Chemoenzymatic synthesis of (protected) psymberlc acid

Article abstract of DOI:10.1002/ejoc.200900292

Two alternative approaches to the side-chain of psymberin (1), psymberic acid (5), have been developed starting from either racemic or enantiopure acetal 6. A five-step chemoenzymatic route provided the PMB-protected acid (S, S)-16 required for the coupli

Full text of DOI:10.1002/ejoc.200900292

FULL PAPER
DOI: 10.1002/ejoc.200900292
Chemoenzymatic Synthesis of (Protected) Psymberic Acid
Jörg Pietruszka*[a] and Robert Christian Simon[a]
Keywords: Antitumor agents / Natural products / Diastereoselectivity / Enzymes / Kinetic resolution
Two alternative approaches to the side-chain of psymberin
(1), psymberic acid (5), have been developed starting from
either racemic or enantiopure acetal 6. A five-step chemoen-
quired for the coupling that should ultimately lead to the nat-
ural product 1.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
zymatic route provided the PMB-protected acid (S,S)-16 re- Germany, 2009)
native routes,[10,11] including a formal synthesis of psym-
Introduction
berin (1).[12] Encouraged by its high biological activity, a
possible biological precursor[13] (seco-psymberin) and a hy-
brid[14] [psympederin (4)] were synthesized and tested for
their biological activity. Furthermore, just recently a series
of analogues were synthesized; their structure–activity rela-
tionships (SAR) were investigated by modifying the unsatu-
rated amide side-chain of psymberin (1; Figure 1).[15]
In 2004 psymberin (1) (Psammocinia, symbiont, pederin)
was isolated from the marine sponges Psammocinia sp. and
Ircinia ramose off the coast of Papua New Guinea by two
independent research groups.[1,2] Its structural resemblance
to other cytotoxins of the pederin family [e.g. pederin (2),
mycalamide A (3) and the non-natural psympederin (4)],
which are known to have strong antitumour properties, also
suggested cytotoxic activity. Screening showed that psym-
berin (1) shows remarkable cytostatic activity against mul-
tiple human cancer cell lines with an LC50 in nanomolar
concentrations.[1,3] The very high biological activity, the
lack of natural availability and its challenging chemical
structure has made psymberin (1) an attractive target for
total synthesis.[4] Its unique structure contains nine ste-
reogenic centres and consists of a central pyran core, a dihy-
droisocoumarin unit and an unsaturated acyclic side-chain.
The stereochemical assignment of the stereogenic centres
relied on the use of multidimensional H and 13C NMR
1
techniques, whereas the absolute and relative configurations
were based on homology to other pederins; stereogenic
centres were also characterized by the comparison of op-
tical rotations and biogenetic origin. However, the stereo-
chemistry at C-4 of the unsaturated amide side-chain ini-
tially remained undefined.[1] Finally, the first total synthesis
by De Brabander and co-workers in 2005 led to the com-
plete structural assignment of psymberin (1) with the (4S)
configuration.[4a] Other approaches to assign the configura-
tion of the amide side-chain were conducted by chemical
correlation[5] and natural product degradation.[6] In ad-
dition, the central pyran core, the dihydroisocumarin unit
and coupling strategies have received considerable atten-
tion;[7–9] apart from the procedures reported for the total
syntheses,[4] a number of publications have dealt with alter-
Figure 1. Members of the pederin family.
In this paper we focus on the side-chain of psymberin (1)
and of the non-natural psympederin (4), psymberic acid (5),
providing a detailed conclusion to our preliminary re-
port.[16] We present an alternative chemoenzymatic route to
the side-chain with a highly diastereoselective aldol reaction
[a] Institut für Bioorganische Chemie der Heinrich-Heine-
Universität Düsseldorf im Forschungszentrum Jülich,
Stetternicher Forst Geb. 15.8, 52428 Jülich, Germany
Fax: +49-2461-616196
E-mail: j.pietruszka@fz-juelich.de
3628
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3628–3634

Chemoenzymatic Synthesis of (Protected) Psymberic Acid
as a key step. To establish the absolute and relative configu-
rations, Ley and co-workers’ butane 2,3-diacetal protected
glycolic acid 6 was used, which provided anti-2,3-dihydroxy
esters after deprotection (Scheme 1).[17a–17c]
Scheme 2. Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, 0 °C; (b) LiHMDS to 6, THF, –78 °C, then precooled 8,
88% over two steps; (c) 1,8-bis(dimethylamino)naphthalene,
Me3OBF4, CH2Cl2, room temp., 95%; (d) CSA, MeOH, room
temp., 88%.
Scheme 1. Retrosynthetic analysis of psymberin (1).
Scheme 3. Reagents and conditions: (a) 1  HCl in THF, 3 d, room
temp. (86%).
Results and Discussion
We started our synthetic endeavour with the oxidation of
the commercially available primary alcohol 7 to the corre-
sponding aldehyde 8 using Dess–Martin periodinane[18a,18b] 11 as well as the product 5 (after treating the acids with
(Scheme 2). Compound 8 could not be stored and was di- small portions of CH2N2) could be separated by HPLC on
rectly employed in the subsequent transformation without a chiral stationary phase. Enzyme-screening was then per-
further purification. Thus, the crude aldehyde 8 was pre- formed in a biphasic system on an analytical scale in order
cooled and then added to the enolate of protected glycolic to find an appropriate hydrolase that might be suitable for
acid 6 at –78 °C to form exclusively the anti-aldol product the enantioselective hydrolysis.[19] After defined periods of
9 in 88% yield (over two steps). Because standard tech- time, small aliquots were taken from the reaction mixture,
niques for the O-methylation did not work, we utilized 1,8- and the enantiomeric excess of the product mixture was de-
bis(dimethylamino)naphthalene (proton sponge) and the termined. Although a moderate enantiomeric excess for the
Meerwein salt to furnish the desired product 10 in high substrate was obtained (Scheme 4), the main drawback was
yield (95%).
that various side-reactions, for example, transesterification,
In analogy to a procedure described in the literature,[17b] occurred. The fact that the tested biocatalysts unfortunately
the deprotection with camphorsulfonic acid (CSA) was retained in all cases the desired (S,S) enantiomer 11, and
straightforward (88% yield), resulting in either the racemic with poor enantioselectivity (E value), rendered the route
methyl ester rac-11 or the enantiomerically pure ester (S,S)- impractical for preparative purposes.
11, depending on the glycolic acid anion equivalent used.
With respect to the envisaged coupling strategy, the
The sequence described was performed by starting from alcohol function requires protection to avoid the side-reac-
acetal rac-6 as well as from the pure enantiomer (R,R)-6. tions mentioned above for the transformation of the ester
Psymberic acid [(2S,3S)-5] itself could also be obtained di- rac-11. For the task at hand, silyl protecting groups seemed
rectly by the convenient hydrolysis of the diacetal (3S,1ЈS)- to be one logical choice. Under standard conditions
10 starting from (R,R)-6 (Scheme 3; 86%).
(Scheme 5) the desired products rac-12 (TES protection)
Next, it was necessary to set up an analytical base for and rac-13 (TPS protection) were obtained in non-opti-
the enzymatic kinetic resolution of the racemic methyl ester mized yields of 80 and 74%, respectively. However, no base-
rac-11 to furnish the acid (2S,3S)-5. The starting material line separation of either pair of enantiomers was obtained
Eur. J. Org. Chem. 2009, 3628–3634
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J. Pietruszka, R. C. Simon
FULL PAPER
Scheme 6. Kinetic resolution of rac-14.
Scheme 4. Enzymatic kinetic resolution of the methyl ester rac-11
in a biphasic system [potassium phosphate buffer (pH = 8.0)/n-
heptane] at 35 °C after 24 h (analytical scale).
We assumed that the alcohol (S,S)-11 was further con-
verted into the hydroxy acid (S,S)-5, but we failed to isolate
it directly from the reaction mixture or after derivatization
(esterification with TMS-diazomethane). As described
above, a similar observation was made when using the un-
protected psymberic ester rac-11 as the substrate in the ki-
netic resolution.
(HPLC analysis). As an alternative, the benzoyl protecting
group was introduced (rac-14; 95% yield from rac-11), be-
cause it has already been successfully applied in the total
synthesis by De Brabander and co-workers;[4a] otherwise,
acetates or long-chain fatty acids would have been the pre-
ferred choice as better selectivity would have been ex-
pected.[21,22]
Finally, the PMB protecting group proved to be appro-
priate for furnishing the desired natural (S,S) enantiomer.
When introducing the PMB group through the use of the
corresponding trichloroacetimidate, ether rac-15 was ob-
tained in only a moderate yield (up to 62%). Different con-
ditions (temperature, solvents) and acids for the activation
were tested (CSA, BF3·Et2O, TfOH, PPTS),[20] but due to
a number of byproducts, isolation of pure ether rac-15
turned out to be a major problem. Eventually, the use of 4-
methoxybenzyl bromide in the presence of nBu4NI gave the
desired product rac-15 in a respectable yield (95%;
Scheme 5). After establishing the analytical tool for de-
termining the enantiomeric excess (HPLC), the substrate
was tested for its suitability in enzymatic kinetic resolution.
Again different lipases and esterases[19] were tested (20 in
total) in an aqueous two-phase system (potassium phos-
phate buffer/n-heptane), but no conversion of the substrate
rac-15 was detected after 24 h. To enhance the conversion
rate we decided to repeat the enzyme-screening in an aque-
ous one-phase system with the main focus on esterases as
they are known to be more suitable for converting simple
alcohols and complex acids.[21,22] Moreover, we increased
the enzyme/substrate ratio to a five-fold excess to ensure
conversion. Under these conditions most of the esterases
showed activity towards the substrate rac-15 (Scheme 7).
Scheme 5. Reagents and conditions: (a) imidazole, TESCl (TES =
Et3Si), CH2Cl2, 0 °C, 80%; (b) imidazole, CH2Cl2, 0 °C, TPSCl
(TPS = tBuPh2Si), 74%; (c) BzCl (Bz = benzoyl), NEt3, DMAP,
CH2Cl2, 0 °C, 95%; (d) PMBBr (PMB = p-methoxybenzyl),
nBu4NI, DMF, NaH, –50 °C, 95 %.
The screening of 24 different hydrolases[19] was only Samples taken after 2 and 24 h allowed us not only to assess
moderately successful. Although none of the lipases used the conversion, but also to determine the enantiomeric ex-
was active towards the substrate, some esterases [esterase cess of the preferentially converted ester 15. Because the
E3 (Roche diagnostics) and esterase BS1 (Codexis)] showed enzymes esterase 001 and esterase BS3 (both from Codexis)
conversion, albeit with only poor selectivity. By using the showed the highest activity and enantioselectivity, we re-
esterase from Bacillus subtilis strain BS1 (Codexis) on a pre- peated the biotransformation on a preparative scale to as-
parative scale, enantiomerically highly enriched starting sign the configuration by comparison of the obtained ana-
material (Ͼ99% ee) could be isolated in 31% yield (56% lytical data with those reported in the literature.[6]
conversion; Entry 1, Scheme 6), but subsequent analysis
It was ascertained that the named enzymes hydrolysed
showed that the wrong enantiomer, (R,R)-14, was obtained. the desired (S,S) enantiomer of rac-15 to give the natural
Next, we focused our attention on the isolation of the PMB-protected psymberic acid (S,S)-16. We repeated the
alcohol (S,S)-11; low conversion was achieved (31%, Entry hydrolysis at different temperatures using esterase BS3[19]
2), and no significant accumulation of the desired product (Entries 1 and 2 in Scheme 8). Because it was found that at
could be detected.
40 °C the enantiomeric purity of (S,S)-16 was not satisfac-
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3628–3634

Chemoenzymatic Synthesis of (Protected) Psymberic Acid
temperature to 30–40 °C did unfortunately not enhance the
conversion rate and hence shorten the reaction time, but led
to denaturation of the enzyme; the reaction stopped in both
cases at low conversion. Subsequent addition of small por-
tions of the enzyme also did not significantly improve the
reaction. Figure 2 displays the HPLC trace of the kinetic
resolution of rac-15 performed on a preparative scale. A
small amount of the product (S,S)-16 was treated with diaz-
omethane (in diethyl ether) to furnish the ester (S,S)-15,
thus determining its optical purity.
Conclusions
We have developed two alternative routes to the acid
side-chain of psymberin (1). Starting from acetal (R,R)-6,
we obtained the unprotected psymberic acid (5) in three
steps in an overall yield of 72%. The biocatalytic route fur-
nished the PMB-protected coupling partner 16. Racemic
methyl ester rac-15 could be obtained in a five-step se-
quence from rac-6 in 69% yield. The ultimate kinetic reso-
lution was optimized (E Ͼ 100) and gave the desired prod-
uct with high selectivity (ee ca. 98%) and in a respectable
yield (47%). Thus, another key intermediate in the synthesis
of a chemoenzymatic natural product has been prepared.
Scheme 7. Enzymatic hydrolysis of ester rac-15 performed in an
aqueous one-phase system (analytical scale).
tory (83% ee), we lowered the temperature to 30 °C. Al-
though the enantiomeric excess of the product was en-
hanced to 89% it still was too low for our purpose. The use
of the esterase 001[19] (Entry 3 in Scheme 8) finally gave the
desired acid (S,S)-16 with high optical purity (ee ca. 98%)
and in good yield (47%; E Ͼ 100). Increasing the reaction
Experimental Section
General: All starting materials were purchased from commercial
suppliers and used as received, unless stated otherwise. All solvents
were dried by common methods prior to use; THF was freshly
distilled from sodium/benzophenone and methanol from calcium
hydride. The hydrolases were used as non-immobilized powders as
purchased.[19] Preparative chromatographic separations were per-
formed by column chromatography on Merck silica gel 60 (0.063–
0.200 µm). Solvents for flash chromatography (PE/EtOAc) were
distilled before use. PE refers to the fraction with a boiling point
in the range 40–60 °C. Celite® refers to Celite 545 (0.02–0.1 mm)
purchased from Sigma–Aldrich. TLC was carried out on precoated
plastic sheets (Polygram® SIL G/UV, Macherey–Nagel) with detec-
tion by UV (254 nm) and/or by staining with cerium molybdenum
solution [phosphomolybdic acid (25 g), Ce(SO4)2·H2O (10 g), conc.
sulfuric acid (60 mL), H2O (940 mL)]. Optical rotations were mea-
sured at 20 °C with a Perkin–Elmer 241 MC Polarimeter against
the sodium D line. 1H and 13C NMR spectra were recorded at
20 °C with a Bruker Avance/DRX 600 spectrometer in CDCl3 with
TMS as an internal standard. Chemical shifts are given in ppm
relative to Me4Si (1H NMR: δ = 0 ppm) or to the resonance of
CDCl3 (13C NMR: δ = 77.0 ppm).
Scheme 8. Kinetic resolution of the PMB-protected psymberic acid
methyl ester (rac-15) on a preparative scale (Entries 1 and 2: ester-
ase BS3; Entry 3: esterase 001).
3-(1Ј-Hydroxy-3Ј-methylbut-3Ј-en-1Ј-yl)-5,6-dimethoxy-5,6-dimeth-
yl-1,4-dioxan-2-one (rac-9): Dess–Martin periodinane[18] (4.46 g,
10.5 mmol) was added in one portion to a stirred solution of
alcohol 7 (906 mg, 10.5 mmol) in wet CH2Cl2 (21 mL) at 0 °C. The
mixture was stirred at room temp. overnight followed by quenching
with saturated aqueous Na2S2O3 solution (150 mL) and half-satu-
rated aqueous NaHCO3 solution (150 mL). After effervescence had
ceased, the mixture was extracted four times with CH2Cl2
(4ϫ5 mL). The combined organic layers were dried with MgSO4,
filtered under dry nitrogen and precooled to –78 °C. The aldehyde
8 was kept in solution until used. Meanwhile, lithium bis(trimethyl-
Figure 2. HPLC trace [column = Chiracel OD-H (4.6ϫ250 mm),
flow = 0.7 mL/min (n-heptane/iPrOH = 98:2)] of the kinetic resolu-
tion of ester rac-15 at the end of the reaction [line 1: unreacted
substrate rac-15; line 2: from product (S,S)-16 after derivatization]
and the remaining substrate (R,R)-15 (line 3).
Eur. J. Org. Chem. 2009, 3628–3634
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J. Pietruszka, R. C. Simon
FULL PAPER
silyl)amide (1.0  in THF, 5.52 mL, 5.52 mmol) was added drop-
wise to a stirred solution of rac-6 (1.00 g, 5.26 mmol) at –78 °C in
THF (15 mL). After stirring for 10 min, the precooled aldehyde
solution (ca. 40 mL) was added in one portion. The mixture was
stirred for a further 10 min, followed by the addition of acetic acid
(664 mg, 11.1 mmol). The solution was then warmed to room temp.
The mixture was concentrated under reduced pressure and purified
by flash column chromatography (eluent: petroleum ether/ethyl
acetate, 90:10) to furnish the aldol product 9 (1.28 g, 4.67 mmol,
89%) as a white crystalline solid. Rf = 0.25 (petroleum ether/ethyl
acetate, 80:20). M.p. 59–63 °C. 1H NMR (600 MHz, CDCl3,
25 °C): δ = 1.43 (s, 3 H, Me), 1.51 (s, 3 H, Me), 1.80 (s, 3 H,
Methyl 2-Hydroxy-3-methoxy-5-methylhex-5-enoate (rac-11): In
analogy to a literature procedure,[17b] ether 10 (1.43 g, 4.96 mmol)
was diluted with dry MeOH (20 mL), and, after 5 min, rac-cam-
phorsulfonic acid was added (1.21 g, 5.21 mmol). Stirring was con-
tinued at room temp. for 15 h. After full conversion (as judged by
TLC), the mixture was extracted four times with CH2Cl2
(4ϫ10 mL) against saturated aqueous NaHCO3 solution, dried
with MgSO4, filtered and concentrated under reduced pressure.
Flash column chromatography (eluent: petroleum ether/ethyl ace-
tate, 85:15) afforded the ester rac-11 as a clear liquid (817 mg,
4.37 mmol, 88%). The data are in full agreement with those re-
ported in the literature.[6] Rf = 0.19 (petroleum ether/ethyl acetate,
CH2=CMe), 2.36 (dd, 3J2Јa,1Ј = 4.2, 2J2Јa,2Јb = 14.8 Hz, 1 H, 2Ј-Ha), 80:20). 1H NMR (600 MHz, CDCl3, 25 °C): δ = 1.78 (s, 3 H, Me),
3
2
4
3
2
2.46 (dd, J2Јb,1Ј = 8.9, J2Јb,2Јa = 14.9 Hz, 1 H, 2Ј-Hb), 3.22 (d, 2.22 (ddd, J4a,6 = 0.8, J4a,3 = 6.0, J4a,4b = 14.5 Hz, 1 H, 4-Ha),
3J3,1Ј = 2.6 Hz, 1 H, 3-H), 3.34 (s, 3 H, OMe), 3.44 (s, 3 H, OMe),
2.37 (ddd, J4b,6 = 0.8, J4b,3 = 7.4, J4b,4a = 14.5 Hz, 1 H, 4-Ha),
4
3
2
3
3
4.18 (d, JOH,1Ј = 2.9 Hz, 1 H, OH), 4.21 (m, 1 H, 1Ј-H), 4.89 (br., 2.96 (d, JOH,2 = 5.2 Hz, 1 H, OH), 3.45 (s, 3 H, OMe), 3.68 (ddd,
2 H, 4Ј-H) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 16.9
(Me at C-5), 17.9 (Me at C-6), 22.7 (Me at C-3Ј), 39.6 (C-2Ј), 49.2
3J3,2 = 2.8, J3,4a = 6.1, J3,4b = 7.5 Hz, 1 H, 3-H), 3.81 (s, 3 H,
3
3
3
3
COOMe), 4.39 (dd, J2,3 = 2.7, J2,OH = 5.2 Hz, 1 H, 2-H), 4.80
(OMe at C-5), 50.3 (OMe at C-6), 70.8 (C-3), 74.4 (C-1Ј), 98.2 (C- (br., 1 H, 6-Ha), 4.84 (br., 1 H, 6-Hb) ppm. 13C NMR (151 MHz,
5), 104.9 (C-6), 113.2 (C-4Ј), 142.0 (C-3Ј), 167.1 (C-2) ppm. IR CDCl3, 25 °C): δ = 22.7 (Me at C-5), 37.9 (C-4), 52.5 (COOMe),
(ATR, film): νmax = 3502, 2949, 1742 (C=O), 1379, 1030 cm–1. MS
58.3 (OMe at C-3), 71.8 (C-2), 81.4 (C-3), 113.3 (C-6), 141.8 (C-5),
173.0 (C-1) ppm. IR (ATR, film): ν = 3463 (OH), 2951, 1735
˜
(EI, 70 eV): m/z (%) = 219 (2) [M – C4H7]+, 116 (94) [C6H12O2]+,
101 (100) [C5H9O2]+. C13H22O6 (274.31): calcd. C 56.92, H 8.08;
found C 56.99, H 8.08.
˜
max
(C=O), 1439, 1217, 1101 cm–1. MS (EI, 70 eV): m/z (%) = 99 (100)
[C6H11O]+. C9H16O4 (188.22): calcd. C 57.43, H 8.57; found C
57.22, H 8.49. The enantiomers were separated on an analytical
scale by HPLC: Chiracel OD-H (4.6ϫ250 mm), flow = 0.4 mL/
min, λ = 202 nm, solvent: n-heptane/isopropyl alcohol 96:4, Rt
[(S,S)-11] = 11.63 min and Rt [(R,R)-11] = 13.73 min. A small sam-
ple (1 µL) of the product (S,S)-16 (see below) was treated with di-
azomethane solution in diethyl ether to determine the ee through
its ester.
(–)-(3S,5R,6R,1ЈS)-3-(1Ј-Hydroxy-3Ј-methylbut-3Ј-en-1Ј-yl)-5,6-di-
methoxy-5,6-dimethyl-1,4-dioxan-2-one [(3S,5R,6R,1ЈS)-9]: The
pure enantiomer was prepared according to the procedure reported
for the racemic mixture, starting from (R,R)-6. [α]2D0 = –161 (c =
0.78, CHCl3).
5,6-Dimethoxy-3-(1Ј-methoxy-3Ј-methylbut-3Ј-en-1Ј-yl)-5,6-dimeth-
yl-1,4-dioxan-2-one (rac-10): 1,8-Bis(dimethylamino)naphthalene
(947 mg, 4.42 mmol; proton sponge) and Me3OBF4 (436 mg,
2.95 mmol) were added in one portion to a stirred solution of aldol
product rac-9 (808 mg, 2.95 mmol) in CH2Cl2 (10 mL). The reac-
tion mixture was stirred at room temp. overnight. Subsequently,
small portions of the proton sponge and Me3OBF4 were added
every 12 h, until the reaction was complete (as judged by TLC). In
total, 3.0 equiv. of base and 2.2 equiv. of the methylating reagent
were used over a period of 3 d. Afterwards, the mixture was filtered
through a plug of Celite®, concentrated under reduced pressure
and purified by flash column chromatography (eluent: petroleum
ether/ethyl acetate, 90:10). The ether rac-10 was obtained as a clear,
colourless liquid (809 mg, 2.80 mmol, 95%). Rf = 0.44 (petroleum
(+)-(2S,3S)-2-Hydroxy-3-methoxy-5-methylhex-5-enoic Acid [(S,S)-
5]: The diacetal (3S,5R,6R,1ЈS)-10 (100 mg, 0.35 mmol) was placed
in a reaction flask and diluted with THF (1.5 mL) before a 1 
aqueous HCl stock solution (500 µL) was added. The mixture was
stirred at room temp. for 3 d before it was diluted with water
(10 mL) and extracted with EtOAc (3ϫ5 mL). The combined or-
ganic layers were dried with MgSO4, filtered and concentrated un-
der reduced pressure. Subsequent purification by flash column
chromatography (eluent: petroleum ether/ethyl acetate, 50:50 +
1 vol.-% acetic acid) gave the desired acid (S,S)-5 (52 mg,
0.30 mmol, 86%) as a clear liquid. The data obtained are in full
agreement with those reported in the literature.[5] Rf = 0.23 (petro-
leum ether/ethyl acetate/acetic acid 49.5:49.5:1). [α]2D2 = +21.6 (c =
1
1
ether/ethyl acetate, 80:20). H NMR (600 MHz, CDCl3, 25 °C): δ
0.25, CHCl3). H NMR (600 MHz, CDCl3, 25 °C): δ = 1.80 (s, 3
3
2
= 1.43 (s, 3 H, Me), 1.49 (s, 3 H, Me), 2.98 (s, 3 H, CH2=CMe),
H, CH2=CMe), 2.31 (dd, J4a,3 = 5.4, J4a,4b = 14.6 Hz, 1 H, 4-
3
2
3
2
2.12 (dd, J2Јa,1Ј = 3.6, J2Јa,2Јb = 14.8 Hz, 1 H, 2Ј-Ha), 2.57 (ddd,
Ha), 2.42 (dd, J4b,3 = 7.5, J4b,4a = 14.5 Hz, 1 H, 4-Hb), 3.49 (s, 3
4J2Јb,4ЈH = 0.8, J2Јb,1Ј = 9.6, J2Јb,2Јa = 14.8 Hz, 1 H, 2Ј-Hb), 3.33
3
2
3
3
3
H, OMe), 3.74 (ddd, J3,2 = 4.0, J3,4a = 5.3, J3,4b = 7.6 Hz, 1 H,
3
(s, 3 H, OMe), 3.41 (s, 3 H, OMe), 3.46 (s, 3 H, 1Ј-OMe), 3.87
3-H), 4.41 (d, J2,3 = 3.9 Hz, 1 H, 2-H), 4.84 (br., 1 H, 6-Ha), 4.88
3
3
3
(br., 1 H, 6-Hb) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ =
22.8 (Me at C-5), 37.5 (C-4), 58.1 (OMe at C-3), 70.9 (C-3), 81.0
(C-2), 114.0 (C-6), 141.2 (C-5), 174.5 (C-1) ppm. IR (ATR, film):
(ddd, J1Ј,3 = 2.4, J1Ј,2Јa = 3.7, J1Ј,2Јb = 9.6 Hz, 1 H, 1Ј-H), 4.45
(d, 3J3,1Ј = 2.4 Hz, 1 H, 3-H), 4.82 (br., 2 H, 4Ј-H) ppm. 13C NMR
(151 MHz, CDCl3, 25 °C): δ = 16.9 (Me at C-5), 17.9 (Me at C-6),
22.7 (Me at C-3Ј), 38.8 (C-2Ј), 49.1 (OMe at C-5), 49.8 (OMe at
C-6), 58.2 (OMe at C-1Ј), 71.1 (C-3), 80.8 (C-1Ј), 98.3 (C-5), 105.2
(C-6), 112.8 (C-4Ј), 142.5 (C-3Ј), 167.8 (C-2) ppm. IR (ATR, film):
ν
= 3408 (OH), 2934, 1724 (C=O), 1444, 1216, 1095, 892 cm–1.
˜
max
MS (EI, 70 eV): m/z (%) = 118 (100) [C4H6O4]+.
Methyl 3-Methoxy-5-methyl-2-(triethylsilyloxy)hex-5-enoate (rac-
12): Imidazole (309 mg, 4.53 mmol) was added to a stirred solution
of alcohol rac-11 (776 mg, 4.12 mmol) in dry CH2Cl2 (6 mL). After
the base had dissolved completely, the solution was cooled to 0 °C,
ν
max = 2948, 1748 (C=O), 1379, 899 cm–1. MS (EI, 70 eV): m/z (%)
˜
= 116 (100) [C6H12O2]+, 101 (93) [C5H9O2]+. C14H24O6 (288.34):
calcd. C 58.32, H 8.39; found C 58.35, H 8.39.
(–)-(3S,5R,6R,1ЈS)-5,6-Dimethoxy-3-(1Ј-methoxy-3Ј-methylbut-3Ј- and chlorotriethylsilane (622 mg, 4.12 mmol) was added dropwise
en-1Ј-yl)-5,6-dimethyl-1,4-dioxan-2-one [(3S,5R,6R,1ЈS)-10]: The
pure enantiomer was prepared according to the procedure reported
for the racemic mixture, albeit starting from (3S,5R,6R,1ЈS)-9.
[α]2D0 = –182 (c = 0.9, CHCl3).
through a syringe. The mixture was warmed to room temp. over-
night, filtered through a plug of Celite® and concentrated under
reduced pressure. Flash column chromatography on silica gel (elu-
ent: petroleum ether/ethyl acetate, 98:2) afforded the protected
3632
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3628–3634

Chemoenzymatic Synthesis of (Protected) Psymberic Acid
alcohol rac-12 as a colourless liquid (990 mg, 3.62 mmol, 80%). Rf
(mc, 2 H, arom. H), 7.60 (mc, 1 H, arom. H), 8.10 (mc, 2 H, arom.
H) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 22.7 (Me at C-
5), 39.1 (C-4), 52.4 (COOMe), 58.3 (OMe at C-3), 73.3 (C-2), 79.5
(C-3), 113.5 (C-6), 128.5 (arom. CH), 129.3 (arom. Cipso), 130.0
(arom. CH), 133.5 (arom. CH), 141.5 (C-5), 165.8 (C-1Ј), 168.6 (C-
1
= 0.73 (petroleum ether/ethyl acetate, 95:5). H NMR (600 MHz,
3
CDCl3, 25 °C): δ = 0.62 (q, J1Ј,2Ј = 7.4 Hz, 6 H, 1Ј-H), 0.96 (t,
3
3J2Ј,1Ј = 7.7 Hz, 9 H, 2Ј-H), 1.78 (s, 3 H, Me), 2.28 (d, J4,3
=
3
3
6.5 Hz, 2 H, 4-H), 3.39 (s, 3 H, OMe), 3.6 (ddd, J3,2 = 4.3, J3,4a
3
= 5.4, J3,4b = 7.0 Hz, 1 H, 3-H), 3.74 (s, 3 H, COOMe), 4.29 (d,
1) ppm. IR (ATR, film): ν
= 2955, 2929, 1724 (C=O), 1602,
˜
max
3J2,3 = 4.3 Hz, 1 H, 2-H), 4.81 (br., 2 H, 6-H) ppm. 13C NMR
1263, 1110, 893 cm–1. MS (ESI): m/z (%) = 315 (100) [M + Na]+.
(151 MHz, CDCl3, 25 °C): δ = 4.6 (C-1Ј), 6.7 (C-2Ј), 22.8 (Me at The enantiomeric excess was determined by HPLC: column = Chir-
C-5), 38.9 (C-4), 51.8 (COOMe), 58.4 (OMe at C-3), 73.5 (C-3),
82.1 (C-2), 112.8 (C-6), 142.5 (C-5), 172.6 (C-1) ppm. IR (ATR,
acel OD-H (4.6ϫ250 mm), flow = 0.5 mL/min, λ = 225 nm, sol-
vent: n-heptane/isopropyl alcohol 95:5, Rt [(S,S)-14] = 14.4 min and
film): ν
= 2954, 2878, 1750 (C=O), 1365, 1111, 725 cm–1. MS Rt [(R,R)-14] = 16.8 min.
˜
max
(EI, 70 eV): m/z (%) = 302 (1) [M]+, 273 (21) [M – C2H5]+, 99 (100)
[C6H11O]+. C15H30O4Si (302.48): calcd. C 59.56, H 10.00; found C
59.19, H 9.87.
(+)-(2S,3S)-1,3-Dimethoxy-5-methyl-1-oxohex-5-en-2-yl Benzoate
[(S,S)-14]: The (S,S) enantiomer was prepared according to the
procedure reported for the racemic mixture. [α]2D0 = +15 (c = 0.16,
CHCl3).
Methyl 2-(tert-Butyldiphenylsilyloxy)-3-methoxy-5-methylhex-5-en-
oate (rac-13): Imidazole (111 mg, 1.63 mmol) was added to a stirred
solution of alcohol rac-11 (279 mg, 1.48 mmol) in dry CH2Cl2
(3 mL). After the base had dissolved completely, the solution was
cooled to 0 °C, and tert-butylchlorodiphenylsilane (428 mg,
1.56 mmol) was added dropwise through a syringe. The mixture
was warmed to room temp. overnight, filtered through a plug of
Celite® and concentrated under reduced pressure. Flash column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate,
98:2) afforded the protected alcohol rac-13 as a colourless oil
(469 mg, 1.10 mmol, 74%). Rf = 0.56 (petroleum ether/ethyl ace-
Methyl 3-Methoxy-2-(4-methoxybenzyloxy)-5-methylhex-5-enoate
(rac-15): nBu4NI (196 mg, 0.53 mmol) was added in one portion to
a
stirred solution of p-methoxybenzyl bromide (801 mg,
3.99 mmol) in DMF (12 mL). The mixture was stirred at room
temp. for 2 h and was then cooled to –50 °C. Then methyl psymber-
ate (rac-11) (500 mg, 2.66 mmol) was added through a syringe, fol-
lowed by solid NaH (80.0 mg, 3.32 mmol). Stirring was continued
for 20 h allowing the mixture to warm to room temp. After comple-
tion of the reaction (as judged by TLC), the mixture was extracted
four times with CH2Cl2 (4ϫ10 mL) against saturated aqueous
NaHCO3 solution, dried with MgSO4, filtered and concentrated
under reduced pressure. Subsequent purification with flash column
chromatography (eluent: petroleum ether/ethyl acetate, 95:5) gave
the product rac-15 as a colourless oil (778 mg, 3.79 mmol, 95%).
The data are in full agreement with those reported in the litera-
1
tate, 85:5). H NMR (600 MHz, CDCl3, 25 °C): δ = 1.12 (s, 9 H,
CMe3), 1.70 (s, 3 H, Me), 2.24 (ddd, 4J4a,6 = 0.6, 3J4a,3 = 4.3, 2J4a,4b
3
= 15.3 Hz, 1 H, 4-Ha), 2.36 (ddd, 4J4b,6 = 0.7, J4b,3 = 8.7 H, J4b,4a
= 15.3 Hz, 1 H, 4-Hb), 3.29 (s, 3 H, OMe), 3.47 (s, 3 H, COOMe),
3
3
3
3.58 (ddd, J3,2 = 3.0, J3,4a = 4.3, J3,4b = 8.7 Hz, 1 H, 3-H), 4.35
3
(d, J2,3 = 3.0 Hz, 1 H, 2-H), 4.72–4.77 (m, 2 H, 6-H), 7.32–7.46
ture.[6] Rf = 0.54 (petroleum ether/ethyl acetate, 80:20). 1H NMR
(m, 6 H, arom. H), 7.65–7.70 (m, 4 H, arom. H) ppm. 13C NMR
(151 MHz, CDCl3, 25 °C): δ = 19.4 (CMe3), 22.7 (Me at C-5), 26.8
(CMe3), 38.9 (C-4), 51.5 (COOMe), 58.2 (OMe at C-3), 73.9 (C-3),
82.4 (C-2), 112.6 (C-6), 127.5 (arom. CH), 127.6 (arom. CH), 129.8
(arom. CH), 133.0 (arom. CH), 133.1 (arom. Cipso), 136.1 (arom.
3
(600 MHz, CDCl3, 25 °C): δ = 1.74 (s, 3 H, Me), 2.30 (dd, J4a,3
=
=
=
2
3
2
4.8, J4a,4b = 14.6 Hz, 1 H, 4-Ha), 2.35 (dd, J4b,3 = 7.8, J4b,4a
3
14.6 Hz, 1 H, 4-Hb), 3.34 (s, 3 H, OMe at C-3), 3.66 (ddd, J3,2
4.5, 3J3,4a = 4.7, J3,4b = 7.8 Hz, 1 H, 3-H), 3.76 (s, 3 H, COOMe),
3
3
3.80 (s, 3 H, OMe), 4.05 (d, J2,3 = 4.4 Hz, 1 H, 2-H), 4.40 (d,
CH), 142.4 (C-5), 171.8 (C-1) ppm. IR (ATR, film): ν
= 3073,
˜
max
2J1Јa,1Јb = 11.5 Hz, 1 H, 1Ј-Ha), 4.65 (d, 2J1Јb,1Јa = 11.5 Hz, 1 H, 1Ј-
2932, 2858, 1759 (C=O), 1428, 1106, 700 cm–1. MS (EI, 70 eV): m/z
(%) = 369 (31) [M – C4H9]+, 99 (56) [C6H11O]+. C25H34O4Si
(426.62): calcd. C 70.38, H 7.99; found C 70.27, H 8.03.
3
Hb), 4.76 (br., 1 H, 6-Ha), 4.80 (br., 1 H, 6-Hb), 6.87 (d, J3Ј,4Ј
=
3
8.6 Hz, 2 H, arom. H), 7.28 (d, J4Ј,3Ј = 8.6 Hz, 2 H, arom. H)
ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 22.8 (Me at C-5),
39.0 (C-4), 51.9 (COOMe), 55.3 (OMe), 58.2 (OMe at C-3), 72.3
(C-1Ј), 79.0 (C-3), 80.8 (C-2), 113.0 (C-6), 113.8 (arom. CH), 129.4
(arom. Cipso), 129.8 (arom. CH), 142.2 (C-5), 159.4 (arom. Cipso),
1,3-Dimethoxy-5-methyl-1-oxohex-5-en-2-yl Benzoate (rac-14):
NEt3 (23.9 mg, 0.24 mmol), BzCl (33.2 mg, 0.24 mmol) and
DMAP (2.39 mg, 0.02 mmol) were added to a stirred solution of
alcohol rac-11 (37 mg, 0.19 mmol) in CH2Cl2 (4 mL) at 0 °C. The
mixture was warmed to room temp. overnight. Because no com-
plete conversion was detected (TLC), the mixture was cooled to
0 °C, and additional small portions of NEt3 (19.8 mg, 0.19 mmol),
BzCl (27.5 mg, 0.19 mmol) and DMAP (2.39 mg, 0.02 mmol) were
added. After complete conversion (as judged by TLC), the reaction
mixture was quenched with a saturated aqueous NH4Cl solution
(2 mL) and extracted three times with CH2Cl2 (3ϫ5 mL). The
combined organic layers were washed with saturated aqueous
NaHCO3 solution, dried with MgSO4, filtered and concentrated
under reduced pressure. Flash column chromatography on silica
(eluent: petroleum ether/ethyl acetate, 98:2) gave the desired diester
as a clear liquid (53 mg, 0.18 mmol, 95%). The spectroscopic data
obtained are in full agreement with those reported in the litera-
ture.[4a,8,10] Rf = 0.15 (n-pentane/ethyl acetate, 98:2). 1H NMR
(600 MHz, CDCl3, 25 °C): δ = 1.80 (s, 3 H, CH2=CMe), 2.41 (dd,
171.6 (C-1) ppm. IR (ATR, film): ν
= 2937, 2836, 1746 (C=O),
˜
max
1613, 1514, 1247, 1103, 1033, 821 cm–1. MS (EI, 70 eV): m/z (%) =
308 (4) [M]+, 253 (6) [C13H17O5]+, 207 (43), 187 (8) [C9H15O4]+,
121 (100) [C8H9O]+, 99 (5) [C6H11O]+. C17H24O5 (308.37): calcd. C
66.21, H 7.84; found C 66.43, H 7.94.
Representative Procedure for the Enzyme-Screening (rac-11, rac-14,
rac-15): A sample (1 mL) was removed from a stock solution of
the enzyme (1 mg/mL) and added to the substrate (2 mg in n-hep-
tane, 1 mL) in a 2 mL Eppendorf vial. The mixture was vigorously
shaken with a Thermomix at 40 °C and 1400 rpm. After defined
periods of time (1, 2, 6 and 24 h), aliquots (15 µL) were taken from
the organic layer, diluted with n-heptane (300 µL) and extracted
against saturated aqueous NaHCO3 solution (500 µL). After effer-
vescence had ceased and the layers separated, a sample (150 µL)
was removed from the organic phase and analysed by HPLC (injec-
tion volume: 5 µL).
2
3
3J4a,3 = 5.1, J4a,4b = 14.6 Hz, 1 H, 4-Ha), 2.52 (dd, J4b,3 = 8.1,
2J4b,4a = 14.6 Hz, 1 H, 4-Hb), 3.50 (s, 3 H, OMe), 3.79 (s, 3 H,
COOMe), 3.92 (ddd, J3,2 = 2.7, J3,4a = 5.2, J3,4b = 8.1 Hz, 1 H,
3-H), 4.86 (br., 2 H, 6-H), 5.55 (d, J2,3 = 2.7 Hz, 1 H, 2-H), 7.47
Enzymatic Kinetic Resolution of Methyl 3-Methoxy-2-(4-methoxy-
benzyloxy)-5-methylhex-5-enoate (rac-15): The esterase 001 (48 mg,
3.2 U/mg) was added to a stirred solution of rac-15 (109 mg,
3
3
3
3
Eur. J. Org. Chem. 2009, 3628–3634
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3633

J. Pietruszka, R. C. Simon
FULL PAPER
[2]
G. R. Pettit, J. Xu, J. Chapius, R. K. Pettit, L. P. Tackett, D. L.
Doubek, J. N. A. Hooper, J. M. Schmidt, J. Med. Chem. 2004,
47, 1149–1152.
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de Voogd, P. Crews, J. Nat. Prod. 2008, 71, 1475–1478.
For total syntheses, see: a) X. Jiang, J. Garcia-Fortanet, J. K.
De Brabander, J. Am. Chem. Soc. 2005, 127, 11254–11255; b)
X. Huang, N. Shao, A. Palani, R. Aslanian, A. Buevich, Org.
Lett. 2007, 9, 2597–2600; c) A. B. Smith III, J. A. Jurica, S. P.
Walsh, Org. Lett. 2008, 10, 5625–5628.
S. Kiren, L. J. Williams, Org. Lett. 2005, 7, 2905–2908.
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4117–4120.
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9, 5385–5388.
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48, 7456–7459.
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130, 12216–12217.
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49, 6061–6064.
J. C. Rech, P. E. Floreancig, Org. Lett. 2005, 7, 5175–5178.
N. Shangguan, S. Kiren, L. J. Williams, Org. Lett. 2007, 9,
1093–1096.
0.35 mmol) in potassium phosphate buffer (10 mL of a 100 m
solution; pH = 8.0) at room temp. The reaction was monitored (pH
electrode) and the pH kept constant (at pH 8.0) by adding small
amounts of a 1  NaOH stock solution. Small samples were taken
to determine the ee of the substrate (R,R)-15. After 65 h, the reac-
tion was complete. The reaction mixture was diluted with a satu-
rated aqueous NaHCO3 solution (50 mL) and extracted three times
with petroleum ether (3ϫ10 mL), acidified to pH = 2.0 with a 2 
aqueous HCl solution and extracted with EtOAc (3ϫ15 mL). The
combined organic layers were dried with MgSO4, filtered and con-
centrated under reduced pressure. The pale-yellow oil was further
purified by flash column chromatography with a gradient (eluent:
petroleum ether/ethyl acetate, 80:20 to 50:50 + 1 vol.-% acetic acid)
to yield the ester (R,R)-15 (52 mg, 0.17 mmol, 49%) and the acid
(S,S)-16 (49 mg, 0.17 mmol, 47%) as colourless oils. The spectro-
scopic data for (R,R)-15 are in agreement with those reported for
the racemic compound rac-15 (see above): [α]2D9 = +53 (c = 0.4,
CHCl3; ee Ͼ 94%) and [α]2D9 = +58 (c = 0.3, CHCl3; ee Ͼ99%)
{ref.[6] [α]2D9 = –57 [c = 0.7, CHCl3; for the (S,S) enantiomer]}. The
data for (S,S)-16 are full in agreement with those reported in litera-
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
ture.[6] Rf
49.5:49.5:1). H NMR (600 MHz, CDCl3, 25 °C): δ = 1.74 (s, 3 H,
= 0.18 (petroleum ether/ethyl acetate/acetic acid,
1
3
2
Me), 2.26 (dd, J4a,3 = 5.5, J4a,4b = 14.5 Hz, 1 H, 4-Ha), 2.41 (dd,
[13] X. Huang, N. Shao, A. Palani, R. Aslanian, A. Buevich, C.
Seidel-Dugan, R. Huryk, Tetrahedron Lett. 2008, 49, 3592–
3595.
3J4b,3 = 7.9, J4b,4a = 14.4 Hz, 1 H, 4-Hb), 3.42 (s, 3 H, OMe), 3.75
(ddd, J3,2 = 3.0, J3,4a = 5.5, J3,4b = 8.0 Hz, 1 H, 3-H), 3.81 (s, 3
H, OMe), 4.15 (d, J2,3 = 3.0 Hz, 1 H, 2-H), 4.57 (d, J1Јa,1Јb
11.3 Hz, 1 H, 1Ј-Ha), 4.68 (d, J1Јb,1Јa = 11.3 Hz, 1 H, 1Ј-Hb), 4.81
2
3
3
3
3
2
[14] X. Jiang, N. Williams, J. K. De Brabander, Org. Lett. 2007, 9,
=
227–230.
2
[15] X. Huang, N. Shao, R. Huryk, A. Palani, R. Aslanian, C. Sei-
del-Dugan, Org. Lett. 2009, 11, 867–890.
[16] B. Henßen, E. Kasparyan, G. Marten, J. Pietruszka, Heterocy-
cles 2007, 245–249.
[17] For Ley’s butane 2,3-diacetals, see: a) S. V. Ley, E. Diez, D. J.
Dixon, R. T. Guy, P. Michael, G. L. Nattrass, T. D. Sheppard,
Org. Biomol. Chem. 2004, 2, 3608–3617; b) S. V. Ley, D. J. Di-
xon, R. T. Guy, M. A. Palomero, A. Polara, F. Rodriguez, T. D.
Sheppard, Org. Biomol. Chem. 2004, 2, 3618–3627; c) S. V. Ley,
A. Polara, J. Org. Chem. 2007, 71, 5943–5959.
[18] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156;
b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–
7287.
[19] Enzymes used and their suppliers: Codexis: esterase BS1 (Ba-
cillus subtilis), esterase BS2 (Bacillus subtilis), esterase BS3 (Ba-
cillus subtilis), esterase SD (Streptomyces diastatochromogenes),
esterase 001, esterase 003, esterase 004, and pig liver esterase
(PLE). Fluka: Candida antarctica lipase B (CAL-B), hog pan-
creas lipase (PPL), amano lipase PS (Burkholderia cepacia),
Rhizopus oryzaea esterase (RO), Rhizopus oryzaea lipase, and
Candida rugosa lipase (CRL). Roche diagonostics: esterase E1
(pig liver esterase), lipase L1 (Burkholderia cepacia), lipase L3
(Candida rugosa), lipase L5 (Candida antarctica lipase A), li-
pase L8 (Thermomyces lanuginosa), and lipase L10 (Alcaligenes
sp.).
[20] CSA = camphorsulfonic acid, TfOH = trifluoromethanesulfo-
nic acid, and PPTS = pyridinium p-toluenesulfonate.
[21] K. Faber in Biotransformations in Organic Chemistry, 5th ed.,
Springer, Heidelberg, 2004, pp. 63–97.
[22] U. T. Bornscheuer, R. J. Kazlauskas in Hydrolases in Organic
Synthesis, 2nd ed., Wiley-VCH, Weinheim, 2006, pp. 61–66.
Received: March 19, 2009
3
(br., 2 H, 6-H), 6.89 (d, J3Ј,4Ј = 8.7 Hz, 2 H, arom. H), 7.29 (d,
3J4Ј,3Ј = 8.7 Hz, 2 H, arom. H) ppm. 13C NMR (151 MHz, CDCl3,
25 °C): δ = 22.7 (Me at C-5), 38.5 (C-4), 55.3 (OMe), 58.4 (OMe
at C-3), 72.9 (C-1Ј), 78.3 (C-3), 80.9 (C-2), 113.5 (C-6), 114.0
(arom. CH), 128.7 (arom. Cipso), 129.9 (arom. CH), 141.6 (C-5),
159.7 (arom. Cipso), 173.1 (C-1) ppm. IR (ATR, film): νmax = 2936,
˜
2837, 1723 (C=O), 1612, 1586, 1513, 1247, 1103, 1032, 820 cm–1.
MS (EI, 70 eV): m/z (%) = 121 (100) [C8H9O]+, 99 (70) [C6H5O]+.
The enantiomeric excess was determined by HPLC: A small sample
(1 µL) of the product (S,S)-16 was treated with diazomethane solu-
tion in diethyl ether to yield the ester 15; column = Chiracel OD-
H (4.6ϫ250 mm), flow = 0.7 mL/min, λ = 202 nm, solvent: n-hep-
tane/isopropyl alcohol, 98:2, Rt [(S,S)-15] = 10.80 min and Rt
[(R,R)-15 = 15.55 min]. [α]2D7 = –24.4 (c = 0.62, CHCl3; ee 98%) {ref.[6]
[α]2D7 = –25.9 [c = 1.1, CHCl3; for the (S,S) enantiomer]}.
Acknowledgments
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
for the generous support of our projects. Donations from BASF
AG, Boehringer Mannheim GmbH (now Roche Diagnostics),
Chemetall GmbH, Cognis GmbH, Julich Chiral Solutions GmbH
(now Codexis), and Wacker AG are greatly appreciated. Further-
more, we thank Dipl.-Chem. Elena Kasparyan and Birgit Henßen
for preliminary experiments towards benzoate 14 (see ref.[16]) as
well as Truc Pham for her support.
[1] R. H. Cichewicz, F. A. Valeriote, P. Crews, Org. Lett. 2004, 6,
1951–1954.
Published Online: June 3, 2009
3634
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3628–3634