12H, therein 1.44/1.33
(2s, 6H, CH3)].
GC: Carlo Erba HRGC S300 Mega Series/FID, H2/Air/
LIPODEX E, 50 m, B 0.25 mm/Inj. 200 ꢂC, Pct. 220 ꢂC/
He, 100 kPa, split 1:20/100 ꢂC isotherm; tR1 = 9.5 min.
(+)-Frontalin; tR2 = 9.9 min. (ꢀ)-Frontalin; solution phase
frontalin: 99:1 (98% ee); solid phase frontalin: 93:7 (86%
ee).
4.11. Solid phase synthesis of (R)-2,6-dimethylhept-6-ene-
1,2-diol, 23
4.11.1. Polymer bound (R)-2-Hydroxy-2,6-dimethylhept-6-
enoic acid ester, 22b. Polymer bound pyruvate 7e
(ꢂ1.025 mmol/2.207 g) was suspended in dry THF
(20 mL) and cooled to ꢀ90 ꢂC. Then a solution of organo-
zinc reagent 21, which had been freshly prepared by the
reaction of ZnCl2 (8.363 mmol/1.140 g) and a solution of
0.62 M Grignard reagent 20 (9.297 mmol/15.0 mL) in
THF as described above, was slowly added over 20 min,
and the resulting mixture was stirred for 2 h at ꢀ78 ꢂC.
The temperature was then raised up to ꢀ20 ꢂC over a per-
iod of 1 h, and finally a 10% aqueous NH4Cl solution
(10 mL) was added and stirring was continued for 15 min
at room temperature. The resin was filtered off and thor-
oughly washed successively with aqueous NH4Cl solution,
water, water/THF (1/1), methanol, dichloromethane,
methanol, dichloromethane, methanol, and dried in vacuo
overnight at 40 ꢂC. 2.448 g pale yellow resin. IR m
(KBr) = ꢂ3503 cmꢀ1(OH), ꢂ1734 cmꢀ1 (COOR); no fur-
ther changes.
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(10 mL) and the resulting mixture filtered under an atmo-
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cooling on an ice bath. The resulting mixture was shaken
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50% over two steps) colorless oil, Rf = 0.28 (PE/EE 1/1),
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25
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Frontalin 24 was prepared by ozonolysis of diol 23 in dry
dichloromethane at ꢀ78 ꢂC and worked up with dimethyl
sulfide and HCl according to the procedure described by
Whitesell and Buchanan.19 The crude product was purified

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