Efficient asymmetric syntheses of (+)-strictifolione

Article abstract of DOI:10.1055/s-2004-822387

The asymmetric synthesis and a formal asymmetric synthesis of (+)-strictifolione are described. As key step in both approaches the Julia-Kocienski olefination to create an E-configured alkene was used. The anti-1,3-diol moiety was synthesized by employing

Full text of DOI:10.1055/s-2004-822387

1486
PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
Efficient
Asymme
i
tric Syn
e
theses of
(
t
e
tifolione r Enders,*a Achim Lenzen,a Michael Müllerb
a
Institut für Organische Chemie, RWTH Aachen, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
b
Institut für Biotechnologie 2, Forschungszentrum Jülich, 52425 Jülich, Germany
Received 29 April 2004
Dedicated to Professor Teruaki Mukaiyama on the occasion of his 77th birthday
Abstract: The asymmetric synthesis and a formal asymmetric syn-
thesis of (+)-strictifolione are described. As key step in both ap-
proaches the Julia–Kocienski olefination to create an E-configured
alkene was used. The anti-1,3-diol moiety was synthesized by em-
ploying a SAMP-hydrazone a,a¢-bisalkylation/deoxygenation pro-
tocol and the stereocentre of the lactone unit is based on an
enzymatic reduction with baker’s yeast. Alternatively, a lactone
precursor could be efficiently synthesized by a (S)-proline catalyzed
a-oxyamination of pent-4-enal.
OH OH
O
1
O
(+)-strictifolione
Key words: asymmetric synthesis, enzymatic reduction, hydra-
zones, natural products, organocatalysis
O
OH
O
2
(+)-Strictifolione (1, Figure 1) has been isolated by Aimi
et al. from the stem bark of Cryptocaria strictifolia in
West Kalimantan, Indonesia.1 Later, Takayama et al. were
able to determine its absolute configuration by an ‘ex-
chiral-pool’ synthesis.2 Shortly thereafter, a formal total
synthesis by Shibasaki et al.3 and an asymmetric total syn-
thesis by BouzBouz and Cossy4 were reported, which
O
kurzilactone
OH OH
O
3
O
mainly relied on synthetic methods developed by these
groups.
Figure 1 (+)-Strictifolione and related w-arylalkyl 6-substituted
5,6-dihydro-a-pyrones.
The main structural features of (+)-strictifolione (1) are an
anti-1,3-diol and a 6-substituted 5,6-dihydro-a-pyrone5
subunit, which are present in various natural products
with important biological activities, e.g. the polyene
macrolides6 and the leptomycin family7 of natural prod-
ucts, respectively. However, not much is known about the
biological activity of 1, a fact which is surprising if one
takes into account that structurally similar w-arylalkyl 6-
substituted 5,6-dihydro-a-pyrones like kurzilactone8 (2,
cytotoxic) and the lactone diol 39 (antifungal) have been
shown to be biologically active. A comparison of 1 and 3
indicates that the absolute configuration of the anti-1,3-
diol subunit might be crucial in this respect. New flexible
and efficient asymmetric syntheses of the title compound
are therefore desirable.
sulfone 6 and the aldehyde 7. The anti-1,3-diol subunit of
6 was planned to be built up starting from 2,2-dimethyl-
1,3-dioxan-5-one SAMP-hydrazone (9) by an a,a¢-double
alkylation protocol.
The asymmetric synthesis of sulfone 6 was carried out as
shown in Scheme 2. Successive alkylation of hydrazone 9
with (2-bromoethoxy)-tert-butyldimethylsilane and (2-io-
doethyl)-benzene according to our previously published
procedure12 yielded the SAMP-hydrazone 12, which was
virtually diastereomerically pure according to 13C NMR
spectroscopy (de ≥ 96%). Due to the proposed mechanism
for the alkylation of SAMP-hydrazones and the order of
the electrophiles used we assume the depicted E-geometry
concerning the C=N double bond.13 Cleavage of the hy-
drazone was easily accomplished utilizing sat. oxalic ac-
id.14 The dioxanone 13 was thus obtained in very good
yield over three steps (68%) with de, ee ≥ 96% (13C
NMR). As has been shown in previous cases,10 the most
suitable reaction sequence for the removal of the keto
group is a radical deoxygenation according to Barton and
McCombie, which was also applied to 13. Its reduction
with NaBH4 yielded a diastereomeric mixture of alcohols
14 (de = 6%), which was transformed to the correspond-
Since we have developed efficient asymmetric approach-
es to both the subunits mentioned above,10,11 we have cho-
sen 1 as an appropriate target in order to demonstrate their
applicability in natural product synthesis. Our retrosyn-
thetic analysis is depicted in Scheme 1 (route I and route
II). In route I the olefin 4 has to be constructed from the
SYNTHESIS 2004, No. 9, pp 1486–1496
x
x
.
x
x
.2
0
0
4
Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822387; Art ID: C03104SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
1487
CH2
CH2
Ph
Ph
Ph
OH OH
O
O
O
O
O
O
O
O
1
H3C CH3
H3C CH3
Oi-Pr
O
N
O
(+)-strictifolione
5
4
route II
route I
O
Ph
S
CH2
O
N
O
+
+
O
N
N
O
O
OTBS
Ph
8
Oi-Pr
H3C CH3
6
7
CH2
O
N
N
10
H3CO
O
O
H3C CH3
9
Scheme 1 Retrosynthetic analysis of (+)-strictifolione.
ing xanthates 15 in excellent yield (99% over two steps). novsky’s criteria.15 Cleavage of the TBS-protecting group
Reduction of 15 was then easily accomplished using of 16 with TBAF gave the primary alcohol 17 (93% over
Bu3SnH and a catalytic amount of AIBN in refluxing tol- two steps), which was converted to the corresponding io-
uene. This yielded the 1,3-dioxane 16 at which stage the dide 18 (84%), followed by a Williamson etherification to
relative orientation of both substituents of the 1,3-dioxane give sulfide 19 (99%). Finally, oxidation with MCPBA
ring could be proven to be trans according to Rych- yielded the desired sulfone 6 (87%).
OCH3
OCH3
OCH3
N
O
N
O
N
N
O
N
O
N
Ph
OTBDMS
OTBDMS
Ph
OTBDMS
a
b
c
O
O
O
O
O
H3C CH3
H3C CH3
H3C CH3
H3C CH3
12
11
13
(de ≥96%)
9
(de ≥96%)
(de, ee ≥96%)
d
R1
O
O
Ph
S
N
Ph
R2
Ph
OTBDMS
j
g
N
N
N
O
O
O
O
O
O
Ph
H3C CH3
H3C CH3
H3C CH3
14: R1 = OH
15: R1 = OC(=S)SCH3
16: R1 = H
17: R2 = OH
18: R2 = I
19: R2 = S(CN4)Ph
6
e
h
(de, ee ≥96%)
f
i
Scheme 2 Reagents and conditions: (a) t-BuLi, THF, –78 °C; Br(CH2)2OTBS, –100 °C→ r.t.; (b) t-BuLi, THF, –78 °C; Ph(CH2)2I, –100 °C
→ r.t., 71% over two steps; (c) sat. aq oxalic acid, Et2O, r.t., 96%; (d) NaBH4, MeOH, 0 °C; (e) NaH, THF, 0 °C; CS2; MeI, 0 °C → r.t., 99%
over two steps; (f) Bu3SnH, AIBN (cat.), toluene, reflux; (g) TBAF, THF, r.t., 93% over two steps; (h) Ph3P, imidazole, I2, Et2O–CH3CN, 0 °C,
84%; (i) 1-Phenyl-1H-tetrazole-5-thiol, NaH, THF–DMF, 0 °C; 18, 0 °C → r.t., 99%; (j) MCPBA, NaHCO3, CH2Cl2, r.t., 87%.
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

1488
D. Enders et al.
PAPER
The synthesis of the aldehyde 7 and the final stages of our pling reaction might be possible. The most obvious varia-
total synthesis are shown in Scheme 3. Swern oxidation of tion in this respect would be the employment of an open-
alcohol 21 (obtained with ee = 89% from the diketoester chain aldehyde instead of a cyclic one like 7. This idea is
20 according to ref.,11b,e the crucial step being an enzymat- outlined in our second retrosynthesis (Scheme 1, route II)
ic reduction with baker’s yeast) gave 7, which was cou- employing the protected a-hydroxy pentenal 8 as the cou-
pled with the sulfone 6 under Barbier-type reaction pling partner of sulfone 6 instead of 7. We thought that the
conditions (i.e. addition of the base to a mixture of sulfone a-silyloxy substituted aldehyde 8 might be obtainable via
and aldehyde). Whereas NaHMDS as base gave (E/Z)-4 in an (S)-proline catalyzed a-oxyamination of pent-4-enal
77% yield and with E/Z = 3.3:1 (according to GC), (10). Such enantioselective catalytic a-hydroxylations of
KHMDS led to a significantly improved E/Z-selectivity of aldehydes17 and ketones18 have recently been developed.
8.5:1 but slightly lower yield (61%). These observations
The realization of this concept is shown in Scheme 4. The
a-oxyamination of pent-4-enal (10) and in situ reduction
with NaBH4 gave the primary alcohol 22 with excellent
parallel those, which had been made by Kocienski et al.16
Both isomers could be separated by preparative HPLC
yielding pure (E)-4 in 52% yield (referring to the coupling
yield (92% over two steps) and enantioselectivity (ee
reaction). Compound (E)-4 could then be transformed to
≥ 98% according to HPLC).17a An enormous advantage in
the final natural product in two further steps. Firstly, both
this respect is the fact that the reaction can be scaled up
acetal protecting groups where cleaved with PPTS. The
easily, which allows for the synthesis of gram quantities
resulting lactol was finally oxidized with MnO2 to (+)-
of 22. Although various conditions for the N-O bond
strictifolione (1) in good yield (69% over two steps; de =
cleavage of 22 were tested, the yields of 23 remained un-
89% for the C6-epimers, ee ≥ 96%).
satisfactory. An explanation for this might be the high po-
larity of 23, which makes its extraction during an aqueous
O
O
O
workup quite difficult. In order to avoid an aqueous work-
up, we finally passed over to an in situ protection of 23.
After SmI2 mediated N-O bond cleavage19 (complete ac-
cording to TLC) the reaction mixture was simply evapo-
rated and subjected to conditions, which had been proven
to be satifactory for pure 23 (i.e. TBSCl, imidazole,
DMF). This ‘one-pot’ sequence gave 24 in moderate yield
(50% over two steps). The selective deprotection of the
primary alcohol in 24 turned out to be the next hurdle.
Among the different conditions tested, the HF·pyridine
complex served best for this purpose (57%).20 Swern oxi-
dation finally gave 8 (98%) without a detectable degree of
racemisation (vide infra).
Cl
Ot-Bu
20
ref.11b,e
a
HO
O
O
O
Oi-Pr
Oi-Pr
21
7
(de ≥98%, after HPLC;
b
ee = 89%)
Ph
O
O
O
H3C CH3
Oi-Pr
(E/Z)-4
c, d
Ph
OH OH
O
1
O
(de = 89%, ee ≥96%)
Scheme 3 Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2,
–78 °C; 21; Et3N, –78 °C → r.t.; (b) 6, DME, –(65–60) °C; base (see
text), –(65–60) °C → r.t. (yield, see text); (c) PPTS, acetone–H2O, r.t.;
(d) MnO2, CH2Cl2, r.t., 69% over two steps.
Scheme 4 Reagents and conditions: (a) (S)-proline (10 mol%),
PhNO, CHCl3, 0 °C; (b) NaBH4, MeOH, 0 °C, 92% over two steps;
(c) CuSO4·5H2O, MeOH, 0 °C → r.t., 28%; (d) SmI2, THF, r.t.; (e)
TBSCl, imidazole, DMF, r.t., 50% over two steps; (f) TBSCl, imida-
zole, DMF, r.t., 91%; (g) HF·pyridine, pyridine, THF, r.t., 57%; (h)
(COCl)2, DMSO, CH2Cl2, –78 °C; 25; Et3N, 0 °C, 98%.
Although we had succeeded in an asymmetric total syn-
thesis of the target molecule in quite a convincing manner
[16% yield (including HPLC) over 13 linear steps; de =
89% for the C6-epimers, ee ≥ 96%], we felt that a further
improvement concerning the E/Z-selectivity in the cou-
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
1489
KH2PO4 (34.0 g) and NaOH (5.82 g) in H2O (500 mL). Distilled sol-
vents were used for column chromatography and reaction workup.
Column chromatography was carried out under pressure using
Merck silica gel 60, particle size 0.040–0.063 mm. Analytical TLC
was performed using precoated, glass backed plates (Merck silica
gel 60 F254) and visualized by either UV radiation or acidic ammo-
nium molybdate(IV). (2-Bromoethoxy)-tert-butyldimethyl-si-
lane,21 2,2-dimethyl-1,3-dioxan-5-one SAMP-hydra-zone (9)12 and
tert-butyl 6-chloro-3,5-dioxohexanoate (20)11b were prepared ac-
cording to the published procedures.
Coupling of sulfone 6 and aldehyde 8 under the same con-
ditions as described above (Barbier-type reaction condi-
tions; KHMDS, DME, –60 °C → r.t.) gave 26 as a single
isomer according to 13C NMR spectroscopy with good
yield (69%) (Scheme 5). In contrast to that, Grignard-type
reaction conditions (i.e. metalation of the sulfone before
the addition of the aldehyde) led to a diminished yield of
only 26%, probably due to self-condensation of the meta-
lated sulfone.16
Optical rotations were measured with a Perkin-Elmer P 241 pola-
rimeter. IR spectra were recorded on a Perkin-Elmer 1760 FT spec-
The fact that 26 was detected as a single isomer does not
only show that the coupling reaction proceeds with a very
high degree of E-selectivity but also that the Swern oxida-
tion, employed for the synthesis of 8, was not accompa-
1
trophotometer. H and 13C NMR spectra were recorded on Varian
Gemini 300, Mercury 300 and Inova 400 spectrometers using TMS
as reference. J values are given in Hz. Mass spectra were obtained
nied by racemization. Cleavage of the TBS-protecting on a Finnigan SSQ 7000 spectrometer (CI 100 eV; EI 70 eV) and
HRMS spectra on a Finnigan MAT 95. Microanalyses were per-
formed on a Heraeus CHN-O-RAPID element analyzer.
group and esterification with acryloyl chloride gave 5
(91% over two steps), an intermediate that had been de-
scribed already by BouzBouz and Cossy in their total syn-
General Workup Procedure
Unless stated otherwise, the reaction workup always followed the
thesis of the title compound.4 Our synthesis of 5 (28%
yield over 13 linear steps; de, ee ≥ 96%) therefore repre-
sents a formal synthesis of (+)-strictifolione (1).
same procedure: After the reaction had been quenched (typically
with sat. aq NaHCO3 or pH 7 buffer), the phases were separated.
The aqueous phase was extracted with an organic solvent for sever-
al times (typically Et2O or CH2Cl2), after which the combined or-
ganic fractions were dried over a drying agent (typically MgSO4).
Subsequent filtration through a pad of glass wool and evaporation
of the volatiles resulted in a residue, which was either purified by
column cromatography or used as such for the next step. This work-
up procedure is summarized in the form: (quenching agent; solvent
used for extraction; drying agent).
CH2
O
OTBS
8
a
CH2
Ph
{(S)-4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-2,2-dimethyl-
[1,3]dioxan-(5E/Z)-ylidene}-[(S)-2-methoxymethylpyrrolodin-
1-yl]-amine (11)
O
O
OTBS
A solution of 9 (1.504 g, 6.2 mmol, 1 equiv) in THF (25 mL) was
cooled to –78 °C. t-BuLi (4.6 mL of a 1.6 N solution in pentane, 6.8
mmol, 1.1 equiv) was slowly added and the solution was stirred for
2 h at that temperature. After the solution had been cooled down to
–100 °C, (2-bromoethoxy)-tert-butyldimethylsilane (1.633 g, 6.8
mmol, 1.1 equiv), dissolved in THF (2 mL), was slowly added. Stir-
ring at –100 °C was continued for 2 h after which the solution was
allowed to warm to r.t. overnight. Workup (pH 7 buffer; Et2O;
MgSO4) yielded crude 11 as a mixture of E- and Z-isomers concern-
ing the C=N double bond. It could be used as such for the next step
without further purification. An analytical sample of (E)-11 was ob-
tained after standing at 4 °C for 2 d and flash column chromatogra-
H3C CH3
26
b, c
ref. 4
CH2
CH2
Ph
1
O
O
O
O
2 steps
H3C CH3
5
phy (n-pentane–Et2O, 6:1, 2% Et3N).; colorless oil; de ≥ 96% by 13
C
(de, ee ≥96%)
NMR; [a]D23 +98.3 (c = 2.10, acetone) {ref.10c, [a]D23 +78.7 (c = 2.0,
Scheme 5 Reagents and conditions: (a) 6, DME, –(65–60) °C;
KHMDS, –(65–60) °C → r.t., 69%; (b) TBAF, THF, r.t.; (c) acryloyl
chloride, Eti-Pr2N, CH2Cl2, –78 °C, 91% over two steps.
acetone)}.
1H NMR (400 MHz, CDCl3): d = 0.05 (s, 3 H, CH3SiCH3), 0.06 (s,
3 H, CH3SiCH3), 0.09 [s, 9 H, C(CH3)3], 1.38 (s, 3 H, CH3CCH3),
1.39 (s, 3 H, CH3CCH3), 1.60–1.70 (m, 2 H, CHHCH2OTBS, NCH-
CHH), 1.83 (m, 2 H, NCH2CH2), 1.96–2.04 (m, 1 H, NCHCHH),
2.20 (m, 1 H, CHHCH2OTBS), 2.40 (q, J = 8.4 Hz, 1 H, NCHH),
In summary, we have presented efficient asymmetric syn-
theses of (+)-strictifolione by employing a SAMP-hydra-
zone a,a¢-bisalkylation/deoxygenation protocol for the 3.03 (m, 1 H, NCHH), 3.23 (dd, J = 9.1, 7.4 Hz, 1 H, CHHOCH3),
3.28–3.34 (m, 1 H, NCH), 3.35 (s, 3 H, OCH3), 3.43 (dd, J = 9.1,
synthesis of anti-1,3-diols on the one hand and an enzy-
3.9 Hz, 1 H, CHHOCH3), 3.71–3.80 (m, 2 H, CH2OTBS), 4.14 (dd,
matic reduction with baker’s yeast for the synthesis of the
J = 15.8, 1.8 Hz, 1 H, CHHC=N), 4.50 (d, J = 15.7 Hz, 1 H,
d-lactone moiety on the other hand. Moreover we have de-
CHHC=N), 4.54 (m, 1 H, CHC=N).
scribed the application of the recently developed organo-
catalytic enantioselective a-oxyamination of aldehydes in
13C NMR (100 MHz, CDCl3): d = –5.3 [Si(CH3)2)], 18.3 [C(CH3)3],
22.7 (NCH2CH2), 24.1 [C(CH3)2], 25.9 [C(CH3)3], 26.7 (NCHCH2),
natural product synthesis.
35.0 (CH2CH2OTBS), 55.3 (NCH2), 58.9 (CH2OTBS), 59.1
(OCH3), 59.7 (CH2C=N), 66.6 (NCH), 67.0 (CHC=N), 75.5
(CH2OCH3), 100.1 [C(CH3)2], 162.7 (C=N).
Reactions were carried out at r.t. under Ar using anhyd solvents un-
less otherwise stated. Phosphate buffer (pH 7) was a solution of
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

1490
D. Enders et al.
PAPER
MS (EI): m/z (%) = 400 (5) [M+], 356 (16), 355 (65) [M+
–
to give 13; yield: 1.652 g (96%); colorless oil which solidifies upon
standing at –20 °C; de, ee ≥ 96% by 13C NMR; [a]D28 –154.8 (c =
1.07, CHCl3).
CH2OCH3], 342 (16) [M+ – CH3COCH3], 297 (34) [M+ – CH2OCH3
– CH3COCH3], 184 (58), 139 (44), 131 (22), 105 (20), 101 (25), 98
(100), 89 (16), 75 (17), 73 (27), 71 (12), 70 (60), 59 (12), 45 (12).
IR (film): 3063 (w), 3028 (m), 2987 (s), 2931 (vs), 2859 (vs), 2741
(w), 1745 (vs), 1604 (w), 1497 (w), 1466 (m), 1379 (s), 1322 (w),
1253 (vs), 1230 (vs), 1176 (s), 1096 (vs, br), 1048 (m), 1009 (w),
955 (m), 836 (vs), 778 (s), 747 (m), 700 (s), 662 (w), 555 (w), 524
(w), 494 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.87 [s, 9
H, C(CH3)3], 1.41 (s, 3 H, CH3CCH3), 1.46 (s, 3 H, CH3CCH3), 1.65
(m, 1 H, CHHCH2OTBS), 1.86 (m, 1 H, PhCH2CHH), 2.09 (m, 1
H, CHHCH2OTBS), 2.20 (m, 1 H, PhCH2CHH), 2.68 (dt, J = 13.7,
8.2 Hz, 1 H, PhCHH), 2.80 (ddd, J = 13.7, 8.8, 5.0 Hz, 1 H, Ph-
CHH), 3.65–3.74 (m, 2 H, CH2OTBS), 4.14 [ddd, J = 9.3, 3.4, 1.2
Hz, 1 H, Ph(CH2)2CH], 4.42 [ddd, J = 7.7, 3.8, 1.1 Hz, 1 H,
CH(CH2)2OTBS], 7.16–7.21 (m, 3 H, PhH), 7.25–7.30 (m, 2 H,
PhH).
13C NMR (100 MHz, CDCl3): d = –5.4 [Si(CH3)2)], 18.2 [C(CH3)3],
24.0 (CH3CCH3), 24.2 (CH3CCH3), 25.9 [C(CH3)3], 30.3
(PhCH2CH2), 31.0 (PhCH2), 32.0 (CH2CH2OTBS), 58.3
(CH2CH2OTBS), 70.8 [CH(CH2)2OTBS], 73.0 [Ph(CH2)2CH],
101.0 [C(CH3)2], 125.8 (p-PhC), 128.2, 128.5 (o-PhC, m-PhC),
141.0 (i-PhC), 211.6 (C=O).
Other spectroscopic data are in accordance with previously pub-
lished data.10c
{(4S,6S)-4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-2,2-dimeth-
yl-6-phenethyl-[1,3]dioxan-(5E)-ylidene}-[(S)-2-methoxymeth-
ylpyrrolidin-1-yl]-amine (12)
Crude 11 thus obtained was dissolved in THF (25 mL) and cooled
to –78 °C. t-BuLi (4.6 mL of a 1.6 N solution in pentane, 6.8 mmol,
1.1 equiv) was slowly added and the solution was stirred for 2 h at
that temperature. After the solution had been cooled to –100 °C, (2-
iodoethyl)-benzene (1.584 g, 6.8 mmol, 1.1 equiv), dissolved in
THF (2 mL), was slowly added. Stirring at –100 °C was continued
for 2 h after which the solution was allowed to warm to r.t. over-
night. Workup (pH 7 buffer; Et2O; MgSO4) and column chromatog-
raphy (n-pentane–Et2O, 30:1, 2% Et3N) provided 12; yield: 2.217 g
(71% over two steps); colorless oil; de ≥ 96% by 13C NMR; [a]D
27
+43.9 (c = 1.02, CHCl3).
IR (film): 3062 (w), 3026 (m), 2931 (vs), 2860 (vs), 2736 (w), 1603
(w), 1497 (w), 1460 (s), 1376 (s), 1330 (w), 1251 (s), 1221 (s), 1163
(m), 1106 (vs), 1052 (s), 1008 (m), 954 (m), 837 (vs), 777 (s), 748
(m), 701 (m), 662 (w), 528 (w), 495 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06 [s, 6 H, Si(CH3)3], 0.90 [s, 9
H, C(CH3)3], 1.33 (s, 3 H, CH3CCH3), 1.42 (s, 3 H, CH3CCH3),
1.51–1.63 (m, 2 H, CHHCH2OTBS, NCHCHH), 1.71 (m, 2 H,
NCH2CH2), 1.99 (m, 2 H, CHHCH2OTBS, PhCH2CHH), 2.10 (m,
1 H, NCHCHHCH2), 2.22 (q, J = 8.3 Hz, 1 H, NCHH), 2.42 (m, 1
H, PhCH2CHH), 2.67–2.72 (m, 2 H, PhCH2), 2.77 (m, 1 H, NCHH),
3.19 (dd, J = 8.8, 8.0 Hz, 1 H, CHHOCH3), 3.27 (m, 1 H, NCH),
3.33 (s, 3 H, OCH3), 3.47 (dd, J = 8.8, 3.8 Hz, 1 H, CHHOCH3),
3.69–3.80 (m, 2 H, CH2OTBS), 4.36 [br d, J = 7.4 Hz, 1 H,
MS (EI): m/z (%) = 335 (10) [M+ – t-Bu], 278 (17), 277 (82) [M+ –
TBS], 259 (18), 247 (31), 207 (12), 201 (17), 185 (26), 157 (16),
147 (40), 146 (12), 145 (13), 144 (13), 143 (37), 134 (11), 133 (100)
[Ph(CH2)2CO+], 131 (66), 129 (15), 118 (31), 117 (40), 115 (11),
+
+
105 (82) [Ph(CH2)2 ], 101 (26), 91 (76) [C7H7 ], 85 (30), 75 (33),
73 (24), 59 (26), 57 (10), 55 (21).
MS (CI, iso-butane): m/z (%) = 394 (28), 393 (100) [MH+], 376
(10), 375 (33), 335 (28) [MH+ – CH3COCH3].
Anal. Calcd for C22H36O4Si (392.60): C, 67.30; H, 9.24. Found C,
67.24; H, 9.25.
Ph(CH2)2CH)], 4.54 [ddd,
J = 8.0, 4.5, 1.3 Hz, 1 H,
CH(CH2)2OTBS], 7.15–7.22 (m, 3 H, PhH), 7.25– 7.29 (m, 2 H,
PhH).
(4S,6S)-4-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-2,2-dimeth-
yl-6-phenethyl-[1,3]dioxan-5-ol (14)
13C NMR (100 MHz, CDCl3): d = –5.3 (CH3SiCH3), –5.2
(CH3SiCH3), 18.3 [C(CH3)3], 22.6 (NCH2CH2), 24.5 (CH3CCH3),
26.0 [C(CH3)3], 26.5 (CH3CCH3), 27.0 (CH2CH2OTBS), 29.1
(PhCH2CH2), 31.1 (PhCH2), 33.6 (NCHCH2CH2), 52.6 (NCH2),
59.0 (OCH3), 59.3 (CH2OTBS), 66.6, 66.7 [NCH,
CH(CH2)2OTBS], 69.6 [Ph(CH2)2CH], 76.0 (CH2OCH3), 100.0
[C(CH3)2], 125.6 (p-PhC), 128.0, 128.5 (o-PhC, m-PhC), 141.8 (i-
PhC), 161.3 (C=N).
Ketone 13 (1.652 g, 4.2 mmol, 1 equiv) was dissolved in MeOH (40
mL) and cooled to 0 °C (no Ar). NaBH4 (0.318 g, 8.4 mmol, 2
equiv) was added in one portion and stirring was continued for 2 h
after which TLC revealed complete consumption of the starting ma-
terial. The solvent was evaporated and the residue taken up in a mix-
ture of CH2Cl2 and pH 7 buffer. The phases were separated and the
aqueous phase was extracted with CH2Cl2. The organic extracts
were combined and dried over MgSO4. The mixture was filtered
through a pad of glass wool and the solvent evaporated. The crude
product thus obtained could be used for the next step without further
purification. An analytical sample of the mixture of diastereomeric
alcohols 14 was obtained by column chromatography (n-pentane–
Et2O, 3:1); colorless oil; de 6% by GC.
MS (EI): m/z (%) = 504 (20) [M+], 460 (34), 459 (100) [M+
–
CH2OCH3], 447 (26), 446 (76) [M+ – CH3COCH3], 402 (23), 401
(72) [M+ – CH2OCH3 – CH3COCH3], 342 (11), 332 (21), 313 (10),
297 (18), 288 (32), 259 (11), 243 (30), 202 (18), 198 (35), 144 (13),
131 (21), 117 (21), 116 (13), 115 (13), 114 (20), 101 (14), 91 (52)
+
IR (CHCl3): 3464 (br s), 3063 (m), 3027 (m), 2987 (s), 2932 (vs),
2859 (vs), 2740 (w), 1604 (w), 1497 (m), 1464 (s), 1380 (s), 1252
(vs), 1228 (vs), 1167 (s), 1091 (vs, br), 1036 (s), 959 (s), 837 (vs),
778 (s), 750 (s), 701 (s), 664 (w), 527 (w), 495 (w) cm–1.
[C7H7 ], 89 (22), 73 (31), 70 (55), 59 (25), 45 (16).
Anal. Calcd for C28H48N2O4Si (504.78): C, 66.62; H, 9.58; N, 5.55.
Found C, 66.76; H, 9.58; N, 6.00.
(4S,6S)-4-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-2,2-dimeth-
yl-6-phenethyl-[1,3]dioxan-5-one (13)
Diastereomer 1
1H NMR (300 MHz, CDCl3): d = 0.08 [s, 6 H, Si(CH3)2], 0.90 [s, 9
H, C(CH3)3], 1.32 (s, 3 H, CH3CCH3), 1.40 (s, 3 H, CH3CCH3),
1.75–2.05 (m, 4 H, PhCH2CH2, CH2CH2OTBS), 2.63 (d, J = 5.4 Hz,
1 H, OH), 2.64–2.71 (m, 1 H, PhCHH), 2.76–2.87 (m, 1 H, Ph-
CHH), 3.55 (m, 1 H), 3.64 (m, 1 H), 3.74–3.83 [m, 3 H,
Ph(CH2)2CH, CHOH, CH(CH2)2OTBS, CH2OTBS], 7.16–7.31 (m,
5 H, PhH).
SAMP-hydrazone 12 (2.217 g, 4.4 mmol) was dissolved in Et2O (50
mL) and stirred vigorously with a sat. aq solution of oxalic acid (20
mL) for 4 h (TLC control; no Ar). The aqueous layer was separated,
extracted with Et2O and the organic extracts were combined and
washed with pH 7 buffer. After re-extraction of the buffer solution
with Et2O all ethereal portions were combined and dried over
MgSO4. The mixture was filtered through a pad of glass wool and
the crude product obtained after evaporation of the solvent was pu-
rified by column chromatography (n-pentane–Et2O, 45:1 → 40:1)
13C NMR (75 MHz, CDCl3): d = –5.4 [Si(CH3)2)], 18.2 [C(CH3)3],
24.2 (CH3CCH3), 24.6 (CH3CCH3), 25.9 [C(CH3)3], 30.4, 31.9,
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
1.61–1.67 (m, H, CH2CH2OTBS), 1.89–1.99 (m,
1491
H,
37.0 (PhCH2CH2, PhCH2, CH2CH2OTBS), 60.0 (CH2OTBS), 69.9,
2
2
73.0, 74.7 [CH(CH2)2OTBS,
[C(CH3)2], 125.8 (p-PhC), 128.3, 128.5 (o-PhC, m-PhC), 142.1
(i-PhC).
Ph(CH2)2CH, CHOH], 100.9
PhCH2CH2), 2.54 (s, 3 H, SCH3), 2.59–2.68 (m, 1 H, PhCHH),
2.77–2.87 (m, 1 H, PhHH), 3.65 (m, 2 H, CH2OTBS), 3.75 [m, 1 H,
Ph(CH2)2CH], 4.27 [m, 1 H, CH(CH2)2OTBS], 5.90 (dd, J = 6.9,
3.7 Hz, 1 H, CHOC=S), 7.16–7.29 (m, 5 H, PhH).
Diastereomer 2
13C NMR (75 MHz, CDCl3): d = –5.4 [Si(CH3)2], 18.2 [C(CH3)3],
19.1 (SCH3), 24.1 (CH3CCH3), 24.6 (CH3CCH3), 25.9 (C(CH3)3),
31.4, 32.1, 34.7 (PhCH2CH2, PhCH2, CH2CH2OTBS), 58.6
(CH2OTBS), 66.5, 70.2 [CH(CH2)2OTBS, Ph(CH2)2CH], 84.8
(CHOC=S), 101.2 [C(CH3)2], 125.9 (p-PhC), 128.4, 128.5 (o-PhC,
m-PhC), 141.6 (i-PhC), 216.6 (CS2).
MS (EI): m/z (%) = 469 (0.5) [M+ – CH3], 427 (1.5) [M+ – t-Bu],
369 (18) [M+ – TBS], 262 (20), 261 (100) [M+ – TBS – COS –
CH3SH], 244 (20), 165 (14), 157 (14), 131 (13), 117 (17), 105 (18),
91 (44), 89 (12), 75 (18), 73 (17).
MS (CI, iso-butane): m/z (%) = 485 (31) [MH+], 429 (17), 428 (28),
427 (100) [MH+ – CH3COCH3], 395 (21), 379 (10), 377 (32) [MH+
– COS – CH3SH], 320 (12), 319 (44) [MH+ – COS – CH3SH –
CH3COCH3].
1H NMR (300 MHz, CDCl3): d = 0.08 [s, 6 H, Si(CH3)2], 0.89 [s, 9
H, C(CH3)3], 1.35 (s, 3 H, CH3CCH3), 1.37 (s, 3 H, CH3CCH3),
1.70–1.91 (m,
2 H), 1.95–2.14 (m, 2 H) (PhCH2CH2,
CH2CH2OTBS), 2.60–2.71 (m, 1 H, CHHCH2OTBS), 2.80–2.91
(m, 1 H, CHHCH2OTBS), 3.13 (d, J = 4.2 Hz, 1 H, OH), 3.50–3.57
(m, 2 H), 3.64 (dt, J = 1.9, 10.3 Hz, 1 H), 3.79–3.85 (m, 1 H), 3.90
[m, 1 H, Ph(CH2)2CH, CHOH, CH(CH2)2OTBS, CH2OTBS], 7.15–
7.30 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = –5.6 [Si(CH3)2], 18.2 [C(CH3)3],
24.1 (CH3CCH3), 24.6 (CH3CCH3), 25.8 [C(CH3)3], 31.8, 32.1,
35.6 (PhCH2CH2, PhCH2, CH2CH2OTBS), 60.1 (CH2OTBS), 70.6,
72.7, 74.3 [CH(CH2)2OTBS, Ph(CH2)2CH, CHOH], 100.7
[C(CH3)2], 125.7 (p-PhC), 128.3, 128.5 (o-PhC, m-PhC), 142.2
(i-PhC).
MS (EI): m/z (%) = 394 (1) [M+], 379 (8) [M+ – CH3], 336 (15) [M+
– CH3COCH3], 279 (18) [M+ – TBS], 262 (26), 261 (61) [M+ – TBS
– H2O], 202 (20), 189 (45), 187 (20), 169 (22), 157 (10), 146 (12),
145 (100), 131 (63), 117 (33), 115 (21), 105 (27), 101 (11), 92 (25),
91 (30), 89 (16), 75 (31), 73 (14), 59 (31).
Anal. Calcd for C24H40O4S2Si (484.79): C, 59.46; H, 8.32. Found C,
59.59; H, 8.28.
tert-Butyl-{2-[(4S,6S)-2,2-dimethyl-6-phenethyl-[1,3]dioxan-4-
yl]-ethoxy}-dimethylsilane (16)
Bu3SnH (5.6 mL, 21.1 mmol, 5 equiv) was dissolved in toluene
(130 mL) and heated to reflux. Then, a solution of xanthate 15
(2.033 g, 4.2 mmol, 1 equiv) in toluene (13 mL) and a sat. solution
of AIBN in toluene (0.8 mL) were added to the reaction mixture
over a time period of 2 h. After complete addition of both solutions
stirring was continued under reflux for 1 h. All volatiles were re-
moved in vacuo and the residue was directly subjected to column
chromatography: The excess of Bu3SnH was first eluted with n-pen-
tane (the tin compound was easily detected by UV radiation) after
which the column was flushed with Et2O. Evaporation of the ethe-
real fractions gave crude 16, which could be used for the next step
without further purification. An analytical sample of 16 was ob-
tained by column chromatography (n-pentane–Et2O = 25:1); color-
less oil; [a]D23 +10.1 (c = 1.04, CHCl3).
Anal. Calcd for C22H38O4Si (394.62): C, 66.96; H, 9.71. Found C,
66.85; H, 9.64.
Dithiocarbonic Acid {(4S,6S)-4-[2-(tert-Butyldimethylsilanyl-
oxy)-ethyl]-2,2-dimethyl-6-phenethyl-[1,3]di-oxan-5-yl} Ester
Methyl Ester (15)
The crude alcohol 14 thus obtained was dissolved in THF (10 mL)
and added to a suspension of NaH (0.337 g of a 60% suspension in
mineral oil, 8.4 mmol, 2 equiv) in THF (30 mL) at 0 °C. After 30
min CS2 (0.89 mL, 14.7 mmol, 3.5 equiv) was added and 30 min lat-
er MeI (0.79 mL, 12.7 mmol, 3 equiv) was added to the reaction
mixture. From this moment stirring was continued at r.t. until TLC
indicated complete conversion of the starting material (about 2 h).
Workup (pH 7 buffer; Et2O; MgSO4) and column chromatography
(n-pentane–Et2O = 50:1 → 45:1 → 40:1) gave 15; yield: 2.033 g
(99% over two steps); yellow oil.
IR (CHCl3): 3063 (w), 3027 (m), 2986 (s), 2934 (vs), 2859 (vs),
2739 (w), 1604 (w), 1496 (m), 1464 (s), 1380 (s), 1252 (vs), 1225
(vs), 1171 (s), 1096 (vs), 1035 (m), 1010 (m), 960 (s), 837 (vs), 777
(s), 753 (m), 700 (m), 662 (w), 526 (w), 496 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.04 [s, 6 H, Si(CH3)2)], 0.89 [s, 9
H, C(CH3)3], 1.33 (s, 3 H, CH3CCH3), 1.36 (s, 3 H, CH3CCH3),
1.56–1.92 (m, 6 H, CH2CH2OTBS, OCHCH2CH, PhCH2CH2),
2.56–2.66 (m, 1 H, PhCHH), 2.72–2.81 (m, 1 H, PhCHH), 3.66 (m,
2 H, CH2OTBS), 3.77 [m, 1 H, Ph(CH2)2CH], 3.99 [m, 1 H,
CH(CH2)2OTBS], 7.15–7.29 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = –5.3 [Si(CH3)2], 18.3 [C(CH3)3],
24.9 [C(CH3)2], 25.9 [C(CH3)3], 31.7, 37.5, 38.8, 39.0
(OCHCH2CH, CH2CH2OTBS, PhCH2CH2, PhCH2), 59.3
(CH2OTBS), 63.4, 65.8 [CH(CH2)2OTBS, Ph(CH2)2CH], 100.3
[C(CH3)2], 125.8 (p-PhC), 128.3, 128.5 (o-PhC, m-PhC), 142.1
(i-PhC).
MS (EI): m/z (%) = 363 (20) [M+ – CH3], 264 (14), 263 (84) [M+ –
TBS], 171 (71), 143 (14), 131 (100), 129 (64), 117 (46), 115 (12),
105 (45), 101 (30), 91 (71), 89 (32), 75 (41), 73 (29), 59 (32), 57
(19), 45 (12).
IR (CHCl3): 3062 (w), 3026 (w), 2987 (m), 2952 (s), 2931 (s), 2858
(s), 1496 (w), 1463 (m), 1427 (w), 1381 (m), 1252 (s), 1208 (vs),
1132 (m), 1091 (s), 1057 (vs), 1009 (m), 962 (m), 884 (m), 837 (s),
777 (m), 700 (w), 664 (w) cm–1.
Diastereomer 1
1H NMR (300 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.88 [s, 9
H, C(CH3)3], 1.32 (s, 3 H, CH3CCH3), 1.44 (s, 3 H, CH3CCH3),
1.64–1.88 (m, 4 H, PhCH2CH2, CH2CH2OTBS), 2.56 (s, 3 H,
SCH3), 2.57–2.65 (m, 1 H, PhCHH), 2.76–2.85 (m, 1 H, PhHH),
3.65 (dd, J = 7.4, 4.7 Hz, 2 H, CH2OTBS), 3.91–4.01 [m, 2 H,
Ph(CH2)2CH, CH(CH2)2OTBS], 5.88 (dd, J = 7.2, 4.0 Hz, 1 H,
CHOC=S), 7.16–7.30 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = –5.4 [Si(CH3)2], 18.2 [C(CH3)3],
19.0 (SCH3), 24.1 (CH3CCH3), 24.7 (CH3CCH3), 25.9 [C(CH3)3],
30.4, 31.6, 36.2 (PhCH2CH2, PhCH2, CH2CH2OTBS), 58.6
(CH2OTBS), 67.4, 69.3 [CH(CH2)2OTBS, Ph(CH2)2CH], 84.5
(CHOC=S), 101.2 [C(CH3)2], 125.9 (p-PhC), 128.4, 128.6 (o-PhC,
m-PhC), 141.5 (i-PhC).
MS (CI, iso-butane): m/z (%) = 380 (29), 379 (100) [MH+], 322
(13), 321 (56) [MH+ – CH3COCH3], 303 (13), 263 (11).
Diastereomer 2
1H NMR (300 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.89 [s, 9
H, C(CH3)3], 1.37 (s, 3 H, CH3CCH3), 1.40 (s, 3 H, CH3CCH3),
Anal. Calcd for C22H38O3Si (378.62): C, 69.79; H, 10.12. Found C,
69.64; H, 9.91.
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

1492
D. Enders et al.
PAPER
2-{(4S,6S)-2,2-Dimethyl-6-phenethyl-[1,3]dioxan-4-yl}-ethanol
(17)
Anal. Calcd for C16H23IO2 (374.26): C, 51.35; H, 6.19. Found C,
51.68; H, 6.39.
The crude TBS-ether 16 thus obtained was dissolved in THF (20
mL; no Ar). TBAF (8 mL of a 1 M solution in THF, 8.0 mmol, 1.9
equiv) was added and the solution was stirred until complete con-
sumption of starting material (about 5 h). Workup of the reaction
(pH 7 buffer; Et2O; MgSO4) and column chromatography (n-pen-
tane–Et2O, 1:1) gave 17; yield: 1.035 g (93% over two steps); col-
5-{2-[(4R,6S)-2,2-Dimethyl-6-phenethyl-[1,3]dioxan-4-yl]-eth-
ylsulfanyl}-1-phenyl-1H-tetrazole (19)
NaH (0.222 g of a 60% suspension in mineral oil, 5.6 mmol, 1.8
equiv) was suspended in a mixture of THF (30 mL) and DMF (5
mL) and cooled to 0 °C. 1-Phenyl-1H-tetrazole-5-thiol (1.101 g, 6.2
mmol, 2 equiv), dissolved in THF (15 mL), was slowly added. After
complete addition, the ice-bath was removed and the solution
stirred for 30 min at r.t. Iodide 18 was taken up in THF (5 mL) and
added. Stirring overnight, workup (sat. aq NaHCO3; Et2O; MgSO4)
and column chromatography (n-pentane–Et2O = 2:1) afforded sul-
orless oil; [a]D +23.1 (c = 0.70, CHCl3) {ref.2, [a]D +24.9
(c = 1.7, CHCl3)}.
23
25
IR (CHCl3): 3416 (s), 3061 (m), 3026 (m), 2986 (s), 2938 (vs), 2878
(s), 1603 (w), 1496 (m), 1454 (m), 1379 (s), 1226 (vs), 1166 (s),
1123 (s), 1059 (s), 1030 (s), 969 (m), 903 (w), 877 (w), 813 (w), 749
(s), 701 (s), 580 (w), 526 (w), 501 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 3 H, CH3CCH3), 1.41 (s,
3 H, CH3CCH3), 1.55–1.92 (m, 6 H, OCHCH2CH, CH2CH2OH,
PhCH2CH2), 2.51 (br s, 1 H, OH), 2.57–2.67 (m, 1 H, PhCHH),
2.73–2.82 (m, 1 H, PhCHH), 3.74–3.84 [m, 3 H, Ph(CH2)2CH,
CH2OH], 4.07 [m, 1 H, CH(CH2)2OTBS], 7.16–7.31 (m, 5 H, PhH).
25
fide 19; yield: 1.299 g (99%); colorless oil; [a]D +5.9 (c = 1.27,
CHCl3).
IR (CHCl3): 2990 (m), 2938 (m), 2860 (w), 1599 (w), 1500 (s),
1456 (w), 1383 (s), 1284 (w), 1223 (s), 1158 (w), 1120 (w), 1023
(m), 954 (w), 913 (w), 757 (vs), 698 (m), 667 (w), 553 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 3 H, CH3CCH3), 1.35 (s,
3 H, CH3CCH3), 1.62 (t, J = 7.7 Hz, 2 H, OCHCH2CH), 1.67–2.12
(m, 4 H, CH2CH2S, PhCH2CH2), 2.56–2.66 (m, 1 H, PhCHH),
2.71–2.81 (m, 1 H, PhCHH), 3.36–3.55 (m, 2 H, CH2S), 3.77 [m, 1
H, Ph(CH2)2CH], 3.96 (m, 1 H, CH(CH2)2S), 7.14–7.30 (m, 5 H,
PhH), 7.51–7.59 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 24.7 (CH3CCH3), 24.9
(CH3CCH3), 29.6 (CH2S), 31.6 (PhCH2), 35.0, 37.4 (CH2CH2S,
PhCH2CH2), 38.3 (OCHCH2CH), 65.0 [CH(CH2)2S], 65.7
[Ph(CH2)2CH)], 100.5 [C(CH3)2], 123.8, 125.8, 128.3, 128.4, 129.8,
130.1, 133.7, 141.9, 154.3 (PhC, CN2).
13C NMR (75 MHz, CDCl3): d = 24.8 (CH3CCH3), 25.0
(CH3CCH3), 31.6 (PhCH2), 37.5, 37.6, 38.4 (OCHCH2CH,
CH2CH2OTBS,
PhCH2CH2),
61.4
(CH2OTBS),
65.8
[Ph(CH2)2CH], 67.1 [CH(CH2)2OTBS], 100.5 [C(CH3)2], 125.8
[p-PhC], 128.4, 128.5 [o-PhC, m-PhC], 141.9 (i-PhC).
MS (EI): m/z (%) = 264 (2) [M+], 250 (11), 249 (73) [M+ – CH3],
246 (8) [M+ – H2O], 204 (11), 171 (30), 143 (18), 129 (42), 117
+
(35), 105 (13), 92 (21), 91 (100) [C7H7 ], 59 (41), 55 (11), 45 (14).
Anal. Calcd for C16H24O3 (264.36): C, 72.69; H, 9.15. Found C,
72.28; H, 9.46.
MS (EI): m/z (%) = 424 (2), 409 (20) [M+ – CH3], 366 (21) [M+ –
CH3COCH3], 275 (17), 233 (16), 189 (24), 179 (35), 178 (12), 151
(18), 129 (12), 118 (14), 117 (43), 105 (13), 92 (13), 91 (100)
(4R,6S)-4-(2-Iodoethyl)-2,2-dimethyl-6-phenethyl-[1,3]dioxane
(18)
+
[C7H7 ], 89 (12), 87 (12), 77 (16), 67 (10), 59 (19), 55 (12).
Alcohol 17 (0.969 g, 3.7 mmol, 1 equiv), Ph3P (2.884 g, 11.0 mmol,
3 equiv) and imidazole (1.497 g, 22.0 mmol, 6 equiv) were dis-
solved in a mixture of Et2O (9 mL) and CH3CN (6 mL) at 0 °C. Io-
dine was added in small portions until a brown color persisted. After
stirring for 1 h the reaction was quenched by the addition of pH 7
buffer. The mixture was diluted with Et2O and Na2SO3 was added
until both phases appeared colorless. The phases were separated and
the aqueous phase was extracted with Et2O. The combined organic
extracts were dried over MgSO4 and filtered through a pad of glass
wool. Evaporation of the solvents and column chromatography (n-
pentane–Et2O, 30:1) afforded 18; yield: 1.156 g (84%); colorless
oil; [a]D23 –8.3 (c = 0.39, CHCl3).
HRMS (EI): m/z [M+ – CH3] calcd for C22H25N4O2S: 409.1698;
found: 409.1698.
Anal. Calcd for C23H28N4O2S (424.56): C, 65.07; H, 6.65; N, 13.20.
Found C, 65.54; H, 6.95; N, 13.20.
5-{2-[(4R,6S)-2,2-Dimethyl-6-phenethyl-[1,3]dioxan-4-yl]-eth-
ylsulfonyl}-1-phenyl-1H-tetrazole (6)
Sulfide 19 (0.219 g, 0.52 mmol, 1 equiv) was dissolved in CH2Cl2
(11 mL). NaHCO3 (0.426 g, 5.1 mmol, 9.8 equiv) and a solution of
MCPBA (0.430 g, 2.5 mmol, 4.8 equiv) in CH2Cl2 (3 mL) were add-
ed. After stirring for 48 h the reaction was worked up (sat. aq
NaHCO3; CH2Cl2; MgSO4) and the residue subjected to column
chromatography (n-pentane–Et2O = 2:1) to give sulfone 6; yield:
IR (CHCl3): 3083 (w), 3061 (m), 3026 (m), 2986 (s), 2935 (vs),
1603 (w), 1496 (m), 1453 (s), 1379 (vs), 1226 (vs), 1176 (s), 1116
(s), 1062 (m), 1022 (s), 943 (w), 894 (w), 842 (w), 748 (s), 701 (s),
603 (w), 579 (w), 529 (w), 509 (m), 484 (w) cm–1.
25
0.204 g (87%); colorless, very sticky oil; [a]D +9.7 (c = 0.60,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 3 H, CH3CCH3), 1.40 (s,
3 H, CH3CCH3), 1.61 (m, 2 H, OCHCH2CH), 1.65–1.89 (m, 2 H,
PhCH2CH2), 1.93 (m, 2 H, CH2CH2I), 2.57–2.66 (m, 1 H, PhCHH),
2.72–2.82 (m, 1 H, PhCHH), 3.19–3.27 (m, 2 H, CH2I), 3.76 [m, 1
H, Ph(CH2)2CH], 3.92 [m, 1 H, CH(CH2)2I], 7.15–7.30 (m, 5 H,
PhH).
13C NMR (75 MHz, CDCl3): d = 2.5 (CH2I), 24.7 (CH3CCH3), 25.1
(CH3CCH3), 31.7 (PhCH2), 37.4, 38.0, 39.2 (OCHCH2CH,
CH2CH2I, PhCH2CH2), 65.8 [Ph(CH2)2CH], 66.4 [CH(CH2)2I],
100.5 [C(CH3)2], 125.8 (p-PhC), 128.3, 128.5 (o-PhC, m-PhC),
141.9 (i-PhC).
IR (CHCl3): 3063 (w), 3026 (m), 2988 (s), 2938 (s), 1598 (m), 1498
(s), 1456 (m), 1380 (s), 1345 (vs), 1292 (w), 1226 (vs), 1189 (m),
1154 (vs), 1119 (s), 1066 (w), 1025 (m), 955 (w), 901 (w), 760 (vs),
695 (s), 625 (m), 576 (w), 547 (m), 525 (m), 457 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (s, 3 H, CH3CCH3), 1.35 (s,
3 H, CH3CCH3), 1.56–1.89 (m, 4 H, PhCH2CH2, OCHCH2CH),
1.97–2.07 (m, 1 H, CHHCH2S), 2.12–2.21 (m, 1 H, CHHCH2S),
2.57–2.64 (m, 1 H, PhHH), 2.72–2.79 (m, 1 H, PhHH), 3.91–3.99
(2 m, 4 H, CH2S, OCHCH2CH), 7.15–7.29 (m, 5 H, PhH), 7.55–
7.69 (m, 5 H, PhH).
13C NMR (100 MHz, CDCl3): d = 24.6 (CH3CCH3), 24.8
(CH3CCH3), 28.1 (CH2CH2S), 31.5 (PhCH2), 37.3, 38.0
(OCHCH2CH, PhCH2CH2), 52.8 (CH2S), 64.5, 65.5 [Ph(CH2)2CH,
CH(CH2)2S], 100.5 [C(CH3)2], 124.9, 125.6, 128.1, 128.2, 129.5,
131.2, 132.8, 141.5, 153.2 (PhC, CN2).
MS (EI): m/z (%) = 374 (11) [M+], 360 (17), 359 (100) [M+ – CH3],
316 (40) [M+ – CH3COCH3], 314 (13), 299 (20), 298 (23) [M+ –
CH3COCH3 – H2O], 171 (32), 143 (11), 129 (15), 117 (30), 105
(12), 92 (18), 91 (87), 59 (31), 55 (20).
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
1493
MS (EI): m/z (%) = 441 (19) [M+ – CH3], 173 (26), 171 (14), 169
3.85 [m, 1 H, Ph(CH2)2CHCH2CH], 3.98 (sep, J = 6.2 Hz, 1 H,
CH3CHCH3), 4.39 (ddd, 10.3, 6.1, 4.3 Hz, H,
CH=CHCHCH2), 5.09 (br s, 1 H, i-PrOCH), 5.56–5.62 (m, 1 H,
i-PrOCHOCHCH=CH), 5.67–5.75 (m, 2 H, i-PrOCHOCHCH,
i-PrOCHCH), 5.99 (m, 1 H, i-PrOCHCH=CH), 7.15–7.20 (m, 3 H,
PhH), 7.24–7.29 (m, 2 H, PhH).
13C NMR (100 MHz, CDCl3): d = 22.2 (CH3CHCH3), 23.8
(CH3CHCH3), 24.78 (CH3CCH3), 24.84 (CH3CCH3), 30.6
(CH=CHCHCH2), 31.6 (PhCH2), 37.4 (PhCH2CH2), 38.1
(29), 147 (13), 143 (11), 131 (12), 129 (24), 119 (14), 118 (27), 117
J
=
1
+
(76), 105 (13), 104 (12), 92 (15), 91 (100) [C7H7 ], 65 (12), 59 (20),
57 (13), 55 (21).
MS (CI, methane): m/z (%) = 485 (9), 457 (4) [MH+], 400 (21), 399
(100) [MH+ – CH3COCH3], 381 (28), 265 (15), 157 (17), 119 (14).
HRMS (EI): m/z [M+ – CH3] calcd for C22H25N4O4S: 441.1679;
found: 441.1677.
(OCHCH2CHO),
[Ph(CH2)2CH],
(CH=CHCHCH2), 69.7 (CH3CHCH3), 93.3 (i-PrOCH), 100.2
(CH3CCH3), 125.6 (p-PhC), 125.9 (i-PrOCHCH), 128.0
(i-PrOCHCH=CH), 128.1, 128.25 (o-PhC/m-PhC), 128.33
(CH=CHCHCH2), 132.2 (CH=CHCHCH2), 141.8 (i-PhC).
MS (EI): m/z (%) = 400 (0.4) [M+], 385 (10) [M+ – CH3], 283 (11),
220 (14), 219 (100), 161 (72), 133 (11), 117 (40), 112 (60), 105
(11), 91 (46), 70 (58), 59 (27).
38.6
66.3
[Ph(CH2)2CHCH2CHCH2],
[Ph(CH2)2CHCH2CH],
65.7
66.6
[(2R,6R)-6-Isopropoxy-3,6-dihydro-2H-pyran-2-yl]-methanol
(21)
Starting from tert-butyl 6-chloro-3,5-dioxohexanoate (20) (2.373 g,
10.1 mmol) the alcohol (2R,6S/R)-21 (0.429 g, 2.5 mmol) was ob-
tained according to the literature (25% yield over 7 steps) with de =
85%, ee = 89%.11b,11e Separation of the minor diastereomer,
(2R,6S)-21, by preparative HPLC (LiChrosorb, n-pentane–Et2O,
1:4) gave alcohol 21 with de ≥ 98%, ee = 89%; yield: 0.336 g (19%
20
over 7 steps and HPLC); colorless solid; [a]D +38.7 (c = 0.66,
22
CHCl3) {ref.11e, [a]D +36.5 (c = 0.26, CHCl3; de = 83%, ee =
HRMS (EI): m/z [M+ – CH3] calcd for C24H33O4: 385.2379; found:
385.2378.
94%)}.
The other spectroscopic data were in full agreement with the litera-
ture.11e
Anal. Calcd for C25H36O4 (400.55): C, 74.96; H, 9.06. Found C,
74.73; H, 9.35.
(4S,6S)-4-{(E/Z)-3-[(2R,6R)-6-Isopropoxy-3,6-dihydro-2H-pyr-
an-2-yl]-allyl}-2,2-dimethyl-6-phenethyl-[1,3]dioxane [(E/Z)-4]
Firstly, alcohol 21 was oxidized to aldehyde 7 under Swern condi-
tions: A solution of oxalyl chloride (0.10 mL, 1.2 mmol, 1.5 equiv)
in CH2Cl2 (3 mL) was cooled to –78 °C. DMSO (0.18 mL, 2.5
mmol, 3.1 equiv) was added in one portion and after stirring for 15
min the alcohol 21 (0.140 g, 0.8 mmol, 1 equiv), dissolved in
CH2Cl2 (2 mL), was slowly added. After 30 min Et3N (0.57 mL, 4.1
mmol, 5 equiv) was added after which stirring was continued for 15
min. The cooling bath was removed and the solution was allowed to
warm to r.t. The reaction mixture was carefully evaporated (alde-
hyde 7 is volatile) and the remaining slurry directly subjected to col-
umn chromatography (n-pentane–Et2O, 3:1). Evaporation of the
solvents yielded aldehyde 7, which was directly used for the next
step: It was dissolved in DME (6.5 mL) and cooled to –(65–60) °C.
Sulfone 6 (8.5 mL of a 0.106 M solution of 6 in DME, 0.90 mmol,
1.1 equiv) was then added and the solution allowed to reach its orig-
inal temperature again. NaHMDS (0.44 ml of a 2 M solution in
THF, 0.88 mmol, 1.08 equiv) was added dropwise and the solution
was warmed to r.t. overnight. Workup (sat. aq NaHCO3; Et2O,
MgSO4) and column chromatography (n-pentane–Et2O, 7:1) afford-
ed 0.249 g (77% over two steps) of a 3.3:1-mixture of (E)-4/(Z)-4.
Both isomers could be separated by preparative HPLC (LiChrosorb,
n-pentane–Et2O, 9:1).
(Z)-4
20
Yield: 0.027 g (9% over two steps and HPLC); colorless oil; [a]D
–6.3 (c = 0.34, CHCl3).
IR (CHCl3): 3026 (m), 2977 (s), 2932 (vs), 1659 (w), 1603 (w),
1496 (m), 1455 (m), 1423 (w), 1378 (s), 1317 (m), 1225 (s), 1182
(s), 1124 (s), 1102 (s), 1057 (s), 1029 (vs), 1003 (vs), 949 (m), 893
(w), 861 (w), 794 (w) 745 (s), 701 (s), 634 (w), 528 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16 (d, J = 6.0 Hz, 3 H,
CH3CHCH3), 1.22 (d, J = 6.0 Hz, 3 H, CH3CHCH3), 1.33 (s, 3 H,
CH3CCH3), 1.35 (s, 3 H, CH3CCH3), 1.59 (t, J = 7.8 Hz, 2 H,
OCHCH2CHO), 1.68–1.76 (m, 1 H, PhCH2CHH), 1.79–1.88 (m, 1
H, PhCH2CHH), 1.89–1.97 (m, 1 H, CH=CHCHCHH), 2.04–
2.13 (m,
1
H, CH=CHCHCHH), 2.31 [m,
2
H,
Ph(CH2)2CHCH2CHCH2], 2.57–2.64 (m, 1 H, PhCHH), 2.73–2.80
(m, 1 H, PhCHH), 3.75 [m, 1 H, Ph(CH2)2CH], 3.82 [m, 1 H,
Ph(CH2)2CHCH2CH], 4.00 (sep, J = 6.2 Hz, 1 H, CH3CHCH3), 4.72
(ddd, J = 11.1, 7.7, 3.4 Hz, 1 H, CH=CHCHCH2), 5.08 (br s,
1 H, i-PrOCH), 5.50–5.62 (m, 2 H, i-PrOCHOCHCH,
i-PrOCHOCHCH=CH), 5.71 (m, 1 H, i-PrOCHCH), 6.00 (m, 1 H,
i-PrOCHCH=CH), 7.15–7.20 (m, 3 H, PhH), 7.25–7.30 (m, 2 H,
PhH).
13C NMR (100 MHz, CDCl3): d = 21.9 (CH3CHCH3), 23.9
(CH3CHCH3), 24.8 [C(CH3)2], 30.6 (CH=CHCHCH2), 31.6
(PhCH2), 34.0 [Ph(CH2)2CHCH2CHCH2], 37.5 (PhCH2CH2), 38.0
(OCHCH2CHO), 62.5 (CH=CHCHCH2), 65.7, 66.2 [Ph(CH2)2CH,
Ph(CH2)2CHCH2CH], 69.2 (CH3CHCH3), 92.6 (i-PrOCH), 100.2
(CH3CCH3), 125.6 (p-PhC), 125.9 (i-PrOCHCH), 128.06
(i-PrOCHCH=CH), 128.11, 128.25 (o-PhC, m-PhC), 128.29
(CH=CHCHCH2), 131.4 (CH=CHCHCH2), 141.8 (i-PhC).
MS (EI): m/z (%) = 400 (0.3) [M+], 385 (3) [M+ – CH3], 325 (14),
283 (12), 273 (10), 220 (14), 219 (100), 213 (14), 161 (84), 150
(10), 142 (10), 133 (16), 131 (11), 117 (54), 112 (82), 105 (18), 91
(74), 81 (28), 70 (90), 59 (37).
HRMS (EI): m/z [M+ – CH3] calcd for C24H33O4: 385.2379; found:
385.2378.
(E)-4
20
Yield: 0.170 g (52% over two steps and HPLC); colorless oil; [a]D
+49.4 (c = 0.67, CHCl3).
IR (CHCl3): 3027 (m), 2980 (s), 2933 (s), 1658 (w), 1603 (w), 1496
(w), 1455 (m), 1379 (s), 1316 (m), 1225 (s), 1183 (m), 1122 (s),
1102 (s), 1058 (s), 1027 (vs), 1001 (s), 971 (s), 750 (m), 719 (m),
701 (m), 527 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.17 (d, J = 6.3 Hz, 3 H,
CH3CHCH3), 1.23 (d, J = 6.3 Hz, 3 H, CH3CHCH3), 1.34 (s, 3 H,
CH3CCH3), 1.36 (s, 3 H, CH3CCH3), 1.59 (m, 2 H, OCHCH2CHO),
1.67–1.77 (m, 1 H, PhCH2CHH), 1.79–1.88 (m, 1 H, PhCH2CHH),
1.95–2.02 (m, 1 H, CH=CHCHCHH), 2.04–2.13 (m, 1 H,
CH=CHCHCHH), 2.14–2.21 [m, 1 H, Ph(CH2)2CHCH2CHCHH],
2.25–2.32 [m, 1 H, Ph(CH2)2CHCH2CHCHH], 2.57–2.65 (m, 1 H,
PhCHH), 2.72–2.80 (m, 1 H, PhCHH), 3.76 [m, 1 H, Ph(CH2)2CH],
The analogous reaction sequence starting from 21 (0.070 g, 0.41
mmol, 1 equiv) but using KHMDS as base (0.5 M in toluene) yield-
ed 0.100 g (61% over two steps) of a 8.5:1 mixture of (E)-4/(Z)-4.
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

1494
D. Enders et al.
PAPER
(+)-Strictifolione, (R)-6-[(E)-(4S,6S)-4,6-Dihydroxy-8-phenyl-
oct-1-enyl]-5,6-dihydropyran-2-one (1)
DMF (4 mL). Imidazole (0.569 g, 8.4 mmol, 8 equiv) and TBS-Cl
(0.630 g, 4.2 mmol, 4 equiv) were added and the reaction was stirred
overnight. The solution was diluted with Et2O. Water was added as
well as a minimum amount of 1 N HCl (to dissolve the precipitate
and to facilitate separation of the phases). The phases were separat-
ed and the aq phase was extracted with Et2O. The combined ethereal
extracts were washed with pH 7 buffer, dried over MgSO4 and fil-
tered through a pad of glass wool. Evaporation of the solvent and
column chromatography (n-pentane–Et2O, 100:1 → 50:1) yielded
24; yield: 0.171 g (50% over two steps); colorless liquid.
Pure (E)-4 (57.6 mg, 0.14 mmol, 1 equiv) was dissolved in a mix-
ture of acetone (6 mL) and water (1 mL; no Ar). PPTS (17.3 mg,
0.08 mmol, 0.5 equiv) was added and the reaction mixture was
stirred for 5 h after which TLC control indicated the absence of
starting material. Saturated aq NaHCO3 (0.4 mL) was added to the
solution. The reaction mixture was diluted with Et2O, dried over
MgSO4 and filtered through a pad of glass wool. The crude product,
obtained after evaporation of the solvent, was dissolved in CH2Cl2
(7 mL) and stirred with MnO2 (170 mg, 2.0 mmol, 14 equiv) for 14
h (no Ar). The slurry was filtered through a pad of celite and the sol-
vent evaporated. Column chromatography (n-pentane–EtOAc =
1:4) afforded 1; yield: 31.2 mg (69% over two steps); colorless sol-
id; de = 89% (C6-epimer), ee ≥ 96% by 13C NMR; [a]D24 +54.1 (c =
0.33, CHCl3) {ref.1, [a]D24 +81.5 (c = 0.52, CHCl3; natural source)}.
1H NMR (400 MHz, CDCl3): d = 1.65 (t, J = 5.6 Hz, 2 H,
HOCHCH2CHOH), 1.74–1.92 (m, 2 H, PhCH2CH2), 2.29 (t, J = 6.6
Hz, 2 H, CH2CH=CHCH), 2.42–2.46 (m, 2 H, CH2CH=CHC=O),
2.54 (d, J = 4.4 Hz, 1 H, OH), 2.64–2.84 (m, 2 H, PhCH2), 2.71 (d,
J = 4.4 Hz, 1 H, OH), 3.98 [m, 1 H, Ph(CH2)2CH], 4.03 [m, 1 H,
Ph(CH2)2CHCH2CH], 4.90 (m, 1 H, CH2CH=CHCH), 5.69 (dd, J =
15.5, 6.5 Hz, 1 H, CH2CH=CHCH), 5.88 (ddt, J = 15.5, 1.0, 7.3 Hz,
1 H, CH2CH=CHCH), 6.05 (dt, J = 9.9, 1.8 Hz, 1 H, CHC=O), 6.89
(ddd, J = 9.6, 4.9, 3.6 Hz, 1 H, CH=CHC=O), 7.18–7.22 (m, 3 H,
PhH), 7.27–7.31 (m, 2 H, PhH).
Starting from 23 (after CuSO4·5H2O-Mediated Cleavage): Diol 23
(0.143 g, 1.4 mmol, 1 equiv) was dissolved in DMF (4 mL). Imida-
zole (0.290, 4.3 mmol, 3 equiv) and TBS-Cl (0.542 g, 3.6 mmol, 2.6
equiv) were added and the reaction was stirred overnight. After di-
lution with Et2O and workup (H2O; Et2O; MgSO4), the obtained
crude product was purified by column chromatography (n-pentane–
24
Et2O, 50:1) to give 24.; yield: 0.421 g (91%); colorless liquid; [a]D
+3.6 (c = 1.13, CHCl3).
IR (film): 3079 (w), 2955 (vs), 2932 (vs), 2859 (vs), 1642 (w), 1470
(s), 1436 (w), 1388 (m), 1362 (m), 1255 (s), 1113 (vs), 1003 (s), 937
(m), 915 (m), 837 (vs), 777 (vs), 734 (w), 668 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.06 [s, 6
H, Si(CH3)2], 0.88 [s, 9 H, C(CH3)3], 0.90 [s, 9 H, C(CH3)3], 2.11–
2.21 (m, 1 H, CH2=CHCHH), 2.30–2.39 (m, 1 H, CH2=CHCHH),
3.43 (dd, J = 9.9, 6.4 Hz, 1 H, OCHH), 3.51 (dd, J = 9.9, 5.4 Hz, 1
H, OCHH), 3.71 (quint, J = 5.8 Hz, 1 H, OCH), 5.00–5.09 (m, 2 H,
CH2=CH), 5.84 (m, 1 H, CH2=CH).
13C NMR (75 MHz, CDCl3): d = –5.4 (SiCH3), –5.3 (SiCH3), –4.7
(SiCH3), –4.4 (SiCH3), 18.2 [C(CH3)3], 18.4 [C(CH3)3], 25.9
[C(CH3)3], 26.0 [C(CH3)3], 39.0 (CH2=CHCH2), 66.9 (OCH2), 72.9
(OCH), 116.8 (CH2=CH), 135.3 (CH2=CH).
MS (EI): m/z (%) = 289 (7) [M+ – CH2=CHCH2], 273 (21) [M+ –
t-Bu], 189 (13), 149 (10), 148 (16), 147 (100), 73 (27), 67 (15).
13C NMR (100 MHz, CDCl3): d = 29.7 (CH2CH=CHC=O), 32.1
(PhCH2), 38.9 (PhCH2CH2), 40.3 (CH2CH=CHCH), 42.1
(HOCHCH2CHOH),
68.2,
68.7
[Ph(CH2)2CH,
Ph(CH2)2CHCH2CH], 77.7 (CH2CH=CHCH), 121.4 (CHC=O),
125.7 (p-PhC), 128.2, 128.3 (o-PhC, m-PhC), 129.7
(CH2CH=CHCH), 131.0 (CH2CH=CHCH), 141.7 (i-PhC), 144.5
(CH=CHC=O), 163.8 (C=O).
The other spectroscopic data were in full agreement with the litera-
ture.1
Anal. Calcd for C17H38O2Si2 (330.65): C, 61.75; H, 11.58. Found C,
61.64; H, 11.69.
(R)-2-(N-Phenylaminooxy)-pent-4-en-1-ol (22)17a
A suspension of (S)-proline (57 mg, 0.5 mmol, 0.1 equiv) in CHCl3
(2.5 mL) was cooled to 0 °C (no Ar). Nitrosobenzene (0.535 g, 5.0
mmol, 1 equiv) and then 10 (1.251 g, 14.9 mmol, 3.0 equiv) were
added, each of them in one portion. The green heterogeneous mix-
ture was stirred until it had turned into a yellow homogeneous one
(about 25 min). This solution was then transferred with a pipette to
a suspension of NaBH4 (0.596 g, 15.8 mmol, 3.2 equiv) in MeOH
(14 mL), which had been cooled to 0 °C before. After stirring for 20
min, sat. aq NaHCO3 (30 mL) was added and stirring was continued
for 40 min. The solution was extracted with CH2Cl2 and the com-
bined extracts were dried over MgSO4. After filtration through a
pad of glass wool and evaporation of the solvent the obtained or-
ange oil was purified by column chromatography (n-pentane–Et2O,
4:1) to give 22; yield: 0.883 g (92% over two steps); orange oil; ee
(R)-Pent-4-ene-1,2-diol (23)
Starting from 22: The a-oxyamination product 22 (0.552 g, 2.9
mmol, 1 equiv) was dissolved in MeOH (9 mL) at 0 °C and
CuSO4·5H2O (0.217 g, 0.87 mmol, 0.3 equiv) was added (no Ar).
After warming to r.t overnight the solvent was evaporated and the
residue was directly subjected to column chromatography (n-pen-
tane–Et2O, 1:1 → Et2O) to give 23; yield: 0.081 g (28%); red oil.
Starting from 24: For obtaining an analytical sample, it turned out
to be much easier to step backwards from 24. The bis-TBS ether 24
(0.177 g, 0.54 mmol, 1 equiv) was dissolved in a mixture of MeOH
(5 mL) and CH2Cl2 (3 mL; no Ar). HCl (1 N, 1 mL) was added and
the reaction was stirred for 2.5 h. After dilution with Et2O and dry-
ing over MgSO4 the mixture was filtered through a pad of glass
wool. Evaporation of the solvent and column chromatography
(n-pentane–EtOAC, 1:1 → EtOAc) afforded an analytically pure
24
≥ 98% by HPLC (Chiralpack AD, n-heptane–EtOH, 95:5); [a]D
+12.3 (c = 0.83, CHCl3) {ref.17a, [a]D +8.0 (c = 0.83, CHCl3)}.
23
sample of 23; yield: 0.046 g (84%); colorless oil; [a]D –9.0 (c =
MS (EI): m/z (%) = 193 (14) [M+], 109 (100) [PhNHOH+], 93 (12),
23
25
0.56, CHCl3), [a]D +11.4 (c = 0.63, MeOH) {ref.22, [a]D +3.3
92 (50) [PhNH+], 65 (14).
(c = 0.25, CHCl3)}.
The other spectroscopic data were in agreement with the literature.22
The other spectroscopic data were in full agreement with the litera-
ture.17a
(R)-2-(tert-Butyldimethylsilanyloxy)-pent-4-en-1-ol (25)
(R)-4,5-Bis-(tert-butyldimethylsilanyloxy)-pent-1-ene (24)
Starting from 22: The a-oxyamination product 22 (0.202 g, 1.0
mmol, 1 equiv) was dissolved in THF (4 mL) and SmI2 (20 mL of
a 0.1 M solution in THF, 2 mmol, 2 equiv) was added dropwise over
a time period of 20 min. After addition and stirring for 2.25 h the
reaction was judged to be complete according to TLC. The solvent
was evaporated and the remaining yellow residue was dissolved in
In a plastic vial the bis-TBS-ether 24 (0.365 g, 1.1 mmol, 1 equiv)
was dissolved in THF (3.4 mL). After the addition of pyridine (0.58
mL) and HF·pyridine (0.1 mL of a 65–70% solution of HF in pyri-
dine) the solution was stirred for 24 h. The solution was diluted with
Et2O and washed with 0.5 M HCl (3 × 5 mL) and sat. aq
CuSO4·5H2O (1 × 5 mL, the aqueous solutions were reextracted
with Et2O each time). All ethereal extracts were combined, dried
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

PAPER
Efficient Asymmetric Syntheses of (+)-Strictifolione
1495
over MgSO4, filtered through a pad of glass wool and evaporated.
1225 (vs), 1165 (m), 1118 (s), 1069 (s), 1026 (w), 972 (m), 941 (w),
913 (s), 835 (vs), 776 (s), 746 (m), 699 (s), 576 (w), 530 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.02 (s, 3 H, CH3SiCH3), 0.04 (s,
3 H, CH3SiCH3), 0.88 [s, 9 H, C(CH3)3], 1.33 (s, 3 H, CH3CCH3),
1.36 (s, 3 H, CH3CCH3), 1.59 (t, J = 7.8 Hz, 2 H, OCHCH2CHO),
Column chromatography (n-pentane–Et2O = 10:1) afforded 25;
24
yield: 0.136 g (57%); colorless liquid; [a]D –15.3 (c = 1.04,
CHCl3).
IR (CHCl3): 3395 (s), 3352 (s), 3076 (m), 2932 (vs), 2889 (s), 2859
(vs), 1642 (m), 1469 (s), 1436 (m), 1388 (m), 1363 (m), 1255 (s),
1106 (br vs), 1046 (s), 1001 (m), 966 (w), 916 (s), 836 (vs), 777 (s),
671 (m), 521 (w), 463 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.09 [s, 6 H, Si(CH3)2], 0.91 [s, 9
H, C(CH3)3], 1.88 (br t, J = 6.2 Hz, 1 H, OH), 2.28 (m, 2 H,
CH2=CHCH2), 3.44–3.50 (m, 1 H, OCHH), 3.54–3.59 (m, 1 H,
OCHH), 3.79 (m, 1 H, OCH), 5.03–5.11 (m, 2 H, CH2=CH), 5.78
(m, 1 H, CH2=CH).
1.63–1.90 (m,
2
H, PhCH2CH2), 2.10–2.31 (m,
4
H,
CH2CH=CHCHCH2), 2.56–2.66 (m, 1 H, PhCHH), 2.71–2.81 (m,
1 H, PhCHH), 3.75 (m, 1 H), 3.83 [m, 1 H, Ph(CH2)2CH,
Ph(CH2)2CHCH2CH], 4.10 (q, J = 5.9 Hz, 1 H, TBSOCH), 4.97–
5.06 (m, 2 H, CH2=CH), 5.44–5.60 (m, 2 H, CH=CH, CH=CH),
5.77 (m, 1 H, CH2=CH), 7.14–7.20 (m, 3 H, o-PhH, p-PhH), 7.24–
7.30 (m, 2 H, m-PhH).
13C NMR (75 MHz, CDCl3): d = –4.7 (CH3SiCH3), –4.3
(CH3SiCH3), 18.3 [C(CH3)3], 24.87 (CH3CCH3), 24.91
(CH3CCH3), 25.9 [C(CH3)3], 31.7 (PhCH2), 37.5, 38.2, 38.6,
43.1 (PhCH2CH2CHCH2CHCH2CH=CHCHCH2), 65.8, 66.4
[Ph(CH2)2CH, Ph(CH2)2CHCH2CH], 73.2 (TBSOCH), 100.3
[C(CH3)2], 116.6 (CH2=CH), 125.76, 125.80 (p-PhC, CH=CHCH),
128.3, 128.5 (o-PhC, m-PhC), 135.2, 135.5 (CH2=CH,
CH=CHCH), 142.0 (i-PhC).
13C NMR (100 MHz, CDCl3): d = –4.6 (CH3SiCH3), –4.4
(CH3SiCH3), 18.1 [C(CH3)3], 25.8 [C(CH3)3], 38.7 (CH2=CHCH2),
65.9 (OCH2), 72.3 (OCH), 117.3 (CH2=CH), 134.1 (CH2=CH).
MS (EI): m/z (%) = 185 (14), 175 (13), 117 (47), 75 (100), 73 (42),
67 (21).
Anal. Calcd for C11H24O2Si (216.39): C, 61.05; H, 11.18. Found C,
60.82; H, 11.30.
MS (EI): m/z (%) = 271 (15), 220 (11), 219 (80), 171 (13), 162 (12),
161 (100), 133 (14), 117 (56), 105 (12), 91 (54), 75 (27), 73 (26), 59
(69).
(R)-2-(tert-Butyldimethylsilanyloxy)-pent-4-enal (8)
A solution of oxalyl chloride (0.08 mL, 0.95 mmol, 1.5 equiv) in
CH2Cl2 (3 mL) was cooled to –78 °C. DMSO (0.15 mL, 2.1 mmol,
3.3 equiv) was added in one portion and after stirring for 15 min the
alcohol 25 (0.137 g, 0.63 mmol, 1 equiv), dissolved in CH2Cl2 (3
mL), was slowly added. After 30 min Et3N (0.45 mL, 3.2 mmol, 5.1
equiv) was added after which the cooling bath was replaced by an
ice bath (0 °C). Stirring was continued for 10 min after which work-
up (H2O; CH2Cl2; MgSO4) followed immediately. Column chroma-
tography (n-pentane–Et2O, 20:1) gave 8; yield: 0.133 g (98%);
colorless liquid; [a]D23 +33.0 (c = 0.98, CHCl3).
HRMS (EI): m/z [M+ – C3H5] calcd for C24H39O3Si: 403.2669;
found: 403.2669.
Acrylic Acid (E)-(R)-1-Allyl-4-{(4S,6S)-2,2-dimethyl-6-phen-
ethyl-[1,3]dioxan-4-yl}-but-2-enyl Ester (5)
TBS ether 26 (23 mg, 0.05 mmol, 1 equiv) was dissolved in THF (4
mL; no Ar). TBAF was added (0.3 mL of a 1 M solution in THF,
0.3 mmol, 5.8 equiv) and the solution was stirred for 2 h. The crude
product, obtained after workup (pH 7 buffer; Et2O; MgSO4), was di-
rectly used for the next step. It was dissolved in CH2Cl2 (4 mL) and
cooled to –78 °C. Eti-Pr2N (0.05 mL, 0.3 mmol, 5.9 equiv) and then
acryloyl chloride (30 mg, 0.33 mmol, 6.4 equiv) were added. After
stirring for 1 h at that temperature the reaction was worked up (pH
7 buffer; CH2Cl2; MgSO4). Column chromatography (n-pentane–
Et2O, 10:1) gave 5.
IR (film): 3081 (m), 2933 (vs), 2893 (s), 2859 (vs), 2802 (m), 2713
(w), 1740 (vs), 1643 (m), 1470 (s), 1435 (w), 1413 (w), 1365 (m),
1327 (w), 1257 (vs), 1113 (vs), 1000 (m), 919 (s), 839 (vs), 780 (s),
675 (m), 577 (w), 509 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.08 (s, 3 H, CH3SiCH3), 0.09 (s,
3 H, CH3SiCH3), 0.92 [s, 9 H, C(CH3)3], 2.31–2.50 (m, 2 H,
CH2=CHCH2), 4.02 (ddd, J = 6.9, 5.3, 1.5 Hz, 1 H, CHCHO), 5.08–
5.16 (m, 2 H, CH2=CH), 5.80 (m, 1 H, CH2=CH), 9.61 (d, J = 1.5
Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = –4.8 (CH3SiCH3), –4.7
(CH3SiCH3), 18.2 [C(CH3)3], 25.7 [C(CH3)3], 37.5 (CH2=CHCH2),
77.3 (OCH), 118.4 (CH2=CH), 132.8 (CH2=CH), 203.7 (CHO).
MS (EI): m/z (%) = 199 (2) [M+ – CH3], 185 (32) [M+ – CHO], 158
(12) [M+ – t-Bu], 157 (100), 129 (11), 127 (64), 115 (10), 101 (23),
75 (57), 73 (61), 59 (11).
22
Yield: 18 mg (91%); colorless oil; [a]D +37.6 (c = 0.48, CHCl3)
{ref.4, [a]D20 +22.9 (c = 4.85, CHCl3)}.
IR (CHCl3): 3064 (m), 3026 (m), 2986 (s), 2936 (s), 1725 (vs), 1638
(m), 1496 (m), 1454 (m), 1405 (s), 1378 (s), 1296 (w), 1267 (m),
1224 (s), 1191 (vs), 1117 (m), 1041 (m), 971 (s), 917 (m), 810 (m),
750 (m), 701 (m), 500 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.33 (s, 3 H, CH3CCH3), 1.35 (s,
3 H, CH3CCH3), 1.57 (m, 2 H, OCHCH2CHO), 1.67–1.76 (m, 1 H,
PhCH2CHH), 1.79–1.88 (m, 1 H, PhCH2CHH), 2.21 (m, 2 H,
CH2CH=CH), 2.41 (m, 2 H, CH2=CHCH2), 2.57–2.64 (m, 1 H, Ph-
CHH), 2.72–2.79 (m, 1 H, PhCHH), 3.74 [m, 1 H, Ph(CH2)2CH],
3.83 [quint, J = 7.1 Hz, 1 H, Ph(CH2)2CHCH2CH], 5.03–5.12 (m, 2
H, CH2=CHCH2), 5.34 (q, J = 6.7 Hz, 1 H, CH=CHCH), 5.52 (dd,
J = 15.4, 7.1 Hz, 1 H, CH2CH=CH), 5.68–5.77 (m, 2 H,
CH2CH=CH, CH2CH=CH2), 5.80 (dd, J = 10.3, 1.5 Hz, 1 H,
CHEH=CHC=O), 6.10 (dd, J = 17.3, 10.4 Hz, 1 H, CH2=CHC=O),
6.39 (dd, J = 17.3, 1.4 Hz, 1 H, CHHZ=CHC=O), 7.15–7.20 (m, 3
H, PhH), 7.25–7.30 (m, 2 H, PhH).
13C NMR (75 MHz, CDCl3): d = 24.9 [C(CH3)2], 31.7 (PhCH2),
37.5, 38.1, 38.5, 39.0 (PhCH2CH2CHCH2CHCH2CH=CHCHCH2),
65.8, 66.1 [Ph(CH2)2CH, Ph(CH2)2CHCH2CH], 73.9 (CH=CHCH),
100.4 [C(CH3)2], 117.9 (CH2=CHCH2), 125.8 (p-PhC), 128.3,
128.5 (o-PhC, m-PhC), 128.8, 130.1 (2 × C), 130.5 (CH2=CHC=O),
133.3 (CH=CH, CH=CH, CH2=CHCH2, CH2=CHC=O), 142.0
(i-PhC), 165.4 (C=O).
HRMS (EI): m/z [M+ – CHO] calcd for C10H21OSi: 185.1362;
found: 185.1362.
{(E)-(R)-1-Allyl-4-[(4S,6S)-2,2-dimethyl-6-phenethyl-[1,3]diox-
an-4-yl]-but-2-enyloxy}-tert-butyldimethylsilane (26)
Sulfone 6 (4.8 mL of a 0.041 M solution of 6 in DME, 0.20 mmol,
1 equiv) and aldehyde 8 (57 mg, 0.27 mmol, 1.3 equiv), dissolved
in DME (2.5 mL), were cooled to –(65–60) °C. KHMDS (0.44 mL
of a 0.5 M solution in toluene, 0.22 mmol, 1.1 equiv) was added
dropwise and the solution was warmed to r.t. overnight. Workup
(sat. aq NaHCO3; Et2O, MgSO4) and column chromatography
(n-pentane–Et2O, 35:1) afforded 26; yield: 61 mg (69%); colorless
oil; de, ee ≥ 96% by 13C NMR; [a]D23 +19.9 (c = 0.57, CHCl3).
IR (CHCl3): 3079 (w), 3027 (w), 2986 (s), 2932 (vs), 2857 (s), 1739
(w), 1641 (w), 1603 (w), 1497 (w), 1462 (m), 1378 (s), 1252 (s),
Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York

1496
D. Enders et al.
PAPER
(11) (a) Wolberg, M.; Hummel, W.; Wandrey, C.; Müller, M.
MS (EI): m/z (%) = 369 (29) [M+ – CH3], 220 (16), 219 (100), 195
(10), 162 (11), 161 (92), 143 (17), 133 (27), 131 (14), 117 (74), 105
(25), 92 (12), 91 (98), 79 (18), 59 (56), 55 (82).
HRMS (EI): m/z [M+ – CH3] calcd for C23H29O4; 369.2066; found:
369.2066.
Angew. Chem. Int. Ed. 2000, 39, 4306; Angew. Chem. 2000,
112, 4476. (b) Wolberg, M.; Hummel, W.; Müller, M.
Chem.–Eur. J. 2001, 7, 4562. (c) Job, A.; Wolberg, M.;
Müller, M.; Enders, D. Synlett 2001, 1796. (d) Vicario, J.
L.; Job, A.; Wolberg, M.; Müller, M.; Enders, D. Org. Lett.
2002, 4, 1023. (e) Enders, D.; Vicario, J. L.; Job, A.;
Wolberg, M.; Müller, M. Chem.–Eur. J. 2002, 8, 4272.
(12) Enders, D.; Voith, M.; Ince, S. J. Synthesis 2002, 1775.
(13) For reviews about the SAMP/RAMP-hydrazone
methodology in asymmetric synthesis, see: (a)Enders, D. In
Asymmetric Synthesis, Vol. 3; Morrison, J. D., Ed.;
Academic Press: Orlando, 1984, 275. (b) Job, A.; Janeck, C.
F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253.
(14) (a) Enders, D.; Hundertmark, T.; Lazny, R. Synlett 1998,
721. (b) For a review about the cleavage of N,N-
dialkylhydrazones, see: Enders, D.; Peters, R.; Wortmann,
L. Acc. Chem. Res. 2000, 33, 157.
(15) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511.
(16) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(17) a-Oxyamination of aldehydes: (a) Brown, S. P.; Brochu, M.
P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808. (b) Zhong, G. Angew. Chem. Int. Ed. 2003, 42,
4247; Angew. Chem. 2003, 115, 4379.
(18) a-Oxyamination of ketones: (a) Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038.
(b) Bøgevig, A.; Sundén, H.; Córdova, A. Angew. Chem. Int.
Ed. 2004, 43, 1109; Angew. Chem. 2004, 116, 1129.
(c) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
Angew. Chem. Int. Ed. 2004, 43, 1112; Angew. Chem. 2004,
116, 1132.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 380) and by the Fonds der Chemischen
Industrie. We thank the companies Degussa AG, BASF AG and the
former Bayer AG for the donation of chemicals.
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Synthesis 2004, No. 9, 1486–1496 © Thieme Stuttgart · New York