Enantiomeric synthesis of the SPIKET-P enantiomers

Article abstract of DOI:10.1055/s-2004-822342

A convenient synthesis of the antipodes of the title compound has been developed starting from (R)-1,2,5,6-dicyclohexylidene mannitol. Some of the key features of the syntheses were simple reaction protocols, and stereoselective inversion of chiral 1,2-diol moiety via neighbouring group assisted acetylation.

Full text of DOI:10.1055/s-2004-822342

PAPER
1037
Enantiomeric Synthesis of the SPIKET-P Enantiomers
E
nantiomeric Synt
n
hesis of the
S
u
PIKET-
P
En
b
antiomers ha Sharma, Prema Iyer, Sunita Gamre, Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai - 400 085, India
Fax +91(22)5505151; E-mail: schatt@apsara.barc.ernet.in
Received 11 February 2004; revised 3 March 2004
rials have been reported for only (2R,8R)-II and involve
multiple protection and deprotection steps.
Abstract: A convenient synthesis of the antipodes of the title com-
pound has been developed starting from (R)-1,2,5,6-dicyclohexy-
lidene mannitol. Some of the key features of the syntheses were
simple reaction protocols, and stereoselective inversion of chiral
1,2-diol moiety via neighbouring group assisted acetylation.
Synthesis of (S,S)-SPIKET II
Keywords: cytotoxic, (R)-1,2,5,6-dicyclohexylidene mannitol,
enantiomeric synthesis
The mannitol derivative 1,10 on NaIO4 cleavage followed
by Wittig–Horner olefination in tandem with triethyl
phosphonoacetate in aqueous medium gave the conjugat-
ed ester 2 in excellent yield. The 1H NMR coupling con-
stant for its olefinic proton revealed it to be predominantly
the E-isomer, although this was of no consequence for the
synthesis. The aqueous Wittig–Horner olefination intro-
duced earlier11a,b is a significant contribution to medicinal
organic chemistry, but has been sparingly used. Earlier,
Takano et al.11b have even carried out the reaction with the
water-soluble glyceraldehyde acetonide.11b In this study,
we have used the more hydrophobic compound 1 for a
tandem two-step reaction sequence. Catalytic hydrogena-
tion of 2 gave the ester 3, which was reduced with LiAlH4
to furnish the alcohol 4. Its bromination afforded the key
synthon 5. Monoalkylation of dithiane with 5 in the pres-
ence of n-BuLi as the base gave the thioacetal 6 in 74%
yield. Its subsequent alkylation with 5, using the same
base, however, did not proceed well, furnishing the de-
sired product 7 in only 25–30% yield. After several trials,
7 could be prepared in 70% yield using a combination of
n-BuLi–t-BuONa as the base.12 Dethioacetalization of 7
in the presence of HgCl213 followed by acidic work-up di-
rectly produced the target spiro compound (S,S)-II via
concomitant deprotection of the acetal group (Scheme 1).
Cyclization of the intermediate tetrol, with identical con-
figuration at positions 2 and 8 is known9a,14 to furnish the
6,6-spiroketals with E,E stereochemistry. Hence, the syn-
thesized compound would be the C2-symmetric
(2S,6S,8S)-II, which is also reflected from its 13C NMR
resonances.
Microtubules that are formed by the self-association of the
a,b-tubulin heterodimers play a crucial role in cell divi-
sion.1,2 Thus, compounds that can prevent polymerization
of tubulin are potential anticancer agents, and have at-
tracted recent attention. The macrocyclic spiroketal lac-
tone, spongistatin 1 (I) is one such compound that has
been isolated from an Eastern Indian Ocean sponge in the
genus Hytrios.3,4 It shows impressive cytotoxicity against
the members of the NCI panel of 60 human cancer cell
lines.3 Based on molecular simulation studies on its bind-
ing interaction with tubulin, the simple spiroketal,
SPIKET-P (II) has been rationally designed as the phar-
macophore of spongistatin 1.5 At nanomolar concentra-
tions, compound II showed promising cytotoxicity
against human breast cancer cells by destroying microtu-
bule organization and inducing apoptosis.6 The 1,7-diox-
aspiro[5.5]undecane moiety present in II also constitutes
the core structural unit in various natural products of bio-
logical interests.3,7 Further, in view of conformational ri-
gidity and thermodynamic stability, these types of
functionalized spiroketals are versatile intermediates in
stereoselective syntheses of complex natural products.8 In
view of the medicinal importance and the impressive per-
formance of II as an anticancer agent, a need to develop
synthesis of its enantiomers, especially from easily acces-
sible materials, was felt. Availability of its enantiomers
would facilitate studies on the stereochemical effect of the
biological activity. Consequently, we have developed a
convenient synthesis of both (R,R)- and (S,S)-II from the
abundant and inexpensive D-mannitol. Herein, we report
the results. Earlier three syntheses of II have been report-
ed. Of these, the synthesis9a of the enantiomers of II via
Sharpless asymmetric dihydroxylation is by far the best in
terms of its brevity and efficiency. However, the chemi-
cals/reagents used in this approach are either expensive or
toxic. The other syntheses5,6,9b from the chiral pool mate-
Synthesis of (R,R)-SPIKET II
Earlier we have reported15 that the stereochemistry of a
1,2-diol can be inverted easily by nucleophilic displace-
ment of its secondary mesylate with an acylating agent. In
the present case, for the synthesis of (R,R)-II, a similar
strategy was used. Thus, 5 was deacetalized with aqueous
trifluoroacetic acid (TFA) to give the tetrol (S,S)-8. Its
mesylation followed by invertive acetylation furnished
the acetate 9 which was directly converted to the acetal
(R,R)-10 by reacting with MeOH and 2,3-dimethoxypro-
SYNTHESIS 2004, No. 7, pp 1037–1040
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x
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x
x
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0
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4
Advanced online publication: 14.04.2004
DOI: 10.1055/s-2004-822342; Art ID: Z02504SS
© Georg Thieme Verlag Stuttgart · New York

1038
A. Sharma et al.
PAPER
Scheme 1 Reagents and conditions. (i) (EtO)2POCH2CO2Et–aq NaHCO3–aq Na2CO3, (ii) H2/10% Pd-C–EtOH, (iii) LiAlH4–Et2O, (iv) Ph3P/
CBr4–Et3N–CH2Cl2, (v) 1,3-Dithiane/n-BuLi–THF, –78 °C, HMPA, (vi) n-BuLi–t-BuONa–THF, –78 °C, 5, (vii) HgCl2/MeOH/D, (viii) 80%
Aqueous trifluoroacetic acid, (ix) MsCl–Et3N; KOAc–Ac2O/D, x) MeOH–2,2¢-dimethoxypropane–amberlyst.
pane in the presence of amberlyst 15®. Subsequently, it
The mixture was stirred for 18 h at r.t. and extracted with Et2O. The
Et2O layer was washed with water until neutral pH, followed by
brine, and dried. Solvent removal followed by column chromatog-
raphy of the residue over silica gel (0–10% EtOAc–hexane) afford-
ed (R)-2.
was converted to (R,R)-II by a similar sequence of reac-
tions as used for the synthesis of its antipode starting from
(R)-5. In analogy of its antipode, the synthesized com-
pound would be (2R,6R,8R)-II.
Yield: 5.6 g (80%); [a]D22 +37.6 (c = 1.1, CHCl3).
The enantiomeric purities of (S,S,S)- and (R,R,R)-II were
IR (film): 1715, 1661, 1448, 1367 cm–1.
determined by HPLC analyses of the respective benzoate
derivatives with a (S,S)-Whelk-O 5 mm chiral column, us-
1H NMR (CDCl3, 200 MHz): d = 1.28 (t, J = 6.5 Hz, 3 H), 1.60 (br
s, 10 H), 3.66 (dd, J = 6, 1.8 Hz, 1 H), 4.08–4.26 (m containing a q
ing 90:10 hexane–i-PrOH as the eluent. For the former,
at d = 4.18, 3 H), 4.57–4.72 (m, 1 H), 6.14 (d, J = 16 Hz, 1 H), 6.83
enantiomeric purity was 98%, while that of (R,R)-II was
found to be 94.8%.
(dd, J = 16, 6 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 23.7, 23.7, 24.9, 35.1, 35.9,
60.3, 68.3, 74.5, 110.6, 122.1, 144.8, 165.8.
The IR spectra were scanned as thin films with a Nicolet 430 FT-IR
spectrophotometer. The H NMR spectra were recorded with a
Bruker AC-200 (200 MHz) instrument. The optical rotations were
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 65.17; H,
8.47.
1
measured with a Jasco DIP 360 polarimeter. All anhydrous reac-
tions were carried out under Ar atmosphere using freshly dried sol-
vents. Unless otherwise mentioned, the organic extracts were dried
over anhyd Na2SO4.
Ethyl (4S)-4,5-Cyclohexylidenedioxypentanoate (3); Typical
Procedure
A mixture of 2 (2.4 g, 10 mmol) and 10% Pd-C (0.1 g) in EtOH (20
mL) was stirred under a positive pressure of H2 until there was no
further gas absorption. The mixture was diluted with Et2O, passed
through a pad (2 inches) of silica gel and the column was washed
with Et2O. Removal of solvent in vacuo gave the ester 3.
Yield: 2.3 g (95%); [a]D22 –3.9 (c = 0.8, CHCl3).
Ethyl (4S)-4,5-Cyclohexylidenedioxypent-2E-enoate (2); Typi-
cal Procedure
To a stirred and cooled (0 °C) suspension of 1 (5.0 g, 14.62 mmol)
in aq NaHCO3 (40 mL, 5%) was added NaIO4 (3.8 g, 17.7 mmol).
After stirring for 1 h, triethyl phosphonoacetate (6.5 mL, mmol) was
added to the reaction mixture followed by aq K2CO3 (50 mL, 6 M).
IR (film): 1736, 1448, 1366 cm–1.
Synthesis 2004, No. 7, 1037–1040 © Thieme Stuttgart · New York

PAPER
Enantiomeric Synthesis of the SPIKET-P Enantiomers
1039
1H NMR (CDCl3, 200 MHz): d = 1.25 (t, J = 6.5 Hz, 3 H), 1.6 (br s,
10 H), 1.78–1.92 (m, 2 H), 2.31–2.48 (m, 2 H), 3.53 (dd, J = 6.0, 1.8
Hz, 1 H), 4.03–4.22 (m, 4 H).
13C NMR (CDCl3, 50 MHz): d = 13.9, 23.6, 23.8, 24.9, 28.7, 30.3,
34.9, 36.4, 60.2, 68.5, 74.3, 109.3, 173.0.
Yield: 1.6 g (74%); [a]D22 +12.8 (c = 0.78, CHCl3).
IR (film): 2940, 1448, 1361, 1277, 1162 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.39–1.60 (m, 12 H), 1.70–1.88
(m, 4 H), 2.01–2.10 (m, 2 H), 2.82–2.87 (m, 4 H), 3.49 (t, J = 6.5
Hz, 1 H), 4.01–4.05 (m, 3 H).
Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C, 64.29; H,
9.27.
13C NMR (CDCl3, 50 MHz): d = 22.8, 23.7, 23.9, 25.0, 25.8, 30.2,
33.1, 35.1, 36.5, 47.2, 68.8, 75.1, 109.0.
Anal. Calcd for C15H26O2S2: C, 59.56; H, 8.66; S, 21.20. Found: C,
59.78; H, 8.81; S, 21.02.
(4S)-4,5-Cyclohexylidenedioxypentan-1-ol (4); Typical Proce-
dure
To a stirred suspension of LiAlH4 (0.69 g, 18.2 mmol) in Et2O (60
mL) was added dropwise 3 (5.5 g, 22.7 mmol) in Et2O (40 mL). The
mixture was stirred at r.t. for 6 h, the excess hydride was decom-
posed by dropwise addition of aq sat. Na2SO4 solution, the superna-
tant decanted and the solid crystalline residue washed with Et2O.
The combined organic extracts were concentrated to obtain pure 4
after column chromatography (silica gel, 0–10% EtOAc–hexane).
Yield: 4.0 g (88%); [a]D22 +9.4 (c = 0.92, CHCl3).
IR (film): 3405, 1448, 1365, 1104 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.37–1.85 (m, 12 H), 2.19–2.35
(m, partially D2O exchangeable, 3 H), 3.50 (t, J = 7.0 Hz, 1 H),
3.64–3.69 (m, 2 H), 4.0–4.12 (m, 2 H).
(2S,10S)-1,2,10,11-Bis(cyclohexylidenedioxy)-undecan-6-one
Trimethylenedithioacetal (7); Typical Procedure
To a cooled (0 °C) and stirred solution of t-BuONa [prepared from
Na (0.092 g, 3.97 mmol) and t-BuOH] in hexane (9.0 mL) was in-
jected n-BuLi (2.5 mL, 1.6 M in hexane, 3.97 mmol). The mixture
was stirred for 1 h at 0 °C, 1 h at r.t., and then cooled to –78 °C. An-
other flask was charged with a solution of 6 (1.2 g, 3.97 mmol) in
THF (10 mL) and n-BuLi (2.5 mL, 1.6 M in hexane, 3.97 mmol)
was injected at –78 °C. After stirring the mixture for 15 min, the
above alkoxide was added into it. After 1 h, the bromide 5 (1.25 g,
4.76 mmol) in THF (10 mL) was added, and the mixture stirred for
3 h at –78 °C and 12 h at r.t. The reaction was quenched with 10%
aq NH4Cl, the organic layer separated and the aqueous layer extract-
ed with Et2O. The combined organic extracts were washed with wa-
ter and brine, and dried. Removal of solvent followed by column
chromatography of the residue (silica gel, 0-10% Et2O–hexane)
gave pure 7.
13C NMR (CDCl3, 50 MHz): d = 23.8, 24.8, 24.9, 28.9, 30.2, 35.0,
36.4, 62.2, 68.9, 75.4, 109.3.
Anal. Calcd for C11H20O3: C, 65.97; H, 10.07. Found: C, 65.79; H,
10.19.
Yield: 1.92 g (70%); [a]D22 +10.4 (c = 0.77, CHCl3).
IR (film): 2939, 1460, 1448, 1163 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.37–1.59 (m, 28 H), 1.84–1.89
(m, 6 H), 2.76–2.82 (m, 4 H), 3.45–3.52 (m, 2 H), 3.99–4.05 (m, 4
H).
(4S)-1-Bromo-4,5-cyclohexylidenedioxypentane (5); Typical
Procedure
To a stirred and cooled (0 °C) solution of CBr4 (9.1 g, 27.4 mmol),
(S)-4 (3.8 g, 19.0 mmol) and Et3N (3.0 mL, 21.5 mmol) in CH2Cl2
(25 mL) was slowly added Ph3P (6.16 g, 23.5 mmol) in CH2Cl2 (25
mL) over a period of 3 h. After stirring for 1 h, the mixture was di-
luted with pentane, and poured in ice-cold half-sat. aq NaHCO3 so-
lution. The organic layer was separated, the aqueous layer was
extracted with pentane, the combined organic extracts dried and
concentrated in vacuo. Removal of solvent in vacuo followed by
column chromatography of the residue (silica gel, 10% Et2O–hex-
ane) gave pure (S)-5.
Yield: 4.15 g (83%); [a]D22 +5.1 (c = 0.94, CHCl3).
IR (film): 2936, 1448, 1364 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.39–1.68 (m, 10 H), 1.70–1.73
(m, 2 H), 1.83–2.07 (m, 2 H), 3.42–3.56 (m, 3 H), 3.9–4.12 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 23.7, 23.9, 25.1, 25.3, 25.9, 33.7,
35.1, 36.5, 38.1, 52.9, 69.0, 75.3, 109.1.
[(2S,8S)-8-(Hydroxymethyl)-1,7-dioxaspiro[5,5]undec-2-
yl]methan-1-ol (II); Typical Procedure
A mixture of 7 (0.5 g, 1.03 mmol) and HgCl2 (0.842 g, 3.1 mmol)
in 90% aq MeOH (10 mL) was refluxed under Ar for 4 h. The mix-
ture was passed through a pad (2 inches) of celite which was eluted
with CH2Cl2. Removal of solvent gave a residue which was taken
up in cold 80% aq trifluoroacetic acid (TFA) (10 mL) and stirred at
0 °C for 2 h. Removal of solvent followed by preparative chroma-
tography (silica gel, 10% EtOAc–hexane) gave pure II.
13C NMR (CDCl3, 50 MHz): d = 23.7, 23.9, 25.0, 29.0, 32.2, 33.5,
35.0, 36.5, 68.8, 74.6, 109.3.
Yield: 0.120 (54%); [a]D22 +58.6 (c = 0.8, CHCl3), {lit.9a [a]D25 +65
(c = 0.042, CHCl3)}.
IR (film): 3380, 2931, 1463, 1454 cm–1.
Anal. Calcd for C11H19O2Br: C, 59.56; H, 8.66; Br, 21.20. Found:
C, 59.78; H, 8.81; Br, 21.02.
1H NMR (CDCl3, 200 MHz): d = 1.24–1.54 (m, 6 H), 1.60–1.75 (m,
4 H), 1.83–2.18 (m, 2 H), 2.78 (br s, 2 H), 3.54 (dd, J = 11.5, 7.5 Hz,
2 H), 3.61 (dd, J = 11.5, 3.0 Hz, 2 H), 3.69–3.9 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 18.4, 25.7, 35.4, 66.4, 68.4, 95.8.
2-[(4S)-4,5-Cyclohexylidenedioxypentyl]-1,3-dithiane (6); Typi-
cal Procedure
To a cooled (–30 °C) and stirred solution of dithiane (0.857 g, 7.14
mmol) in THF (25 mL) was injected n-BuLi (4.5 mL, 1.6 M in hex-
ane, 7.15 mmol). After stirring for 0.5 h at the same temperature, the
mixture was cooled to –78 °C and then HMPA (3 mL) was added.
After stirring the mixture for 15 min, 5 (1.88 g, 7.15 mmol) in THF
(10 mL) was added to the mixture. Stirring was continued for 3 h at
–78 °C and 12 h at r.t. The reaction was quenched with 10% aq
NH4Cl, the organic layer separated and the aq layer extracted with
Et2O. The combined organic extracts were washed with water and
brine, and dried. Removal of solvent followed by column chroma-
tography of the residue (silica gel, 0–10% Et2O–hexane) gave pure
6.
(4S)-1-Bromopentane-4,5-diol (8); Typical Procedure
A solution of 5 (2.0 g, 7.6 mmol) in 80% aq trifluoroacetic acid
(TFA) (15 mL) was stirred at 0 °C till completion of the reaction (cf.
TLC, 3 h). After concentrating the mixture in vacuo, the trace quan-
tity of TFA was removed azeotropically with toluene. The residue
was purified by column chromatography (silica gel, 15% EtOAc–
hexane) to give pure 8.
Yield: 1.02 g (72%); [a]D22 –2.2 (c = 1.61, CHCl3).
IR (film): 3404, 2941, 1443, 1170 cm–1.
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A. Sharma et al.
PAPER
1H NMR (CDCl3, 200 MHz): d = 1.42–1.63 (m, 2 H), 1.79–2.25 (m,
partially D2O exchangeable, 4 H), 3.38–3.52 (m, 3 H), 3.62–3.78
(m, 2 H).
1H NMR (CDCl3, 200 MHz): d = 1.39 (s, 3 H), 1.45 (s, 3 H), 1.57–
1.75 (m, 2 H), 1.83–2.12 (m, 2 H), 3.52 (t, J = 6 Hz, 2 H), 3.45–3.75
(m, 1 H), 4.05–4.21 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 24.8, 26.9, 38.3, 73.6, 74.1.
13C NMR (CDCl3, 50 MHz): d = 22.1, 23.9, 25.3, 35.9, 64.8, 71.2,
107.1.
Anal. Calcd for C5H11BrO2: C, 32.81; H, 6.06; Br, 43.65. Found: C,
33.07; H, 5.84; Br, 43.49.
(2R,8R)-SPIKET (II)
[a]D22 –57.8 (c = 0.75, CHCl3), {lit.5 [a]D22 –59.4 (c = 0.7, CHCl3)}.
(4R)-4,5-Diacetoxy-1-bromopentane (9); Typical Procedure
To a cooled (0 °C) and stirred mixture of 8 (1.0 g, 5.46 mmol) and
Et3N (2.2 mL, 16.38 mmol) in CH2Cl2 (20 mL) was slowly injected
mesyl chloride (1.0 mL, 13.1 mmol). After 1 h, when the reaction
was complete, the mixture was poured in ice cooled 10% aq NH4Cl.
The organic layer was separated, the aqueous portion extracted with
CHCl3, the combined organic extracts washed with aq sat. NH4Cl
solution and dried. Removal of solvent gave the corresponding
dimesylate, which was directly used for the next step.
IR (film): 2980, 1360, 1180 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.62–1.96 (m, 4 H), 2.77 (s, 6 H),
3.44–3.54 (m, 3 H), 3.63–3.71 (m, 2 H).
IR (film): 3440, 2927, 1470, 1451 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.24–1.57 (m, 6 H), 1.62–1.77 (m,
4 H), 1.80–2.21 (m, 2 H), 2.61 (br s, 2 H), 3.58 (dd, J = 11.2, 7.2 Hz,
2 H), 3.63 (dd, J = 11.2, 3.0 Hz, 2 H), 3.75–3.9 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 18.1, 25.9, 35.6, 64.8, 68.8, 96.1.
References
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A mixture of the above compound, acetic anhydride (5.0 mL) and
anhyd potassium acetate (4.29 g, 40.0 mmol) was refluxed for 4 h.
The mixture was brought to r.t., poured in ice-water and stirred for
1 h. The aqueous laver was extracted with Et2O, the Et2O layer sep-
arated, washed with water and brine and dried. Removal of solvent
followed by column chromatography of the residue (silica gel, 0–
10% Et2O–hexane) gave pure 9.
Yield: 1.08 (74%); [a]D22 –36.2 (c = 0.8, CHCl3).
IR (film): 2958, 1741, 1228 cm–1.
(6) Uckun, F. M.; Mao, C.; Vassilev, A. O.; Huang, H.; Jan, S.-
T. Bioorg. Med. Chem. Lett. 2000, 10, 541.
1H NMR (CDCl3, 200 MHz): d = 1.42–1.63 (m, 2 H), 1.79–2.25 (m,
2 H), 2.07 (s, 6 H), 3.55 (t, J = 7 Hz, 2 H), 3.88–4.14 (m, 2 H), 4.21–
4.28 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.9, 23.6, 27.9, 44.3, 64.7, 70.6,
170.4, 170.6.
(7) Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc.
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1999, 10, 883.
Anal. Calcd for C9H15BrO4: C, 40.47; H, 5.66; Br, 29.91. Found: C,
40.72; H, 5.48; Br, 29.72.
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Chim. Acta 1980, 63, 1960.
(4R)-4,5-Isopropylidenedioxy-1-bromopentane (10); Typical
Procedure
A mixture of 9 (0.9 g, 3.37 mmol), 2,2-dimethoxypropane (5.0 mL),
and amberlyst 15® (0.1 g) in MeOH (5.0 mL) was stirred at r.t for
12 h. The mixture was filtered and concentrated in vacuo to give a
residue, which upon column chromatography (silica gel, 0–5%
Et2O–hexane) gave pure 10.
(14) Sauret, S.; Cuer, A.; Gourcy, J.-G.; Jeminet, G. Tetrahedron
1993, 49, 2621.
22
(15) Chattopadhyay, S.; Mamdapur, V. R.; Chadha, M. S. Bull.
Chim. Soc. Fr. 1990, 127, 108.
(16) Yang, W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451.
Yield: 0.609 g (81%); [a]D22 –7.5 (c = 0.68, CHCl3), {lit.16 [a]D
7.2 (c = 0.88, CHCl3)}.
IR (film): 2985, 2936, 1454, 1378, 1369 cm–1.
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Synthesis 2004, No. 7, 1037–1040 © Thieme Stuttgart · New York