Enantioselective synthesis of axially chiral tetrasubstituted allenes via lipase-catalyzed desymmetrization

Article abstract of DOI:10.1055/s-0032-1317524

Lipase from Pseudomonas fluorescens efficiently catalyzes the transesterification of prochiral tetrasubstituted allenic diols yielding highly enantioenriched axially chiral allenyl monoesters. In combination with subsequent 5-endo-trig cyclizations gemina

Full text of DOI:10.1055/s-0032-1317524

PAPER
▌3789
paper
Enantioselective Synthesis of Axially Chiral Tetrasubstituted Allenes via
Lipase-Catalyzed Desymmetrization
Lipase-Catalyzed Desymmetrization of Prochiral Allenic Diols
Matthias Hammel, Jan Deska*
Department für Chemie, Universität zu Köln, 50939 Cologne, Germany
Fax +49(221)4705102; E-mail: jan.deska@uni-koeln.de
Received: 05.08.2012; Accepted after revision: 12.10.2012
tution pattern, the synthesis was accomplished by either
SN2′-type substitution using alkyl cuprates7 or through a
palladium-catalyzed Tsuji-type coupling with the respec-
tive arylzinc nucleophiles,8 followed by acid-catalyzed
Abstract: Lipase from Pseudomonas fluorescens efficiently cata-
lyzes the transesterification of prochiral tetrasubstituted allenic di-
ols yielding highly enantioenriched axially chiral allenyl
monoesters. In combination with subsequent 5-endo-trig cycliza-
tions geminally disubstituted dihydrofurans are accessible in high acetonide cleavage.
optical purity.
H
Key words: allenes, axial chirality, desymmetrization, biocataly-
sis, 5-endo-trig cyclization
PhZnBr
AcO
O
H
H2SO4
Pd(PPh3)4 (5 mol%)
Ph
Ph
R
MeOH, 0 °C
THF, 0 °C to r.t.
OH
OH
In constant search of highly selective protocols for the
preparation of optically pure chiral molecules, organic
chemists have shown growing interest in the use of
biocatalysts1 – and lipases in particular2 – to accomplish
this ever-demanding task. Naturally designed to break
down fats and thus well adjusted to perform in a hydro-
phobic environment, lipases offer a high tolerance to-
wards nonaqueous media and provide considerable
activity and stability in strictly organic solvent systems.3
But by far the most striking features are the remarkably
broad acceptance of different substrate structures and the
variety of transformations catalyzed by this class of en-
zymes.2,4 In quest of novel, synthetically valuable, non-
classical targets for biocatalytic investigations, we and
others became interested in the use of allenes as potential
hydrolase substrates and in recent years, a number of suc-
cessful procedures for the enzymatic kinetic resolution of
axially chiral allenic derivatives have been reported.5
Though being an efficient and preparatively simple ap-
proach to obtain optically active compounds, resolution
always comprises a yield limitation of 50% of the enantio-
pure material. To address this issue, we recently presented
an alternative approach by employing prochiral allenic di-
ols.6 Using lipase from porcine pancreas, the enantiose-
lective desymmetrization proceeded smoothly and axially
chiral allenyl esters were isolated in high yield and with
excellent enantiopurity.
O
O
O
1a
2a
89% yield
Ph
AcO
O
R
R2CuMgBr
H2SO4
THF, –78 °C to r.t.
MeOH, 0 °C
OH
OH
R = Me, Et, n-Pr, n-Bu
1b
2b–e
37–81% yield
RZnBr
Pd(PPh3)4 (5 mol%)
AcO
O
H2SO4
THF, 0 °C to r.t.
MeOH, 0 °C
OH
OH
R = Ph, 4-MeOC6H4, 4-ClC6H4,
2-naphthyl, hept-1-ynyl
1c
2b,f–i
48–83% yield
Scheme 1 Synthesis of tri- and tetrasubstituted allenic diols
With the diol substrates in hand, we turned our attention
to the intended biocatalytic transformation. As lipase from
porcine pancreas (PPL) proved to be well suited for this
purpose in the desymmetrization of trisubstituted allenes
we supposed that this enzyme would also be able to cata-
lyze transesterifications of related tetrasubstituted sub-
strates to some extent. However, under the conditions
elaborated before, using vinyl butyrate as acyl donor in
1,4-dioxane at 40 °C, the reaction with diol 2b proceeded
sluggishly, and after three days only 18% conversion was
observed. Nevertheless, the enantioselectivity and the se-
lectivity for the monoacylated product 3b were promising
(Table 1, entry 1). In order to reduce the reaction time, the
loading of the biocatalyst was gradually increased and
with the successive addition of portions of 500 g/mol of
Based on our studies regarding the desymmetrization of
trisubstituted allenic diols, our aim was to further investi-
gate the extended substrate scope of this reaction and in
particular, turn our attention to related tetrasubstituted de-
rivatives. Hence, a series of allene diols 2 were prepared
from propargylic acetate precursors 1a–c in moderate to
good yields (Scheme 1). Depending on the desired substi-
SYNTHESIS 2012, 44, 3789–3796
Advanced online publication: 25.10.2012
DOI: 10.1055/s-0032-1317524; Art ID: SS-2012-Z0645-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
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1
1
4
3
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2
1
0
X

3790
M. Hammel, J. Deska
PAPER
the protein over four days high conversion and good enan- contrast to the desymmetrization of trisubstituted allenes
tioselectivity were achieved (Table 1, entry 4). However, using PPL where a rather wide range of different aryl sub-
from a practical point of view such a high enzyme loading stituents was well tolerated, PFL turned out to be much
seemed rather inappropriate. Thus, we took a step back to more sensitive in this regard. Whereas p-chlorophenyl de-
reassess the influence of different lipases as potential rivative 3f was accessible in 98% ee, the 2-naphthyl- and
transesterification catalysts for this particular challenge. p-anisyl-substituted monoesters 3g and 3h suffered from
While most of them failed to combine high reactivity with diminished enantioselectivity. On the other hand, nonaryl
good selectivities (Table 1, entries 5–8), lipase from Pseu- substrate 2i, bearing a heptynyl substituent, was desym-
domonas fluorescens (PFL) was able to trigger rapid for- metrized very fast and gave rise to the dienyne 3i in 93%
mation of highly enantioenriched monobutyrate 3b (Table yield and 99% ee.
1, entry 9). Finally, further reduction of the protein load-
Although PPL and PFL show variably pronounced selec-
ing to 50 g/mol also minimized the undesired overacyla-
tivities for different kinds of allene substrates, the general
tion reaction to the dibutyrate 4b (Table 1, entry 10).
stereochemical outcome, that is, the preference for a par-
Interestingly, PFL was previously identified as inferior ticular enantiomer, was identical in all cases studied so
catalyst in the desymmetrization of trisubstituted allenic far. Thus, referring to our investigations on trisubstituted
diols.6a Direct comparison between the desymmetrized allenic diols we presumed that also in the case of tetrasu-
products 3a and 3b nicely illustrates this preference to- bstituted allenes the R-enantiomers were formed preferen-
wards the higher substituted allene derivatives (Figure 1). tially. In order to validate this hypothesis, comparative
While the enantiomeric excess of the trisubstituted allene studies on the chiroptical properties of the desymmetriza-
3a did not exceed 70%, PFL-catalyzed desymmetrization tion product 3a, which was obtained in 98% ee by desym-
of 2b delivered highly enantioenriched 3b (97% ee) in metrization using PPL and whose absolute configuration
very good yield. In the same way, the higher homologue was assigned previously, and its tetrasubstituted analogue
3c bearing an ethyl substituent was efficiently synthesized 3b (97% ee) were conducted. At a comparable level of op-
in high yield and 94% ee, though, requiring substantially tical purity, 3a and 3b both showed levorotatory specific
longer reaction time. Extension of the alkyl chain beyond rotation at the same order of magnitude with values of
the ethyl length (3d and 3e) further decreased the reaction [α]D20 –35.6 for 3a (c 0.50, CHCl3) and [α]D20 –27.3 for 3b
rate, but even these monobutyrates could be isolated in (c 0.83, CHCl3), respectively. Likewise, circular dichro-
good yield with enantiomeric excesses still above 70%. In ism spectra of 3a and 3b, recorded in n-hexane, appear
Table 1 Lipase-Screening for the Desymmetrization of 2ba
O
lipase
vinyl butyrate
OH
OH
OH
O
O
+
1,4-dioxane, 40 °C
O
O
2b
3b
4b
O
Entry
Lipase from
Loading (g/mol)
Time (h)
Conv. (%)
ee (%)
3b/4b
1
porcine pancreas
porcine pancreas
porcine pancreas
porcine pancreas
C. antarctica A
C. antarctica B
M. miehei
100
72
72
72
96
4
18
59
77
83
99
90
98
23
88
99
88
92
95
95
13
96
42
37
97
97
50:1
50:1
50:1
50:1
1:5
2
300
3
1000
3 × 500
100
4b
5
6
100
1
1:3
7
100
4
1:4
8
T. lanuginosa
P. fluorescens
P. fluorescens
100
4
20:1
9:1
9
100
6
10
50
20
20:1
a Reaction conditions: diol 2b (19.0 mg, 0.10 mmol), vinyl butyrate (64 μL, 0.50 mmol), lipase, 1,4-dioxane (0.5 mL) at 40 °C; conversion and
enantiomeric excess were determined by HPLC on chiral phase from the crude reaction mixture.
b Successive addition of portions of the enzyme after 24 and 48 h.
Synthesis 2012, 44, 3789–3796
© Georg Thieme Verlag Stuttgart · New York

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Lipase-Catalyzed Desymmetrization of Prochiral Allenic Diols
3791
H
OH
O
OH
O
O
3b (20 h)
90%, 97% ee
3a (16 h)
69%, 68% ee
O
OH
O
3c (77 h)
84%, 94% ee
O
OH
O
OH
O
O
3e (103 h)
79%, 81% ee
3d (103 h)
76%, 74% ee
O
OH
O
Cl
O
Figure 2 Circular dichroism spectra of 3a and 3b
3f (18 h)
81%, 98% ee
from its corresponding acetonide.11,12 In a more controlled
fashion, metal-catalyzed cycloisomerization was
achieved using silver nitrate in aqueous acetone.6a,13 Start-
ing from enantioenriched 3b, perfect axial-to-central chi-
rality transfer was observed and after hydrolysis,
dihydrofuran 5 bearing a quaternary stereogenic center
was obtained in good yield and 97% ee (Scheme 2). Even
more functionalized 3-iododihydrofuran 6 was accessible
by treatment of allenol 3b with N-iodosuccinimide,5g that
led to fast halocyclization, again with complete conserva-
tion of enantiomeric purity.
OH
O
OH
O
MeO
3h (29 h)
O
3g (29 h)
67%, 82% ee
59%, 75% ee
O
OH
O
3i (10 h)
93%, 99% ee
O
Figure 1 Influence of different substituents in the PFL-catalyzed al-
lene desymmetrization. Reagents and conditions: diol 2 (0.20 mmol),
vinyl butyrate (127 μL, 1.0 mmol), 1,4-dioxane (1.0 mL), lipase from
P. fluorescens (10 mg), 40 °C; reaction time in parentheses.
AgNO3
(10 mol%)
OH
acetone–H2O
50 °C
then NaOH
O
MeOH–H2O
r.t.
5
very similar in shape with negative Cotton effects around
235 and 265 nm (Figure 2). Both results strongly support
the proposed R-selectivity in the PFL-catalyzed allene
diol desymmetrization.
79% yield, 97% ee
OH
O
O
Apart from being an interesting target for stereochemical
investigations, axially chiral allenes can serve as valuable
building blocks in stereoselective synthesis.9 Heterofunc-
tionalized cumulenes such as allene carboxylic acids, α-
allenyl amides as well as α-allenols represent exquisite
precursors for 5-endo-trig cyclizations that would lead to
the corresponding five-membered heterocycles.10 During
the course of our studies, we already observed undesired
cycloisomerization of 2b to give rac-5 as minor side prod-
uct in the Brønsted acid catalyzed liberation of the diol
3b (97% ee)
O
N-iodosuccinimide
I
O
CH2Cl2
0 °C
O
6
81% yield, 97% ee
Scheme 2 Synthesis of 2,2-disubstituted dihydrofurans
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3789–3796

3792
M. Hammel, J. Deska
PAPER
FT-IR (ATR): 2992 (w), 2941 (w), 2924 (w), 2874 (w), 2247 (w),
1742 (s), 1447 (w), 1371 (m), 1296 (w), 1263 (m), 1225 (s), 1134
(m), 1065 (m), 1016 (m), 968 (m), 831 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 4.13 (d, 2J = 12.5 Hz, 2 H), 4.00
(d, 2J = 12.5 Hz, 2 H), 2.10 (s, 3 H), 1.85 (s, 3 H), 1.44 (s, 3 H), 1.40
(s, 3 H).
In conclusion, we have developed a practical method for
the synthesis of highly optically enriched, axially chiral,
fully substituted allene derivatives based on a biocatalytic
desymmetrization using commercially available lipase
from Pseudomonas fluorescens. In combination with 5-
endo-trig cyclizations, functionalized dihydrofurans con-
taining quaternary stereogenic centers were generated
with high enantiomeric excess. Further extension of this
methodology to exocyclic allene diols and thus applica-
tion in the synthesis of spirocyclic ethers are currently un-
der investigation.
13C NMR (75 MHz, CDCl3): δ = 169.8, 98.7, 84.7, 74.3, 70.3, 66.3,
26.8, 21.7, 19.8, 3.8.
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.33; H,
7.53.
Allenic Diols 2b–e by Copper Catalysis; General Procedure
At –78 °C, a solution of the alkylmagnesium halide (1 M, 3.0 mL,
3.0 mmol) in THF was added dropwise to a solution of CuBr·Me2S
(308 mg, 1.5 mmol) in anhyd THF (15 mL) and the mixture was
stirred at –78 °C for 30 min. Acetate 1b (274 mg, 1.0 mmol), dis-
solved in anhyd THF (2 mL), was slowly added and the solution
was allowed to warm up to r.t. overnight. After dilution with EtOAc
(20 mL), the organic layer was washed with sat. aq NH4Cl solution
until the blue color disappeared, dried (MgSO4), and concentrated
in vacuo. The residue was redissolved in MeOH (5 mL) and cooled
to 0 °C before one drop of concd H2SO4 was added. After 30 min,
sat. aq NaHCO3 (10 mL) and EtOAc (20 mL) were added, the aque-
ous layer was extracted with EtOAc (2 × 10 mL) and the combined
organic layers were dried (MgSO4). The solution was concentrated
in vacuo and the residue purified by column chromatography.
All reactions were performed under argon atmosphere in oven-dried
glassware. Anhyd THF was freshly distilled from sodium and ben-
zophenone, anhyd CH2Cl2 was distilled from CaH2, anhyd 1,4-diox-
ane was purchased from VWR International. Commercially
available reagents were used without further purification. All prod-
ucts were purified by column chromatography over silica gel
[Macherey-Nagel MN-Kieselgel 60 (40–60 μm, 240–400 mesh)].
Analytical TLC was performed on Macherey-Nagel precoated silica
gel plates (Alugramm Sil G/UV254), visualization of the com-
pounds was achieved by UV light (254 nm), KMnO4 solution or
Hanessian’s stain. Uncorrected melting points were measured on a
Büchi melting point apparatus using open glass capillaries. 1H and
13C NMR spectra were recorded on a Bruker Avance 300 spectrom-
eter at r.t. at 300 and 75 MHz, respectively. Chemical shifts are re-
ported in parts per million (ppm) referenced to TMS. IR spectra
were recorded on a Shimadzu IRAffinity-1 FT-IR-spectrometer, ab-
sorption bands are reported in wave numbers (cm–1). High-resolu-
tion mass spectrometry was performed on a Finnigan MAT 900 S
spectrometer. High-performance liquid chromatography was per-
formed on a Merck D-7000 with a Merck L-4500 PDA-detector us-
ing an analytical Daicel Chiralpak column (250 mm × 4.6 mm).
Optical rotations were measured on a Perkin-Elmer 343plus. Circu-
lar dichroism spectra were recorded on a Jasco J-810 CD-spectro-
polarimeter.
2-Hydroxymethyl-4-phenylpenta-2,3-dien-1-ol (2b)
Yield: 153 mg (0.81 mmol, 81%); yellow solid; mp 78 °C; Rf = 0.13
(SiO2, cyclohexane–EtOAc, 1:1).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR = 14.4 min.
FT-IR (ATR): 3294 (br, m), 2980 (s), 2930 (s), 2868 (s), 1956 (m),
1734 (s), 1597 (s), 1491 (m), 1443 (m), 1398 (m), 1159 (w), 994 (s),
974 (m), 758 (s), 692 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.38 (d, 3J = 7.7 Hz, 2 H), 7.31 (t,
3J = 7.5 Hz, 2 H), 7.26–7.17 (m, 1 H), 4.31 (s, 4 H), 2.64 (s, 2 H),
2.13 (s, 3 H).
Acetates 1b,c; General Procedure
13C NMR (75 MHz, CDCl3): δ = 200.3, 136.7, 128.5, 127.2, 125.9,
106.2, 104.3, 62.5, 17.3.
At 0 °C, a solution of 2,2-dimethyl-1,3-dioxan-5-one (1.70 g, 10.0
mmol) in anhyd THF (10 mL) was added to a solution of the al-
kynylmagnesium bromide (0.5 M in THF, 22 mL, 11.0 mmol) and
the reaction mixture was stirred for 1 h at 0 °C. Ac2O (1.22 g, 1.14
mL, 12.0 mmol, 1.2 equiv) was added and the stirring was contin-
ued for 1 h at 0 °C. Sat. aq NH4Cl (20 mL) was added and the aque-
ous phase was extracted with EtOAc (3 × 25 mL). The combined
organic layers were dried (MgSO4), concentrated in vacuo, and the
crude acetate was purified by column chromatography.
Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.53; H,
7.42.
2-Hydroxymethyl-4-phenylhexa-2,3-dien-1-ol (2c)
Yield: 103 mg (0.50 mmol, 50%); colorless solid; mp 75 °C; Rf =
0.23 (SiO2, cyclohexane–EtOAc, 1:1).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR = 13.6 min.
2-Acetoxy-5,5-dimethyl-2-phenylethynyl-1,3-dioxane (1b)
Yield: 1.65 g (6.02 mmol, 60%); yellow solid; mp 52 °C; Rf = 0.23
(SiO2, cyclohexane–EtOAc, 9:1).
FT-IR (ATR): 3275 (br, m), 2967 (m), 2924 (w), 2907 (w), 2868
(w), 1948 (m), 1595 (w), 1454 (m), 1404 (m), 1375 (m), 1232 (m),
1201 (w), 1004 (s), 966 (s), 752 (m), 681 cm–1 (s).
FT-IR (ATR): 2988 (w), 2943 (w), 2872 (w), 2361 (s), 2342 (m),
2232 (w), 1734 (s), 1491 (w), 1474 (w), 1445 (w), 1373 (s), 1232
(s), 1193 (m), 1136 (s), 1068 (s), 1045 (m), 827 (s), 754 (s), 688
cm–1 (s).
3
1H NMR (300 MHz, CDCl3): δ = 7.31 (d, J = 7.8 Hz, 2 H), 7.24
3
(dd, J = 7.5 Hz, 2 H), 7.18–7.11 (m, 1 H), 4.26 (s, 4 H), 2.41 (q,
3J = 7.3 Hz, 2 H), 2.36 (s, 2 H), 1.05 (t, 3J = 7.3 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.44–7.28 (m, 5 H), 4.24 (d, 2J =
12.4 Hz, 2 H), 4.13 (d, 2J = 12.4 Hz, 2 H), 2.13 (s, 3 H), 1.47 (s, 3
H), 1.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.6, 131.9, 128.9, 128.2, 121.7,
98.8, 88.0, 83.9, 70.4, 66.2, 26.8, 21.7, 19.9.
13C NMR (75 MHz, CDCl3): δ = 199.6, 136.4, 128.5, 127.2, 126.1,
111.6, 108.4, 62.5, 23.2, 12.7.
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.14; H,
7.87.
2-Hydroxymethyl-4-phenylhepta-2,3-dien-1-ol (2d)
Yield: 89 mg (0.41 mmol, 41%); colorless solid; mp 72 °C; Rf =
0.31 (SiO2, cyclohexane–EtOAc, 1:1).
Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.01; H,
6.80.
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (98:2), 1 mL/min, 245–
255 nm; tR = 38.5 min.
2-Acetoxy-5,5-dimethyl-2-(prop-1-ynyl)-1,3-dioxane (1c)
Yield: 1.36 g (6.41 mmol, 64%); yellow waxy solid; Rf = 0.19 (SiO2,
cyclohexane–EtOAc, 9:1).
Synthesis 2012, 44, 3789–3796
© Georg Thieme Verlag Stuttgart · New York

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Lipase-Catalyzed Desymmetrization of Prochiral Allenic Diols
3793
FT-IR (ATR): 3277 (br, m), 2955 (m), 2924 (w), 2868 (w), 2361
(w), 1952 (m), 1595 (w), 1452 (m), 1404 (m), 1342 (m), 1230 (w),
1203 (w), 1005 (s), 997 (s), 960 (m), 742 (m), 684 cm–1 (s).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR = 26.0 min.
FT-IR (ATR): 3227 (br, m), 2965 (w), 2918 (w), 2860 (w), 2361 (s),
2342 (s), 1956 (w), 1406 (m), 1379 (w), 1201 (w), 1037 (m), 993
(s), 855 (m), 817 (s), 748 (s), 660 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.82–7.72 (m, 4 H), 7.58–7.55 (m,
1 H), 7.46–7.44 (m, 2 H), 4.39 (s, 4 H), 2.48 (s, 2 H), 2.25 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 200.9, 134.1, 133.6, 132.7, 128.2,
1H NMR (300 MHz, CDCl3): δ = 7.39 (d, 3J = 7.8 Hz, 2 H), 7.32 (t,
3
3J = 7.5 Hz, 2 H), 7.26–7.20 (m, 1 H), 4.34 (s, 4 H), 2.45 (t, J =
7.4 Hz, 2 H), 2.22 (br s, 2 H), 1.55 (tq, 3J = 7.4 Hz, 2 H), 0.99 (t, 3J =
7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 199.9, 136.5, 128.6, 127.3, 126.3,
109.8, 107.6, 62.7, 32.5, 21.4, 14.0.
127.9, 127.7, 126.4, 126.0, 124.9, 123.9, 106.6, 104.7, 62.6, 17.4.
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.03; H,
8.33.
Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.71; H,
6.75.
2-Hydroxymethyl-4-phenylocta-2,3-dien-1-ol (2e)
Yield: 87 mg (0.38 mmol, 38%); colorless solid; mp 76 °C; Rf =
0.31 (SiO2, cyclohexane–EtOAc, 1:1).
2-Hydroxymethyl-4-(4-methoxyphenyl)penta-2,3-dien-1-ol (2h)
Yield: 131 mg (0.60 mmol, 60%); pale yellow solid; mp 80 °C; Rf =
0.14 (SiO2, cyclohexane–EtOAc, 1:1).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (98:2), 1 mL/min, 245–
255 nm; tR = 37.6 min.
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 260
nm; tR = 24.5 min.
FT-IR (ATR): 3231 (br, m), 2955 (m), 2928 (m), 2872 (w), 2857
(w), 1954 (w), 1595 (w), 1491 (w), 1452 (m), 1431 (w), 1369 (w),
1228 (w), 1151 (m), 1051 (s), 1016 (s), 997 (s), 756 (s), 692 cm–1
(s).
FT-IR (ATR): 3291 (br, m), 2961 (w), 2922 (w), 2868 (w), 1954
(w), 1605 (m), 1510 (s), 1452 (w), 1396 (w), 1346 (w), 1294 (m),
1254 (s), 1180 (s), 1119 (w), 1029 (m), 9995 (s), 833 (s), 692 cm–1
(m).
1H NMR (300 MHz, CDCl3): δ = 7.31 (d, 3J = 8.5 Hz, 2 H), 6.86 (d,
3J = 8.5 Hz, 2 H), 4.32 (s, 4 H), 3.80 (s, 3 H), 2.15 (br s, 2 H), 2.12
(s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.39 (d, 3J = 7.5 Hz, 2 H), 7.32 (t,
3
3J = 7.5 Hz, 2 H), 7.26–7.20 (m, 1 H), 4.34 (s, 4 H), 2.48 (t, J =
7.3 Hz, 2 H), 1.56–1.37 (m, 4 H), 0.93 (t, 3J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 199.8, 136.5, 128.6, 127.3, 126.3,
110.2, 107.7, 62.7, 30.3, 30.1, 22.6, 14.1.
13C NMR (75 MHz, CDCl3): δ = 199.4, 159.0, 127.1, 114.0, 106.5,
104.5, 62.7, 55.5, 17.6.
Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.38; H,
8.69.
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.51; H,
7.25.
Allenic Diols 2f–i by Palladium Catalysis; General Procedure
Anhyd ZnBr2 (931 mg, 4.0 mmol, dried in vacuo with a heatgun)
and Pd(PPh3)4 (58 mg, 0.05 mmol) were dissolved in anhyd THF
(10 mL) and cooled down to 0 °C. A solution of the Grignard re-
agent (1 M, 4.0 mL, 4.0 mmol) was added dropwise and stirring was
continued for 30 min at 0 °C. Acetate 1c (212 mg, 1.0 mmol), dis-
solved in anhyd THF (2 mL), was added to the yellow suspension
and the reaction mixture was allowed to warm up to r.t. overnight.
Sat. aq NaHCO3 solution (10 mL) and EtOAc (20 mL) were added
and the aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. The residue was redissolved in MeOH (5 mL) and cooled to
0 °C before one drop of concd H2SO4 was added. After 30 min, sat.
aq NaHCO3 (10 mL) and EtOAc (20 mL) were added, the aqueous
layer was extracted with EtOAc (2 × 10 mL) and the combined or-
ganic layers were dried (MgSO4). The solution was concentrated in
vacuo and the residue purified by column chromatography.
2-Hydroxymethyl-4-methylundeca-2,3-dien-5-yn-1-ol (2i)
Yield: 151 mg (0.72 mmol, 72%); colorless oil; Rf = 0.13 (SiO2, cy-
clohexane–Et2O, 6:4).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (97:3), 0.7 mL/min,
254 nm; tR = 16.4 min.
FT-IR (ATR): 3302 (br, m), 2927 (m), 2858 (m), 2361 (w), 1954
(w), 1458 (m), 1431 (m), 1402 (m), 1236 (m), 1004 cm–1 (br, m).
1H NMR (300 MHz, CDCl3): δ = 4.27 (s, 4 H), 2.31 (t, 3J = 7.2 Hz,
2 H), 2.02 (br s, 2 H), 1.90 (s, 3 H), 1.56–1.27 (m, 6 H), 0.92 (t, 3J =
7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 204.7, 161.0, 104.9, 92.7, 76.8,
62.1, 31.2, 28.4, 22.2, 21.0, 19.6, 14.9.
PFL-Catalyzed Desymmetrization; General Procedure
To a solution of diol 2b–i (0.20 mmol) and vinyl butyrate (127 μL,
1.0 mmol) in 1,4-dioxane (1.0 mL) was added lipase from Pseudo-
monas fluorescens (10 mg, Amano lipase from P. fluorescens, Sig-
ma) and the suspension was incubated for 10–103 h at 40 °C. The
reaction mixture was filtered through cotton, concentrated in vacuo,
and the crude product was purified by column chromatography.
4-(4-Chlorophenyl)-2-hydroxymethylpenta-2,3-dien-1-ol (2f)
Yield: 149 mg (0.66 mmol, 66%); colorless solid; mp 77 °C; Rf =
0.17 (SiO2, cyclohexane–EtOAc, 1:1).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR = 18.0 min.
(R)-2-Hydroxymethyl-4-phenylpenta-2,3-dien-1-yl Butyrate
(3b)
FT-IR (ATR): 3235 (br, m), 2984 (w), 2922 (w), 2870 (w), 2361 (s),
2342 (s), 1960 (w), 1717 (w), 1489 (m), 1412 (w), 1229 (w), 1155
(w), 1094 (m), 1058 (m), 1007 (s), 964 (w), 629 cm–1 (s).
Yield: 47 mg (180 μmol, 90%); 97% ee; colorless oil; Rf = 0.59
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –27.3 (c 0.83, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.32–7.25 (m, 4 H), 4.33 (s, 4 H ),
2.36 (s, 2 H), 2.11 (s, 3 H).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR (R)-3b = 9.7 min, (S)-3c = 10.8 min.
13C NMR (75 MHz, CDCl3): δ = 200.3, 135.3, 133.0, 128.7, 127.2,
106.6, 103.6, 62.5, 17.4.
HRMS (EI): m/z [M – CH3]+ calcd for C11H11ClO2: 209.0369;
found: 209.0370.
FT-IR (ATR): 3420 (br, m), 2963 (w), 2936 (w), 2874 (w), 1956
(w), 1734 (s), 1597 (w), 1493 (w), 1445 (w), 1369 (w), 1252 (m),
1169 (s), 1080 (m), 1069 (m), 979 (m), 759 (s), 692 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.39–7.20 (m, 5 H), 4.77 (s, 2 H),
4.23 (s, 2 H), 2.30 (t, 3J = 7.4 Hz, 2 H), 2.13 (s, 3 H), 2.14 (br s, 1
H), 1.63 (tq, 3J = 7.4 Hz, 2 H), 0.93 (t, 3J = 7.4 Hz, 3 H).
2-Hydroxymethyl-4-(2-naphthyl)penta-2,3-dien-1-ol (2g)
Yield: 148 mg (0.62 mmol, 62%); yellow solid; mp 94 °C; Rf = 0.22
(SiO2, cyclohexane–EtOAc, 1:1).
13C NMR (75 MHz, CDCl3): δ = 201.9, 173.9, 136.4, 128.5, 127.3,
126.0, 104.7, 103.0, 62.5, 61.6, 36.3, 18.5, 17.1, 13.8.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3789–3796

3794
M. Hammel, J. Deska
PAPER
Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C, 73.73; H,
7.75.
FT-IR (ATR): 3435 (br, m), 2965 (m), 2934 (w), 2876 (w), 1956
(w), 1734 (s), 1491 (w), 1458 (m), 1414 (m), 1371 (w), 1252 (m),
1167 (s), 1094 (s), 1011 (s), 827 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.33–7.24 (m, 4 H), 4.76 (s, 2 H),
4.23 (s, 2 H), 2.30 (t, 3J = 7.4 Hz, 2 H), 2.13 (br s, 1 H), 2.10 (s, 3
H), 1.63 (tq, 3J = 7.4 Hz, 2 H), 0.93 (t, 3J = 7.4 Hz, 3 H).
(R)-2-Hydroxymethyl-4-phenylhexa-2,3-dien-1-yl Butyrate (3c)
Yield: 46 mg (167 μmol, 84%); 94% ee; colorless oil; Rf = 0.59
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –29.2 (c 0.81, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR (R)-3c = 9.5 min, (S)-3b = 10.8 min.
13C NMR (75 MHz, CDCl3): δ = 201.7, 173.8, 134.8, 133.0, 128.5,
127.2, 103.8, 103.3, 62.2, 61.4, 36.1, 18.4, 17.0, 13.6.
FT-IR (ATR): 3453 (br, m), 2965 (m), 2934 (w), 2874 (w), 1953
(w), 1736 (s), 1597 (w), 1493 (w), 1456 (m), 1375 (w), 1252 (m),
1169 (s), 1080 (m), 1015 (m), 970 (m), 754 (s), 692 cm–1 (s).
Anal. Calcd for C16H19ClO3: C, 65.19; H, 6.50. Found: C, 64.92; H,
6.66.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.29 (m, 4 H), 7.24–7.20 (m,
1 H), 4.78 (s, 2 H), 4.23 (s, 2 H), 2.48 (t, 3J = 7.3 Hz, 2 H), 2.30 (t,
3J = 7.4 Hz, 2 H), 2.13 (br s, 1 H), 1.63 (tq, 3J = 7.4 Hz, 2 H), 1.12
(t, 3J = 7.3 Hz, 3 H), 0.93 (t, 3J = 7.4 Hz, 3 H).
(R)-2-Hydroxymethyl-4-(2-naphthyl)penta-2,3-dien-1-yl Bu-
tyrate (3g)
Yield: 42 mg (135 μmol, 67%); 82% ee; colorless oil; Rf = 0.55
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –23.1 (c 0.72, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 201.4, 173.8, 136.1, 128.4, 127.2,
126.1, 111.8, 105.1, 62.5, 61.6, 36.2, 23.1, 18.4, 13.6, 12.5.
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 255
nm; tR (R)-3g = 14.7 min, (S)-3g = 24.7 min.
FT-IR (ATR): 3395 (br, m), 3055 (w), 2963 (m), 2932 (w), 2874
(w), 1954 (w), 1734 (s), 1628 (s), 1599 (w), 1504 (w), 1456 (m),
1412 (w), 1371 (m), 1273 (m), 1169 (s), 1090 (m), 1013 (m), 856
(m), 817 (s), 746 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.83–7.74 (m, 4 H), 7.56–7.45 (m,
3 H), 4.83 (s, 2 H), 4.29 (s, 2 H), 2.32 (t, 3J = 7.4 Hz, 2 H), 2.29 (br
s, 1 H), 2.26 (s, 3 H), 1.65 (tq, 3J = 7.4 Hz, 2 H), 0.94 (t, 3J = 7.4 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 202.5, 174.0, 133.7, 133.6, 132.7,
128.2, 128.0, 127.7, 126.4, 126.1, 125.0, 124.0, 105.0, 103.4, 62.5,
61.7, 36.3, 18.5, 17.2, 13.8.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3 + Na: 333.1467;
found: 333.1469.
Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.08; H,
8.49.
(R)-2-Hydroxymethyl-4-phenylhepta-2,3-dien-1-yl Butyrate
(3d)
Yield: 44 mg (153 μmol, 76%); 74% ee; colorless oil; Rf = 0.62
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –17.3 (c 0.71, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (98:2), 1 mL/min, 245–
255 nm; tR (R)-3d = 18.8 min, (S)-3d = 20.3 min.
FT-IR (ATR): 3455 (br, m), 2961 (m), 2932 (w), 2872 (w), 1954
(w), 1736 (s), 1597 (w), 1493 (w), 1454 (m), 1379 (w), 1250 (m),
1169 (s), 1080 (m), 1016 (m), 970 (m), 758 (m), 692 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.39–7.29 (m, 4 H), 7.24–7.20 (m,
1 H), 4.77 (s, 2 H), 4.23 (s, 2 H), 2.44 (t, 3J = 7.4 Hz, 2 H), 2.31 (t,
3J = 7.4 Hz, 2 H), 2.13 (br s, 1 H), 1.64 (tq, 3J = 7.4 Hz, 2 H), 1.54
(tq, 3J = 7.4 Hz, 2 H), 0.99 (t, 3J = 7.3 Hz, 3 H), 0.93 (t, 3J = 7.4 Hz,
3 H).
(R)-2-Hydroxymethyl-4-(4-methoxyphenyl)penta-2,3-dien-1-yl
Butyrate (3h)
Yield: 42 mg (117 μmol, 59%); 75% ee; colorless oil; Rf = 0.51
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –2.4 (c 0.76, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 201.8, 173.9, 136.1, 128.6, 127.3,
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 264
nm: tR (R)-3h = 16.1 min, (S)-3h = 19.4 min.
126.3, 109.8, 104.2, 62.6, 61.8, 36.3, 32.3, 21.3, 18.5, 13.9, 13.8.
Anal. Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C, 74.51; H,
8.47.
FT-IR (ATR): 3435 (br, m), 2963 (m), 2936 (w), 2876 (w), 1955
(w), 1734 (s), 1607 (m), 1578 (w), 1510 (s), 1599 (w), 1458 (m),
1418 (w), 1369 (m), 1292 (m), 1244 (s), 1175 (s), 1030 (s), 970 (m),
829 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.30 (d, 3J = 8.2 Hz, 2 H), 6.86 (d,
3J = 8.4 Hz, 2 H), 4.76 (s, 2 H), 4.21 (s, 2 H), 3.80 (s, 3 H), 2.30 (t,
3J = 7.3 Hz, 2 H), 2.13 (br s, 1 H), 2.10 (s, 3 H), 1.64 (tq, 3J = 7.4 Hz,
2 H), 0.93 (t, 3J = 7.4 Hz, 3 H).
(R)-2-Hydroxymethyl-4-phenylocta-2,3-dien-1-yl Butyrate (3e)
Yield: 48 mg (158 μmol, 79%); 81% ee; colorless oil; Rf = 0.62
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –18.6 (c 0.74, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (98:2), 1 mL/min, 245–
255 nm; tR (S)-3e = 17.7 min, tR (R)-3e = 18.8 min.
FT-IR (ATR): 3455 (br, m), 2959 (m), 2932 (w), 2872 (w), 1954
(w), 1736 (s), 1597 (w), 1495 (w), 1457 (m), 1377 (w), 1250 (m),
1169 (s), 1078 (m), 1015 (m), 970 (m), 760 (m), 692 cm–1 (s).
13C NMR (75 MHz, CDCl3): δ = 201.3, 173.9, 159.1, 128.6, 127.2,
114.0, 104.4, 102.9, 62.7, 61.7, 55.4, 36.3, 18.5, 17.3, 13.8.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.29 (m, 4 H), 7.24–7.20 (m,
1 H), 4.77 (s, 2 H), 4.23 (s, 2 H), 2.46 (t, 3J = 7.2 Hz, 2 H), 2.31 (t,
3J = 7.4 Hz, 2 H), 2.11 (br s, 1 H), 1.64 (tq, 3J = 7.4 Hz, 2 H), 1.55–
1.34 (m, 4 H), 0.93 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 201.8, 174.0, 136.2, 128.6, 127.3,
126.3, 110.0, 104.2, 62.7, 61.7, 36.3, 30.1, 30.0, 22.5, 18.5, 14.1,
13.8.
Anal. Calcd for C17H22O4: C, 70.23; H, 7.64. Found: C, 69.82; H,
7.94.
(R)-2-Hydroxymethyl-4-methylundeca-2,3-dien-5-yn-1-yl Bu-
tyrate (3h)
Yield: 52 mg (186 μmol, 93%); 99% ee; colorless oil; Rf = 0.23
(SiO2, cyclohexane–Et2O, 7:3); [α]D20 –42.5 (c 0.91, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (97:3), 0.7 mL/min,
254 nm; tR (R)-3h = 10.8 min, (S)-3h = 11.9 min.
Anal. Calcd for C19H26O3: C, 75.46; H, 8.67. Found: C, 75.47; H,
8.67.
FT-IR (ATR): 3412 (br, m), 2931 (s), 2860 (m), 1958 (w), 1738 (s),
1458 (m), 1369 (m), 1246 (m), 1169 (s), 1092 (m), 1017 (s), 976 (s),
631 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 4.67 (s, 2 H), 4.14 (s, 2 H), 2.32
(t, 3J = 7.4 Hz, 2 H), 2.28 (t, 3J = 7.1 Hz, 2 H), 1.86 (s, 3 H), 1.65
(tq, 3J = 7.4 Hz, 2 H), 1.55–1.25 (m, 6 H), 0.94 (t, 3J = 7.4 Hz, 3 H),
0.89 (t, 3J = 7.1 Hz, 3 H).
(R)-4-(4-Chlorophenyl)-2-hydroxymethylpenta-2,3-dien-1-yl
Butyrate (3f)
Yield: 48 mg (163 μmol, 81%); 98% ee; colorless oil; Rf = 0.56
(SiO2, cyclohexane–EtOAc, 1:1); [α]D20 –28.2 (c 0.55, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (95:5), 1 mL/min, 245–
255 nm; tR (R)-3f = 11.4 min, (S)-3f = 12.9 min.
Synthesis 2012, 44, 3789–3796
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lipase-Catalyzed Desymmetrization of Prochiral Allenic Diols
3795
13C NMR (75 MHz, CDCl3): δ = 206.6, 173.7, 122.2, 101.3, 93.0,
89.6, 61.9, 61.2, 36.1, 31.1, 28.3, 22.2, 20.8, 19.5, 18.4, 13.9, 13.7.
Acknowledgment
Financial support by the Fonds der Chemischen Industrie is grate-
fully acknowledged.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3 + Na: 301.1774;
found: 301.1775.
Silver-Catalyzed Cycloisomerization; (R)-4-Hydroxymethyl-2-
methyl-2-phenyl-2,5-dihydrofuran (5)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Monobutyrate 3b (90.1 mg, 346 μmol, 97% ee) was dissolved in
acetone (1.0 mL) and a solution of AgNO3 (9.0 mg, 53 μmol) in
H2O (0.25 mL) was added. The reaction mixture was stirred for 37
h at 50 °C in the dark. After dilution with Et2O (10 mL), the organic
layer was washed with H2O (5 mL) and brine (5 mL), dried
(MgSO4), and concentrated in vacuo. The residue was redissolved
in MeOH (1.0 mL) and treated with 1 M aq NaOH (0.5 mL, 500
μmol) at r.t. for 1 h. The reaction mixture was extracted with Et2O
(3 × 5 mL), the combined organic layers were dried (MgSO4), and
concentrated in vacuo prior to purification of the alcohol 5 by col-
umn chromatography (SiO2, cyclohexane–EtOAc, 7:3); yield: 51.9
mg (273 μmol, 79%); 97% ee; colorless oil; Rf = 0.38 (SiO2, cyclo-
hexane–EtOAc, 1:1); [α]D20 +109.6 (c 0.47, CHCl3).
References
(1) (a) Koeller, K. M.; Wong, C.-H. Nature 2001, 409, 232.
(b) Faber, K. Biotransformations in Organic Chemistry, 5th
ed.; Springer: Berlin, 2008. (c) Gotor, V.; Alfonso, I.;
García-Urdiales, E. Asymmetric Organic Synthesis with
Enzymes; Wiley-VCH: Weinheim, 2008. (d) Drauz, K.;
Gröger, H.; May, O. Enzyme Catalysis in Organic Synthesis:
A Comprehensive Handbook, 3rd ed.; Wiley-VCH:
Weinheim, 2012.
(2) (a) Schmid, R. D.; Verger, R. Angew. Chem. Int. Ed. 1998,
37, 1608; Angew. Chem. 1998, 110, 1694 . (b) Bornscheuer,
U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis –
Regio- and Stereoselective Biotransformations, 2nd ed.;
Wiley-VCH: Weinheim, 2005.
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (98:2), 1 mL/min, 221
nm; tR (R)-4 = 24.7 min, (S)-4 = 26.5 min.
FT-IR (ATR): 3366 (br, m), 2972 (w), 2924 (w), 2853 (w), 2361
(w), 2332 (w), 1491 (w), 1445 (m), 1364 (w), 1242 (m), 1194 (w),
1163 (w), 1063 (m), 1024 (s), 864 (m), 759 (s), 698 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.43–7.23 (m, 5 H), 5.93 (s, 1 H),
4.77 (d, 2J = 12.0 Hz, 1 H), 4.69 (d, 2J = 12.0 Hz, 1 H), 4.26 (s, 2 H),
1.87 (br s, 1 H), 1.67 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 146.3, 139.1, 128.9, 128.3, 126.8,
124.6, 91.2, 74.3, 58.8, 28.4.
HRMS (EI): m/z [M – CH3]+ calcd for C11H11O2: 175.0759; found:
175.0760.
(3) (a) Klibanov, A. M. Nature 2001, 409, 241. (b) Reetz, M. T.
Curr. Opin. Chem. Biol. 2002, 6, 145.
(4) For examples of non-hydrolase activity by lipases, see:
(a) Torre, O.; Alfonso, I.; Gotor, V. Chem. Commun. 2004,
1724. (b) Svedendahl, M.; Hult, K.; Berglund, P. J. Am.
Chem. Soc. 2005, 127, 17988. (c) Carlqvist, P.; Svedendahl,
M.; Branneby, C.; Hult, K.; Brinck, T.; Berglund, P.
ChemBioChem 2005, 6, 331. (d) Li, C.; Feng, X.-W.; Wang,
N.; Zhou, Y.-J.; Yu, X.-Q. Green Chem. 2008, 10, 616.
(5) (a) Ramaswamy, S.; Hui, R. A. H. F.; Jones, J. B. J. Chem.
Soc., Chem. Commun. 1986, 1545. (b) Gil, G.; Ferre, E.;
Meou, A.; Le Petit, J.; Triantaphylides, C. Tetrahedron Lett.
1987, 28, 1647. (c) Jones, B. C. N. M.; Silverton, J. V.;
Simons, C.; Megati, S.; Nishimura, H.; Maeda, Y.; Mitsuya,
H.; Zemlicka, J. J. Med. Chem. 1995, 38, 1397. (d) Pietzsch,
M.; Vielhauer, O.; Pamperin, D.; Ohse, B.; Hopf, H. J. Mol.
Cat. B: Enzym. 1999, 6, 51. (e) Cipiciani, A.; Bellezza, F.
J. Mol. Cat. B: Enzym. 2002, 17, 261. (f) Carballeira, J. D.;
Krumlinde, P.; Bocola, M.; Vogel, A.; Reetz, M. T.;
Bäckvall, J.-E. Chem. Commun. 2007, 1913. (g) Deska, J.;
Bäckvall, J.-E. Org. Biomol. Chem. 2009, 7, 3379.
(h) Deska, J.; del Pozo Ochoa, C.; Bäckvall, J.-E. Chem.–
Eur. J. 2010, 16, 4447.
Iodocyclization; (S)-3-Iodo-2-methyl-2-phenyl-2,5-dihydrofu-
ran-4-ylmethyl Butyrate (6)
At 0 °C, N-iodosuccinimide (74.2 mg, 330 μmol) was added in
small portions to a solution of 3b (78.1 mg, 300 μmol, 97% ee) in
anhyd CH2Cl2 (1.5 mL). After 2 h at 0 °C, the reaction mixture was
diluted with EtOAc (5 mL) and the EtOAc layer was washed with
sat. aq NaHCO3 (5 mL), aq 1 M Na2S2O3 (5 mL), and brine (5 mL).
The organic layer was dried (Na2SO4), concentrated in vacuo and
the residue was purified by column chromatography (SiO2, cyclo-
hexane–EtOAc, 96:4); yield: 94.0 mg (243 μmol, 81%); 97% ee;
20
colorless oil; Rf = 0.37 (SiO2, cyclohexane–EtOAc, 9:1); [α]D
+68.5 (c 0.78, CHCl3).
HPLC: Chiralpak AD-H, n-hexane–i-PrOH (99:1), 1 mL/min, 225
nm; tR (S)-6 = 11.1 min, (R)-6 = 12.2 min.
(6) (a) Manzuna Sapu, C.; Bäckvall, J.-E.; Deska, J. Angew.
Chem. Int. Ed. 2011, 50, 9731; Angew. Chem. 2011, 123,
9905. (b) For a review on enzyme-catalyzed
FT-IR (ATR): 2965 (m), 2849 (m), 1735 (s), 1654 (w), 1445 (m),
1369 (m), 1342 (m), 1246 (m), 1165 (s), 1066 (m), 1043 (m), 958
(m), 759 (s), 739 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.47–7.29 (m, 5 H), 4.86 (d,
2J = 12.9 Hz, 1 H), 4.79 (d, 2J = 12.9 Hz, 1 H), 4.76 (s, 2 H), 2.34 (t,
3J = 7.4 Hz, 2 H), 1.76 (s, 3 H), 1.68 (tq, 3J = 7.4 Hz, 2 H), 0.97 (t,
3J = 7.4 Hz, 3 H).
desymmetrizations, see: García-Urdiales, E.; Ignacio, A.;
Gotor, V. Chem. Rev. 2005, 105, 313.
(7) (a) Rona, P.; Crabbé, P. J. Am. Chem. Soc. 1969, 91, 3289.
(b) Zelder, C.; Krause, N. Eur. J. Org. Chem. 2004, 3968.
(8) (a) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am.
Chem. Soc. 1985, 107, 2196. (b) Keinan, E.; Bosch, E.
J. Org. Chem. 1986, 51, 4006. (c) For a review on
palladium-catalyzed allenylation, see also: Tsuji, J.; Mandai,
T. Angew. Chem., Int. Ed. Engl. 1996, 34, 2589.
(9) (a) Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004. (b) Ma, S. Chem. Rev.
2005, 105, 2829. (c) Yu, S.; Ma, S. Angew. Chem. Int. Ed.
2012, 51, 3074; Angew. Chem. 2012, 124, 3128 .
13C NMR (75 MHz, CDCl3): δ = 173.3, 143.1, 138.4, 128.2, 127.9,
126.2, 101.8, 75.8, 62,3, 36.0, 24.9, 18.6, 13.8.
Anal. Calcd for C16H19IO3: C, 49.76; H, 4.96. Found: C, 50.17; H,
5.02.
HRMS (ESI): m/z [M + Na]+ calcd for C16H19IO3 + Na: 409.0271;
found: 409.0271.
(10) (a) Ma, S. Acc. Chem. Res. 2003, 36, 701. (b) Álvarez-
Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem.
Rev. 2008, 108, 3174. (c) Shen, H. C. Tetrahedron 2008, 64,
© Georg Thieme Verlag Stuttgart · New York
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3885. (d) Rudolph, M.; Hashmi, A. S. K. Chem. Commun.
2011, 47, 6536.
Obviously, even trace amounts of acid in the NMR solvent
seem to favor cyclization as signals of the corresponding
dihydrofuran appear as minor impurities in the NMR
spectra; see the Supporting Information.
(11) For Brønsted acid mediated cycloisomerization of allene
carboxylates, see: (a) Musierowicz, S.; Wróblewski, A. E.
Tetrahedron 1977, 34, 461. (b) Krause, N.; Laux, M.;
Hoffmann-Röder, A. Tetrahedron Lett. 2000, 41, 9613.
(12) Especially the anisyl derivatives 2h and 3h showed high
susceptibility to acid-catalyzed cycloisomerization.
(13) (a) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58,
7180. (b) Larivée, A.; Unger, J. B.; Thomas, M.; Wirtz, C.;
Dubost, C.; Handa, S.; Fürstner, A. Angew. Chem. Int. Ed.
2011, 50, 304; Angew. Chem. 2011, 123, 318 .
Synthesis 2012, 44, 3789–3796
© Georg Thieme Verlag Stuttgart · New York