Enantioselective synthesis of the C10-C20 fragment of fusicoccin A

Article abstract of DOI:10.1021/jo201020v

A synthesis of the fully protected C-ring fragment of the tricyclic diterpene fusicoccin A is reported. The desired cyclopentenyl halides 5a,b are obtained in a total of nine steps. Key transformations of the synthesis sequence are a nonconventional Cr-catalyzed allylic oxidation of a protected intermediate cylcopentenone, a diastereoselective addition of a propenyl Grignard/CeCl₃ reagent to the unmasked cyclopentenone, and an asymmetric hydroboration of the isopropenyl substituent. The protected and suitably functionalized C-ring fragment paves the way to explore further the total synthesis of fusicoccin A.

Full text of DOI:10.1021/jo201020v

ARTICLE
pubs.acs.org/joc
Enantioselective Synthesis of the C10ÀC20 Fragment of Fusicoccin A
Anja Richter,†,‡ Christian Hedberg,†,‡ and Herbert Waldmann*,†,‡
†Fakult€at Chemie, Chemische Biologie, Technische Universit€at Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
‡Abteilung Chemische Biologie, Max-Planck-Institut f€ur Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
S Supporting Information
b
ABSTRACT: A synthesis of the fully protected C-ring fragment
of the tricyclic diterpene fusicoccin A is reported. The desired
cyclopentenyl halides 5a,b are obtained in a total of nine steps.
Key transformations of the synthesis sequence are a noncon-
ventional Cr-catalyzed allylic oxidation of a protected inter-
mediate cylcopentenone, a diastereoselective addition of a
propenyl Grignard/CeCl3 reagent to the unmasked cyclopen-
tenone, and an asymmetric hydroboration of the isopropenyl
substituent. The protected and suitably functionalized C-ring fragment paves the way to explore further the total synthesis of
fusicoccin A.
’ INTRODUCTION
step. The stereochemical outcome of this transformation should
be controlled by chelation of samarium. Accordingly, the C(1)À
C(11) bond was disconnected to yield the fully functionalized
linear precursor 1.
The configuration at C(14) and the choice of the leaving
group were considered to be crucial, and we chose a stable carba-
mate as leaving group that would release CO2 upon cylization.
The precursor 1 was traced back to the A-ring fragment 2 and
the C-ring fragment 3. Coupling of these fragments by means
of a Grignard-type addition should follow the Cram chelate
model.21,22 Alternatively, an asymmetric NozakiÀHiyamaÀ
Kishi reaction could be considered.23
We planned to synthesize the C-ring fragment 3 from
commercially available 3-methyl-2-cyclopenten-1-one (6) as
shown in Scheme 1. The synthesis plan included establishment
of the stereochemistry at C(14) by means of a Grignard
addition24 to the carbonyl group of intermediate 5 anti to the
substituent at C(12). For introduction of the required protected
alcohol at C(12) in the appropriate configuration, we envisioned
an allylic oxidation/reduction strategy.
The glycosylated phytotoxic diterpene fusicoccin A
(Scheme 1) isolated from the fungus Fusicoccum amygadaly1
stabilizes the proteinÀprotein interaction between the autoinhi-
bitory region of the plant plasma membrane H+-ATPase and a
14À3À3 protein.2À4 14À3À3 proteins may be attractive targets
for new drug discovery programs, since these conserved adapter
proteins5 play important roles in the regulation of numerous
pharmacologically relevant proteins.6,7 Notably, fusicoccin A
induces apoptosis in a wide panel of human cancer cell lines in
combination with interferon-R treatment.8 Other representa-
tives of the fusicoccane family, in particular cotylenin A, induce
differentiation in murine and human myeloid leukemia cell,9,10
and in combination with rapamycin cotylenin A causes growth
arrest in breast carcinoma MCF-7 cells.11 Kato et al. succeeded in
the synthesis of the related natural products albolic acid and
ceroplastol II and established a route to cotylenol.12À14 How-
ever, a total synthesis of fusicoccin A has not been reported. For
the synthesis of the central 5À8À5-membered scaffold charac-
teristic for the fusicoccines, several methods have been
reported.15À18 Herein, we outline a possible approach toward
fusiccocin A and describe the enantioselective synthesis of its
C-ring fragment.
’ RESULTS AND DISCUSSION
Synthesis of Cyclopentenones 5 by Allylic Oxidation and
Enantioselective Reduction. The synthesis of cyclopentenones
5a,b involved halogenation of the unsaturated cyclic ketone 6,
allylic oxidation, enantioselective reduction, and protection/
deprotection steps (Scheme 2).
Halogenation of 6 employing established procedures, e.g.
addition of the corresponding halogen to the enone and sub-
sequent elimination,25,26 gave vinyl halides 7a,b in low yields.
’ RETROSYNTHETIC ANALYSIS
In planning the fusicoccin synthesis, we envisaged forma-
tion of the highly decorated eight-membered B-ring as the crucial
step (Scheme 1). It was planned to employ an 8-endo radical
cyclization induced by samarium(II)19,20 for this purpose.
Addition of a radical generated from an appropriately placed
aldehyde to a double bond embedded in the five-membered
C-ring and concomitant loss of a leaving group at C(14) would
simultaneously install the C(10)ÀC(14) double bond in one
Received: May 24, 2011
Published: July 14, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis of Fusicoccin A and of Its Fully Protected C-Ring Fragment
Scheme 2. Synthesis of Chiral Cyclopentenones 5a,b
As an alternative, iodination using iodine and substoichiometric
amounts of pyridinium dichromate27 was employed, which gave
7b in high yield. To allow for regioselective allylic oxidation, the
keto group of intermediates 7 was protected as a cyclic acetal.25,28
Allylic oxidation with selenium dioxide29 often yields mixtures of
racemic alcohol and the desired ketone, which may be hard
to separate and the ketal group is acid-sensitive. Therefore,
this oxidant and transformations proceeding under acidic con-
ditions were not considered. For selective allylic oxidation of
olefin 8a several established methods were explored, which are
summarized in Table 1 of the Supporting Information. In the
majority of the cases decomposition, deprotection of the carbo-
nyl compound, or only partial conversion was observed. The best
results were achieved by employment of a solution of TBHP in
dichloroethane as modification of Pearson’s chromium-catalyzed
oxidation method.30 With this reagent oxidation of 8a,b pro-
ceeded in preparatively viable yields of up to 74% and without
substantial formation of byproduct.
Due to the sensitivity of 9a,b, the crude oxidation products
were directly subjected to enantioselective reduction,31 using the
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CBS catalyst and borane, yielding the allylic alcohols 10a,b with
high enantiomeric excess (>98% ee). The absolute configuration
of the allylic alcohols was confirmed by Mosher ester analysis,32
which revealed that reduction using (S)-(À)-2-methyloxazabor-
olidine resulted in the formation of the R alcohol. This result is in
agreement with the expected transition state for the CBS
reduction. Protection of the alcohol group either as benzyl ether
or as p-methoxybenzyl ether and subsequent cleavage of the ketal
using acetone/water and p-TsOH gave the desired building
blocks 5a,b in 30% yield over four steps from ketones 7.
of isopropylmagnesium chloride24 to the carbonyl group of 5a
promoted by CeCl3 was explored. Thereby compound 5a was
converted into the two separable diasteromers of the cotylenin
building block, which were formed in a ratio of 4:1 in favor of the
desired diastereomer 11 (Scheme 3). Under comparable condi-
tions 5b only underwent halogen/metal exchange. In order to
introduce the correctly configured side chain of fusicoccin, the
use of an organometallic isopropenyl reagent was investigated.
Isopropenyllithium,24 generated in situ,33 adds to 5a anti to the
protected alcohol with an appreciable selectivity of 9:1; however,
yields were not reproducible (Scheme 3). In contrast, the reagent
obtained from isopropenylmagnesium bromide34 and CeCl3
reliably gave 12a,b in high yield and with high diasteroselectivity
(Scheme 3). The configuration of all products of the Grignard-
type addition reactions, shown in Scheme 3, was verified by
NOESY experiments. Observed NOE signal enhancements
are highlighted by arrows, indicating that the nucleophiles
preferably add anti to the protected alcohol at C(12) of the
cyclopentyl ring.
Syntheses of Cyclopentenes 3a,b. For establishment of the
quaternary stereocenter at C(14), initially the Grignard addition
Scheme 3. Addition of Isopropyl and Isopropenyl Reagents
to Halovinyl Ketones 5a,b
For completion of the synthesis of the C-ring fragment, 12a,b
were subjected to asymmetric hydroboration with (+)-(Ipc)2BH35
and alcohols 13a,bwere obtained with 75% and 80% de, respectively
(Scheme 4). The configuration of the hydroboration product 13a
was determined by means of NMR investigations. For conclusive
analysis, diol 13a was converted to the structurally more rigid
carbonate 15. Subsequent NOE experiments (signal enhancements
are indicated by arrows in Scheme 4) revealed that the desired
product was formed. Notably, the use of (À)-isopinocampheylbor-
ane as hydroborating agent led to reduction but not to reversal of
stereoselectivity. This finding indicates that the hydroboration is not
reagent- but substrate-controlled. The use of 9-BBN as hydroborat-
ing agent did not lead to product formation.
Subsequent selective protection of the primary alcohol by
O-alkylation and, finally, establishment of the quaternary diethyl-
carbamate yielded fully functionalized fragments 3a,b with >95%
diastereomeric purity.
Scheme 4. Synthesis of Fully Functionalized C-Ring Fragments 5a,b and 1D-NOE Experiments of 15
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In conclusion, we have developed a highly stereoselective
synthesis of the C-ring fragment of fusicoccin A. The desired
vinyl halides 3a,b were obtained in a total of nine steps. Key
transformations of the reaction sequence are a nonconven-
tional Cr-catalyzed allylic oxidation using tert-butylhydroper-
oxide in dichloromethane, a diastereoselective Grignard
addition, and an asymmetric hydroboration with diisopino-
campheylborane. The availability of these fragments opens up
the opportunity to further investigate the total synthesis of
fusicoccin A.
[C8H11O2Br]+ 217.9937, obsd 217.9928; calcd for [C8H11O281Br]+
219.9922, obsd 219.992 06.
9-Bromo-8-methyl-1,4-dioxaspiro[4.4]non-8-en-7-one (9a).
6-Bromo-7-methyl-1,4-dioxaspiro[4.4]-non-6-ene (8a; 11.5 g, 52.3 mmol,
1.00 equiv) was dissolved in 130 mL of a 29% solution of TBHP in
C2H4Cl2 (523 mmol, 10.0 equiv) under an inert gas atmosphere, and
molecular sieves (4 Å) were added. Cr(CO)6 (1.20 g, 5.32 mmol, 0.50
equiv) was added, and the reaction mixture was stirred under argon
at 40 °C for 48 h and for an additional 2 days at room temperature
(GC/MS analysis indicated complete conversion). The reaction mixture
was filtered and washed with EtOAc. The filtrate was diluted with water
and extracted three times with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and evaporated to dryness.
The resulting dark green oil was dissolved in EtOAc and filtered over
Celite. The solvent was evaporated to yield 7.10 g of a slightly yellow wax
as the crude desired product (30.5 mmol, 58%). An analytically pure
sample of 9a was obtained by column chromatography on deactivated
silica gel (cyclohexane/EtOAc 9:1). Rf = 0.42 (cyclohexane/EtOAc
7/3). IR (ATR): 2976 (w), 2956 (w), 2912 (m), 2890 (w), 2845 (w),
’ EXPERIMENTAL SECTION
Reagents, solvents, and the starting materials were purchased
from commercial sources. All reactions were carried out using
anhydrous solvents and under an inert gas atmosphere unless
otherwise specified. THF and methanol were purchased as anhy-
drous solvents in Sure-Seal bottles and used without any further
treatment. DCM was freshly distilled over calcium hydride. 1H and
13C NMR and NOESY spectra were acquired on a 400, 500, or 600
MHz machine. Chemical shifts are reported in ppm (δ), and the
coupling constants are given in Hz (J). NMR peak assignments are
based on 2D NMR experiments (COSY, TOCSY, HSQC, HMBC).
Numbering of the fusicoccin scaffold in Scheme 1 was employed for
signal assignment. The sample concentration c is given in g/100 mL
for the measurement of the optical rotations. Chiral GC chromato-
grams were recorded to calculate ee values.
1
1668 (m), 1471 (m), 1440 (m) cmÀ1. H NMR (400 MHz, CDCl3
filtered over basic Al2O3): δ 4.29 (m, 2H, CH2-ketal), 4.09 (m, 2H,
CH2-ketal), 2.78 (s, 2H, H-13), 1.84 (s, 3H, H-18) ppm. 13C NMR
(100.6 MHz, CDCl3 filtered over basic Al2O3): δ 199.4 (Cq, C12), 152.8
(Cq, C14), 145.0 (Cq, C11), 110.5 (Cq, C10), 66.8 (CH2, 2C-ketal),
47.6 (CH2, C13), 10.1 (CH3, C18) ppm. HRMS (EI): m/z [M]+ calcd
for [C8H9O379Br]+ 231.9730, obsd 231.9725; calcd for [C8H9O381Br]+
233.9709, obsd 233.9704.
Preparation of 2-Bromo-3-methyl-2-cyclopentenone (7a)25,28
.
(S)-9-Bromo-8-methyl-1,4-dioxaspiro[4.4]non-8-en-7-
ol (10a). A solution of (R)-2-methyl-CBS-oxazaborolidine in THF
(3.00 mL, 1.00 M, 3.05 mmol, 0.10 equiv) was transferred under
positive argon pressure to a flame-dried two-necked round-bottom
flask containing 58.0 mL of THF. After the solution was cooled to
0 °C, dimethyl sulfideÀborane complex (5.80 mL, 60.9 mmol, 2.00
equiv) was added dropwise and the mixture was stirred for 20 min at
0 °C. A solution of 9a (7.10 g, 30.4 mmol, 1.00 equiv) in 30.0 mL of
THF was added at 0 °C over a period of 3.5 h using a syringe pump,
and the reaction mixture was stirred for 1.5 h at 0 °C. Methanol was
added carefully, and the quenched reaction mixture was warmed to
room temperature overnight. Water was added, and the mixture was
extracted three times with diethyl ether. The combined organic
layers were washed with brine and dried over MgSO4, and the
solvent was evaporated to dryness to yield 9.50 g of crude 10a as a
pale yellow wax (99% ee by chiral GC). The crude product was used
without further purification for the next steps. For analytical
purposes 50.0 mg of the crude product was purified by column
chromatography on silica gel which had been pretreated with NEt3
(cyclohexane/EtOAc 9/1 to 7/3) to obtain 24.0 mg of the pure
Under argon a solution of 3.70 mL of bromine (73.2 mmol, 1.10 equiv) in
60.0 mL of DCM was added to a solution of 6.40 g of 3-methyl-2-cyclo-
pentenone (6; 66.5 mmol, 1.00 equiv) in 70.0 mL of DCM within 45 min
while the temperature was kept below 5 °C. The mixture was stirred until
nearly complete decoloration (2 h); 13.7 mL of triethylamine was added at
5 °C, and the reaction mixture was stirred overnight at room temperature. To
the resulting black mixture was added 30.0 mL of 1.00 M HCl carefully. After
stirring for 30 min, the layers were separated and the aqueous layer was
extracted once with DCM. The combined organic layers were washed with
saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated
in vacuo. Distillation under reduced pressure (0.7À1.2 mbar, oil bath
temperature 90À110 °C, bp 70 °C) yielded 5.30 g of a pale yellow solid.
Recrystallization from pentane delivered 3.70 g of the desired product (20.9
mmol, 33%) as colorless crystals. Rf = 0.35 (cyclohexane/EtOAc 7/3). Mp:
1
53.5 °C. H NMR (400 MHz, CDCl3): δ 2.67À2.65 (m, 2H, H-13),
2.57À2.53 (m, 2H, H-12), 2.81 (s, 3H, H-18) ppm. 13C NMR (100.7 MHz,
CDCl3): δ 201.5 (Cq, C14), 173.4 (Cq, C11), 123.4 (Cq, C10), 33.5 (CH2,
C13), 32.4 (CH2, C12), 19.1 (CH3, C18) ppm. HRMS (EI): m/z calcd for
[C6H7OBr]+ 173.9675, obsd 173.9674; calcd for [C6H7O81Br]+ 175.9654,
obsd 175.9654.
product as a colorless wax. Rf = 0.11 (cyclohexane/EtOAc 7/3).
1
[R]20 = À20.9° (c = 0.72, CHCl3 filtered over basic Al2O3). H
Preparation of 6-Bromo-7-methyl-1,4-dioxaspiro[4.4]non-
6-ene (8a)25,28. To a solution of 21.7 g (124.2 mmol, 1.00 equiv) of 10
under argon in 73.4 mL of triethyl orthoformate (434.7 mmol, 3.50 equiv)
were added 48.5 mL of ethylene glycol (869.5 mmol, 7.00 equiv) and 236
mg of p-toluenesulfonic acid (1.24 mmol, 0.01 equiv). The reaction mixture
was stirred at room temperature until the starting material was completely
consumed (GC/MS, 15 h). Water was added, and the mixture was extracted
three times with cyclohexane. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo. After distillation
over K2CO3 under reduced pressure (0.7À0.9 bar, oil bath temperature
85À95 °C, bp 60À65 °C) 21.5 g (97.9 mmol, 79%) of a colorless wax was
obtained. 1H NMR (400 MHz, CDCl3): δ 4.18 (m, 2H, CH2-ketal), 3.98
(m, 2H, CH2-ketal), 2.35 (m, 2H, H-12), 2.17 (m, 2H, H-13), 1.80 (s, 3H,
H-18) ppm. 13C NMR (100.7 MHz, CDCl3): δ 144.6 (Cq, C11), 141.9
(Cq, C14), 119.3 (Cq, C10), 66.0 (2CH2, 2C-ketal), 34.7 (CH2, C13),
33.1 (CH2, C12), 16.7 (CH3, C18) ppm. HRMS (EI): m/z calcd for
D
NMR (400 MHz, CDCl3 filtered over basic Al2O3): δ 4.53 (s, br,
1H, H-12), 4.19 (m, 2H, CH2-ketal), 3.98 (m, 2H, CH2-ketal), 2.62
(dd, 2J = 14.1, 3J = 7.1 Hz, 1H, H-13), 2.02 (dd, 2J = 14.2, 3J = 3.4 Hz,
1H, H-13), 1.86 (s, 3H, H-18), 1.75 (s, br, 1H, OH) ppm. 13C NMR
(100.6 MHz, CDCl3 filtered over basic Al2O3): δ 146.3 (Cq,
C14), 124.1 (Cq, C11), 115.2 (Cq, C10), 74.5 (CH, C12), 66.3
(CH2, C-ketal), 65.6 (CH2, C-ketal), 45.7 (CH2, C13), 13.6 (CH3,
C18) ppm. HRMS (EI): m/z [M]+ calcd for [C8H11O379Br]+
233.9886, obsd 233.9884; calcd for [C8H11O381Br]+ 235.9866,
obsd 235.9864.
(S)-4-(Benzyloxy)-2-bromo-3-methylcyclopent-2-enone
(5a). In a flame-dried two-necked round-bottom flask NaH (3.20 g,
80.7 mmol, 2.00 equiv) was suspended in 150 mL of THF under
an argon counterflow. A solution of crude 10a (9.50 g, 40.3 mmol,
1.00 equiv) in 100 mL of THF was added dropwise over 30 min at
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0 °C. The reaction mixture was stirred for 1.5 h at room temperature,
HMPA (19.8 mL, 161.3 mmol, 4.00 equiv) and benzyl bromide
(9.60 mL, 80.7 mmol, 2.00 equiv) were added, and the mixture was
stirred overnight at room temperature. After it was cooled with an ice
bath, the mixture was carefully diluted with water and extracted three
times with EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, and evaporated to dryness to give 25.0 g of
crude (S)-8-(benzyloxy)-6-bromo-7-methyl-1,4-dioxaspiro[4.4]non-
6-ene as a yellow liquid. The crude product was used for the
next reaction without further purification: Rf = 0.58 (cyclohexane/
EtOAc 7/3).
2J = 14.1, 3J = 7.3, 1H. H-13), 2.00À1.94 (m, 2H, H-13, H-15), 1.82 (d,
4J = 1.0, 3H, H-18), 1.68 (s, br, 1H, OH), 1.00 (d, 3J = 6.8, 3H, H-19),
0.82 (d, 3J = 6.8, 3H, H-20) ppm. 13C NMR (101 MHz, CDCl3): 141.8
(Cq, C11), 138.4 (Cq, Ph), 129.3 (Cq, C14), 128.6 (2CH), 127.9
(CH), 127.8 (2CH), 87.6 (Cq, C10), 82.3 (CH, C13), 71.4 (CH2Ph),
37.1 (CH2, C13), 35.2 (CH, C15), 18.4 (CH3, C19), 16.3 (CH3,
C20), 14.0 (CH3, C18) ppm. HRMS (CI): m/z [M À OH]+ calcd
for [C16H20OBr]+ 307.0692, obsd 307.0689; calcd for [C16H20O81Br]
309.0672, obsd 309.0671.
(1S,4S)-4-(Benzyloxy)-2-bromo-3-methyl-1-(prop-1-en-2-
yl)cyclopent-2-enol (12a). In a flame-dried Schlenk tube a water-
free CeCl3 suspension in THF (2.63 mL, 0.10 g/mL, 1.07 mmol, 3.00
equiv; for the preparation see ref 24) was added via a transfer cannula to
a solution of 5a (100 mg, 356 μmol, 1.00 equiv) in 5.0 mL of THF under
positive argon pressure. The suspension was stirred for 3 h at room
temperature, and a solution of isopropylmagensium bromide in THF
(2.10 mL, 0.50 M, 1.07 mmol, 3.00 equiv) was added dropwise within
20 min under argon. The reaction mixture was stirred at room tem-
perature until starting material was no longer detectable by GC/MS or
TLC (20 min). After it was cooled with an ice bath, the reaction mixture
was carefully diluted with water and extracted three times with diethyl
ether. The combined organic layers were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification by column chromatog-
raphy on silica gel (cyclohexane/EtOAc 9/1) provided 90.1 mg (279
μmol, 78%, >80% de by NMR) of the desired 12a as a slightly yellow oil.
A solution of 25.0 g of crude (S)-8-(benzyloxy)-6-bromo-7-methyl-
1,4-dioxaspiro[4.4]non-6-ene and ca. 100 mg of TsOH in 160 mL of
acetone/water (25/1) was stirred for 20 h at room temperature and for
an additional 4 h at 40 °C until conversion was complete (monitored by
GC/MS). The reaction mixture was cooled to room temperature,
diluted with water, and extracted three times with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and evapo-
rated to dryness. Purification by means of column chromatography on
silica gel (cyclohexane/EtOAc 9/1) yielded 4.40 g of 5a (15.5 mmol,
30% over four steps) as a yellow, viscous oil, Rf = 0.52 (cyclohexane/
EtOAc 7/3). [R]20D = 46.4 deg (c = 1.13, CHCl3). 1H NMR (400 MHz,
2
CDCl3): δ 7.40À7.31 (m, 5H, Ph), 4.67 (d, J = 11.6, 1H, CH2Ph),
2
3
4.58À4.55 (m, 2H, CH2Ph, H-12), 2.81 (dd, J = 18.1, J = 5.9, 1H,
H-13), 2.50 (dd, 2J = 18.1, 3J = 1.6, 1H, H-13), 2.19 (s, 3H, H-18) ppm.
13C NMR (100.6 MHz, CDCl3): δ 197.3 (Cq, C14), 171.0 (Cq, C11),
137.2 (Cq, Ph), 128.8 (2CH, Ph), 128.4 (CH, Ph), 128.1 (2CH, Ph),
126.0 (Cq, C10), 77.6 (CH, C12), 72.2 (CH2 CH2Ph), 40.8 (CH2,
C13), 16.3 (CH3, C18) ppm. HRMS (CI): m/z [M + H]+ calcd for
[C13H14O279Br]+ 281.0172, obsd 281.0161; calcd for [C13H14O281Br]+
283.0151, obsd 283.0142.
Rf = 0.45 (cyclohexane/EtOAc 7/3). [R]20 = À19.1° (c = 1.12,
D
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.36À7.34 (m, 4H, Ph),
7.30 (m, 1H, Ph), 5.15 (td, 4J = 0.8, 2J = 1.5, 1.5, 1H, H-19), 4.96 (m, 1H,
H-19), 4.59 (d, 2J = 11.8, 1H, CH2Ph), 4.51 (d, 2J = 11.8, 1H, CH2Ph),
4.34 (m, 1H, H-12), 2.61 (dd, 2J = 13.9, 3J = 7.2, 1H, H-13), 2.26 (s, br,
1H, OH), 2.09 (dd, 2J = 14.0, 3J = 4.1, 1H, H-13), 1.87 (d, 4J = 0.8, 3H,
H-18), 1.61 (dd, 4J = 0.7, 1.4, 3H, H-20) ppm. 13C NMR (100.6 MHz,
CDCl3): δ 146.2 (Cq, C15), 142.0 (Cq, C11), 138.3 (Cq, Ph), 128.6
(2CH, Ph), 128.4 (Cq, C10), 127.9 (CH, Ph), 127.9 (2CH, Ph), 111.6
(CH2, C19), 86.0 (Cq, C14), 82.2 (CH, C12), 70.8 (CH2Ph), 43.8
(CH2, C13), 18.6 (CH3, C20), 14.0 (CH3, C18) ppm. HRMS (CI): m/z
[M À OH]+ calcd for [C16H18O79Br]+ 305.0536, obsd 305.0535; calcd
for [C16H18O81Br]+ 307.0515, obsd 307.0516.
(1S,4S)-4-(Benzyloxy)-2-bromo-1-isopropyl-3-methylcy-
clopent-2-enol (11). In a flame-dried Schlenk tube a water-free
CeCl3 suspension in THF (13.2 mL, 0.10 g/mL, 5.34 mmol, 1.50 equiv;
for the preparation see ref 24) was added via a transfer cannula to a
solution of isopropylmagnesium chloride in THF (2.76 mL, 2.00 M, 5.34
mmol, 1.50 equiv) at 0 °C under positive argon pressure. The suspen-
sion was stirred for 1 h with ice bath cooling, and a solution of 5a (1.00 g,
3.56 mmol, 1.00 equiv) in 4.00 mL of THF was added dropwise within
25 min under argon. The reaction mixture was stirred at 0 °C until
starting material was no longer detectable by GC/MS or TLC (1 h). The
reaction mixture was carefully diluted with water and extracted three
times with diethyl ether. The combined organic layers were washed with
brine, dried over MgSO4, and evaporated to dryness. Purification by
column chromatography on silica gel (cyclohexane/EtOAc 9/1) pro-
vided 585 mg (1.80 mmol, 51%) of the desired cis isomer 11 as a slightly
yellow oil, 181 mg of a diastereomeric mixture, and 131 mg of the pure
trans isomer (81% overall yield). Analytical data of the cis isomer 11 are
as follows. Rf = 0.58 (cyclohexane/EtOAc 9/1). [R]20D = +13.6° (c =
0.90, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.38À7.33 (m, 4H, Ph),
7.30 (m, 1H, Ph), 4.60 (d, 2J = 11.7, 1H, CH2Ph), 4.49 (d, 2J = 11.7, 1H,
CH2Ph), 4.23 (ddd, 3J = 7.2, 3.3, 4J = 0.8, 1H, H-12), 2.49 (dd, 2J = 14.3,
3J = 7.2, 1H, H-13), 2.02 (m, 1H, H-15), 1.97 (s, br, 1H, OH), 1.84 (d, 4J =
0.8, 3H, H-18), 1.82 (m, 1H, H-13), 1.03 (d, 3J = 6.3, 3H, H-19), 0.66
(d, 3J = 6.8, 3H, H-20) ppm. 13C NMR (101 MHz, CDCl3): δ 140.5 (Cq,
C11), 138.3 (Cq, Ph), 130.5 (Cq, C14), 128.6 (2CH), 127.9 (3CH),
86.73 (Cq, C10), 82.2 (CH, C12), 70.8 (CH2Ph), 37.9 (CH, C15), 34.3
(CH2, C13), 17.6 (CH3, C19/20), 16.4 (CH3, C19/20), 13.9 (CH3,
C18) ppm. HRMS (CI): m/z [M À OH]+ calcd for [C16H10OBr]+
307.0692, obsd 307.0699; calcd for [C16H10O81Br]+ 309.0672, obsd
309.0684. Analytical data of the trans isomer are as follows. Rf = 0.57
(1S,4S)-4-(Benzyloxy)-2-bromo-1-sec-butyl-3-methylcy-
clopent-2-enol (13a). In a flame-dried Schlenk tube freshly prepared
(+)-(Ipc)2BH16 (136 mg, 475 μmol, 2.00 equiv) was suspended in
1.00 mL of THF under positive argon pressure. At 0 °C a solution of 12a
(76.8 mg, 238 μmol, 1.0 equiv) in 500 μL of THF was added dropwise
within 5 min. The reaction mixture was stirred for 2.5 h until complete
conversion and warmed to room temperature. At 0 °C aqueous NaOH
(1.40 mL, 2.00 M, 2.79 mmol, 10.5 equiv) and an aqueous H2O2
solution (136 μL, 30%, 1.33 mmol, 5.00 equiv) were added, and stirring
was continued for 2 h at room temperature. After addition of water to the
mixture it was extracted three times with diethyl ether. The combined
organic layers were washed with brine, dried over MgSO4, and evapo-
rated to dryness at room temperature (caution! the product is very acid-
and temperature-sensitive). After purification by column chromatogra-
phy on deactivated silica gel (cyclohexane/EtOAc 7/3) 86.9 mg of 13a
was obtained as a colorless oil (217 μmol, 91%). For determination of
the diastereomeric excess by means of GC-MS, an analytical sample was
dissolved in N,O-bis(trimethylsilyl)acetamide and the solution stirred at
80 °C for 30 min. de = 75%. Rf = 0.12 (cyclohexane/EtOAc 7/3).
[R]20D = À10.3° (c = 1.15, THF). 1H NMR (400 MHz, CDCl3 filtered
2
over basic Al2O3): δ 7.38À7.26 (m, 5H, Ph), 4.58 (d, J = 11.8, 1H,
CH2Ph), 4.48 (d, 2J = 11.8, 1H, CH2Ph), 4.25 (ddd, 3J = 7.0, 4.2, 4J = 0.7,
1H, H-12), 3.79 (m, 1H, H-19), 3.35 (m, 1H, H-19), 2.81 (s, 1H,
OH), 2.59 (dd, 3J = 7.0, 2J = 14.0, 1H, H-13), 2.14 (m, 1H, H-15), 1.93
20
1
(cyclohexane/EtOAc 7/3). [R]D = À15.8° (c = 0.24, CHCl3). H
NMR (400 MHz, CDCl3): δ 1.36 - 1.34 (m, 4H, Ph), 1.29 (m, 1H, Ph),
4.62 (d, 2J = 11.8, CH2Ph), 4.52À4.47 (m, 2H, CH2Ph, H-12), 2.16 (dd,
3
2
4
(dd, J = 4.1, J = 14.0, 1H, H-13), 1.85 (d, J = 0.7, 3H, H-18), 1.78
(m, 1H, OH), 0.98 (d, 3J = 7.0, 3H, H-20) ppm. 13C NMR (100.6 MHz,
6698
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The Journal of Organic Chemistry
ARTICLE
CDCl3 filtered over basic Al2O3): δ 142.0 (Cq, C11), 138.2 (Cq, Ph),
128.6 (2CH, Ph), 128.4 (Cq, Ph), 127.9 (CH, Ph), 127.9 (2CH, Ph),
85.7 (Cq, C14), 81.5 (CH, C12), 71.0 (CH2Ph), 65.3 (CH2, C19),
42.9 (CH, C15), 42.8 (CH2, C13), 14.0 (CH3, C18), 11.7 (CH3,
C20) ppm. HRMS (ESI): m/z [M]+ calcd for [C16H21O379BrNa]+
363.0566, obsd 363.0566; calcd for [C16H21O381BrNa]+ 365.0546, obsd
365.0546.
(1S,4S)-4-(Benzyloxy)-1-((R)-1-(benzyloxy)propan-2-yl)-2-
bromo-3-methylcyclopent-2-enol (14a). In a flame-dried
Schlenk tube NaH (3.60 mg, 60%, 90.6 μmol, 1.50 equiv) was suspended
under an argon counterflow in 150 μL of THF at 0 °C. To this
suspension was added dropwise a solution of 13a (20.6 mg, 60.4 μmol,
1.00 equiv) in 150 μL of THF. The mixture was stirred for 20 min at
0 °C, HMPA (23.2 μL, 133 μmol, 2.20 equiv) and benzyl bromide (7.90
μL, 66.4 μmol, 1.10 equiv) were added, and the reaction mixture was
stirred for 3 h at room temperature. After cooling with an ice bath, water
was added carefully and the mixture was extracted three times with
diethyl ether. The combined organic layers were washed with brine,
dried over MgSO4, and evaporated to dryness. Column chromatography
on deactivated silica gel (cyclohexane/EtOAc 9/1) yielded the desired
isomer 14a (13.5 mg, 52%, >95% de by NMR). Data for the major
(CH2Ph), 41.6 (2CH2-carbamate), 40.5 (CH2, C13), 40.4 (CH,
C15), 13.8 (CH3-carbamate), 13.8 (CH3, C18), 13.7 (CH3-carbamate),
12.9 (CH3, C20) ppm. HRMS (ESI): m/z [M]+ calcd for [C28H36-
O4N79BrNa]+ 552.1720, obsd 552.1715; calcd for [C28H36O4-
N81BrNa]+ 554.1700, obsd 554.1693.
Mosher Ester Preparation of ent-10a. Preparation of (S)-
Mosher Ester. In a flame-dried Schlenk tube 15.0 mg (63.8 μmol, 1.00
equiv) of ent-10a together with 16.4 mg (70.2 μmol, 1.10 equiv) of
(S)-(À)-R-methoxy-R-(trifluoromethyl)phenylacetic acid were dis-
solved in 1.00 mL of freshly distilled DCM under argon. A 40.8 mg
portion (198 μmol, 3.10 equiv) of DCC and 24.2 mg of 4-DMAP (198
μmol, 3.10 equiv) were added, and the reaction mixture was stirred at
room temperature for 2 h. Water was added, and the mixture was
extracted three times with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and evaporated. After column
chromatography on deactivated silica gel (NEt3, cyclohexane/EtOAc 9/
1) 18.6 mg of the desired (S)-Mosher ester (41.2 μmol, 65%) was
obtained as a slightly yellow oil: Rf = 0.56 (cyclohexane/EtOAc 7/3).
[R]D20 = +0.74° (c = 1.27, CHCl3 filtered over basic Al2O3). 1H NMR
(400 MHz, CDCl3 filtered over basic Al2O3) δ 7.53 (m, 2H, Ph),
7.41À7.40 (m, 3H, Ph), 5.70 (dd, 1H, 3J = 6.9, 3.5, H-12), 4.23À4.16
(m, 2H, CH2-ketal), 4.20 (m, 1H, CH2-ketal), 3.96 (m, 1H, CH2-ketal),
3.55 (s, 3H, OMe), 2.81 (dd, 1H, 4J = 14.4, 3J = 7.0, H-13), 2.16 (dd, 1H,
isomer are as follows. Rf = 0.46 (cyclohexane/EtOAc 7/3). [R]20
=
D
1
À1.62° (c = 0.56, MeOH). H NMR (400 MHz, CDCl3 filtered over
basic Al2O3): δ 7.36À7.26 (m, 10H, Ph), 4.52 (m, 2H, CH2Ph), 4.44 (d,
2J = 11.8, 1H, CH2Ph), 4.39 (d, 2J = 11.8, 1H, CH2Ph), 4.20 (ddd, 3J =
7.0, 4.4, 4J = 1.0, 1H, H-12), 3.57 (dd, 2J = 9.5, 3J = 6.6, 1H, H-19), 3.26
(m, 1H, H-19), 2.63 (dd, 2J = 13.8, 3J = 7.1, 1H, H-13), 2.26 (m, 1H,
3
4J = 14.4, J = 3.6, H-13), 1.66 (s, 3H, H-18) ppm. 13C NMR (100.7
MHz, CDCl3 filtered over basic Al2O3): δ 166.5 (Cq, CO), 141.5 (Cq,
C11), 132.1 (Cq, Ph), 129.9 (CH, Ph), 128.6 (3CH, Ph), 127.3 (CH,
Ph), 126.9 (Cq, CF3), 115.9 (Cq, C10), 78.0 (CH, C12), 66.5 (CH2,
C-ketal), 66.0 (CH2, C-ketal), 55.4 (CH3, OMe), 42.8 (CH2, C13), 13.5
(C3, C18) ppm. HRMS (EI): m/z [M]+ calcd for [C18H18O5BrF3]+
450.0290, obsd 450.0280.
2
3
4
H-15), 1.91 (dd, J = 13.8, J = 4.4, 1H, H-13), 1.81 (d, J = 1.0, 3H,
3
H-18), 0.99 (d, J = 7.0, 3H, H-20) ppm. 13C NMR (100.6 MHz,
CDCl3 filtered over basic Al2O3): δ 141.6 (2Cq, Ph), 138.4 (Cq, C11),
128.6 (2CH, Ph), 128.5 (2CH, Ph), 128.3 (Cq, C10), 127.8 (6CH, Ph),
85.5 (Cq, C14), 81.5 (CH, C12), 73.5 (CH2Ph), 72.8 (CH2, C19),
70.6 (CH2Ph), 42.9 (CH2, C13), 40.9 (CH, C15), 13.9 (CH3, C18),
12.1 (CH3, C20) ppm. HRMS (ESI): m/z [M]+ calcd for [C23H27-
O379BrNa]+ 453.1036, obsd 453.1031; calcd for [C23H27O381BrNa]+
455.1015, obsd 455.1010.
Preparation of (R)-Mosher Ester. In a flame-dried Schlenk tube 5.00
mg (21.3 μmol, 1.0 equiv) of ent-10a was dissolved in a mixture of 330
μL of CHCl3 and 5.30 μL (65.9 μmol, 3.10 equiv) of pyridine. Under
argon 7.50 μL of (S)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetyl
chloride (40.4 μmol, 1.10 equiv) was added. After stirring at room
temperature for 3 h starting material was no longer detectable by TLC.
The mixture was diluted with water and extracted three times with
diethyl ether. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo. After column chroma-
tography on deactivated silica gel (NEt3, cyclohexane/EtOAc 9/1) 5.00
mg (11.1 μmol, 52%) of a slightly yellow oil was obtained: Rf = 0.56
(cyclohexane/EtOAc 7/3), [R]D20 = +49.9° (c = 0.39, CHCl3 filtered
(1S,4S)-4-(Benzyloxy)-1-((R)-1-(benzyloxy)propan-2-yl)-2-
bromo-3-methylcyclopent-2-enyl Diethylcarbamate (3a).
To a solution of 14a (13.7 mg, 31.7 μmol, 1.00 equiv) in 400 μL of
THF in a flame-dried Schlenk tube was added a small amount of NaH (at
least 3.00 mg oil free, washed with pentane, ca. 90%, 63.5 μmol, at least
2.00 equiv) under argon pressure. The resulting suspension was stirred
for 40 min at room temperature, and small amounts of 4-DMAP and
diethylcarbamoyl chloride (44.0 μL, 318 μmol, 10.0 equiv) were added.
The reaction mixture was stirred overnight at 60 °C and cooled to room
temperature, and water was added. The mixture was extracted three
times with EtOAc. The combined organic layers were washed once with
brine and evaporated to dryness. The crude product was purified by
column chromatography on silica gel which had been pretreated with
NEt3 (cyclohexane/EtOAc 9/1 to 4/1) to yield 10.6 mg of the desired
building block 6a (20.0 μmol, 63%, 95% de by NMR) as a slightly yellow
1
over basic Al2O3). H NMR (400 MHz, CDCl3 filtered over basic
Al2O3): δ 7.51 (m, 2H, Ph), 7.42À7.38 (m, 3H, Ph), 5.71 (ddd, 1H, 3J =
7.2, 4.0, 4J = 1.0, H-12), 4.22À4.13 (CH2, CH2-ketal), 4.03À3.91 (CH2,
CH2-ketal), 3.54 (q, 3H, 4J = 1.2, OMe), 2.79 (dd, 1H, 2J = 14.3, 3J = 7.2,
H-13), 2.03 (M, 1H, H-13), 1.80 (d, 4J = 1.0, 3H, H-18) ppm.
Preparation of (3S,5S,10R)-3-(Benzyloxy)-1-bromo-2,10-
dimethyl-6,8-dioxaspiro[4.5]dec-1-en-7-one (15). To a solu-
tion of 27.0 mg of 14a (79.1 μmol, 1.0 equiv) in 1.00 mL of THF was
added 191 μL of pyridine (2.37 mmol, 30.0 equiv), and the solution was
cooled to 0 °C. A solution of 62.4 μL of phosgene in toluene (119 μmol,
1.50 equiv, 20% in toluene) was added. A slightly yellow precipitate
formed. The same amount of phosgene was added a second time at 0 °C,
and the reaction mixture was stirred for 14 h at room temperature under
argon. The reaction was quenched by the addition of saturated NaHCO3
solution, and the mixture was extracted three times with diethyl ether.
The combined organic layers were washed once with water and brine,
dried over MgSO4, and concentrated in vacuo. After purification by
column chromatography on deactivated silica gel (NEt3, cyclohexane/
EtOAc 9/1 to 7/3) 14.7 mg of a slightly yellow oil (40.3 μmol, 51%) was
obtained: Rf = 0.3 (cyclohexane/EtOAc 1/1). [R]D20 = 57.1° (c = 0.30,
THF). 1H NMR (400 MHz, MeOD): δ 7.39À7.33 (m, 4H, Ph),
oil. Rf = 0.52 (cyclohexane/EtOAc 7/3). [R]20 = À0.93° (c = 0.48,
D
1
MeOH). H NMR (400 MHz, CDCl3 filtered over basic Al2O3): δ
7.34À7.28 (m, 10H, Ph), 4.58 (d, 2J = 12.1, 1H, CH2Ph), 4.50 (d, 2J =
12.1, 1H, CH2Ph), 4.43 (d,2J = 12.1, 1H, CH2Ph), 4.38 (d, 2J = 12.1, 1H,
CH2Ph), 4.27 (ddd, 3J = 7.2, 5.4, 4J = 1.0, 1H, H-12), 3.43 (dd, 2J = 9.5,
3J = 3.7, 1H, H-19), 3.31 (dd, 2J = 9.5, 3J = 7.6, 1H, H-19), 3.28À3.15 (m,
4H, CH2-carbamate), 2.81 (dd, 2J = 13.6, 3J = 7.2, 1H, H-13), 2.67À2.55
(m, 2H, H-15, H-13), 1.83 (d, 4J = 1.0, 3H, H.18), 1.09 (t, 3J = 7.1, 6H,
3
CH3-carbamate), 1.05 (d, J = 6.9, 3H, H-20) ppm. 13C NMR (100.6
MHz, CDCl3 filtered over basic Al2O3): δ 154.0 (Cq, CO), 142.4 (Cq,
C11), 138.8 (Cq, Ph), 138.6 (Cq, Ph), 128.5 (4CH, Ph), 127.8 (2CH,
Ph), 127.7 (2CH, Ph), 127.6 (2C, Cq, CH, Ph), 123.9 (Cq, C10), 91.3
(Cq, C14), 81.7 (CH, C12), 73.1 (CH2Ph), 71.3 (CH2, C19), 70.1
2
7.29 (m, 1H, Ph), 4.70 (m, H-19), 4.61 (d, J = 11.8, 1H, CH2Ph),
6699
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The Journal of Organic Chemistry
ARTICLE
4.56 (d, 2J = 11.8, 1H, CH2Ph), 4.39 (ddq, 3J = 7.0, 5.0, 4J = 0.9, 1H, H-12),
4.27 (dd, 2J= 11.3, 3J= 5.8, 1H, H-19), 2.77 (dd, 2J=14.0, 3J=6.9, 1H, H-13),
2.56 (m, 1H, H-15), 2.27 (dd, 2J = 14.0, 3J = 5.0, 1H, H-13), 1.88 (d, 4J =
1.0, 3H, H-18), 0.87 (d, 3J = 6.9, 3H, H-20) ppm. 1H NMR (400 MHz,
CDCl3): δ 7.38À7.29 (m, 5H, Ph), 4.75 (m, 1H, H-19), 4.54 (dd, 2J =
11.9, 1H, CH2Ph), 4.51 (dd, 2J = 11.9, 1H, CH2Ph), 4.29 (m, 1H, H-12),
4.16 (dd, 2J = 11.3, 3J = 5.8, 1H, H-19), 2.56 (dd, 2J = 14.0, 3J = 6.9, 1H,
combined organic layers were washed with brine, dried over MgSO4, and
evaporated to dryness. The remaining yellow oil was dissolved in EtOAc
and filtered several times over Celite. The filtrate was evaporated to
dryness to yield 517 mg of a slightly yellow wax as the crude product 9b
(30.5 mmol, 58%). Rf = 0.46 (cyclohexane/EtOAc 9/1). IR (ATR):
1
2980 (w), 2900 (w), 1706 (vs), 1622 (m), 1472 (w) cmÀ1. H NMR
(400 MHz, CDCl3, filtered over basic Al2O3): δ 4.30 (m, 2H, CH2-
ketal), 4.09 (m, 2H, CH2-ketal), 2.78 (s, 2H, H-13), 1.87 (s, 3H, H-18)
ppm. 13C NMR (100.6 MHz, CDCl3): δ 199.3 (Cq, C12), 151.7 (Cq,
C11), 135.2 (Cq, C14), 111.3 (Cq, C10), 66.6 (2CH2-ketal), 47.3 (CH2,
C13), 13.1 (CH3, C18) ppm. HRMS (EI): m/z [M]+ calcd for
[C8H9O3I]+ 279.9591, obsd 279.9597.
4
H-13), 2.49À2.41 (m, 2H, H-15, H-13), 1.89 (d, J = 1.0, 3H, H-18),
0.84 (d, 3J = 6.9, H-20) ppm. 13C NMR (100.7 MHz, CDCl3): δ 148.4
(Cq, CO), 147.6 (Cq, Ph), 137.9 (Cq, C11), 128.7 (2CH, Ph), 128.1
(CH, Ph), 127.8 (2CH, Ph), 119.2 (Cq, C10), 93.1 (Cq, C14), 80.1 (CH,
C12), 70.7 (CH2, CH2Ph), 69.9 (CH2, C19), 46.5 (CH2, C13), 35.4
(CH, C15), 14.1 (CH3, C18), 10.2 (CH3, C20) ppm. HRMS (ESI): m/z
[M + H]+ calcd for [C17H20O4Br]+ 367.0540, obsd 367.0541; calcd for
[C17H20O481Br]+ 369.0519, obsd 369.0519. To confirm the configura-
tion of 14a, 1D-NOE spectra in MeOD were recorded (see Scheme 4).
Preparation of 2-Iodo-3-methyl-2-cyclopentenone (7b)26.
A 3.40 mL portion of 3-methylcyclopentenone (6; 33.3 mmol, 1.00
equiv) was dissolved in 216 mL of freshly distilled DCM. At room
temperature under argon 12.7 g of iodine (49.9 mmol, 1.50 equiv) and
3.8 g of pyridinium dichromate (10.0 mmol, 0.30 equiv) were added.
The reaction mixture was stirred for 48 h at room temperature under
argon until completeness. The mixture was filtered, and the precipitate
was washed carefully with DCM. Subsequently, 1.00 M HCl was added
to the filtrate, the layers were separated, and the organic layer was
washed again with 1.00 M HCl, saturated Na2S2O3 solution, and brine.
After it was dried over MgSO4, the organic layer was taken to dryness.
The crude product was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 9/1 to 7/3); 6.10 g (27.4 mmol, 82%) of the
desired product as a slightly yellow wax was obtained. Rf = 0.29
(S)-9-Iodo-8-methyl-1,4-dioxaspiro[4.4]non-8-en-7-ol (10b).
A mixture of (R)-2-methyl-CBS-oxazaborolidine solution in THF (185 μL,
1.00 M, 185 μmol, 0.10 equiv) and 4.0 mL of THF under argon in a flame-
dried two-necked round-bottom flask was cooled to 0 °C, and dimethyl
sulfideÀborane (350 μL, 3.69 mmol, 2.00 equiv) was added dropwise. After
the mixture was stirred for 30 min at 0 °C, a solution of 9b (517 mg, 1.85
mmol, 1.00 equiv) in 4.00 mL of THF was added at 0 °C over a period of 3 h
using a syringe pump and stirring was continued for 30 min at 0 °C.
Methanol was added carefully at 0 °C, and the mixture was warmed to room
temperature. Water was added, and the mixture was extracted three times
with diethyl ether. The combined organic layers were washed with brine,
dried over MgSO4, and evaporated to dryness to yield 399 mg of crude 10b
as a pale yellow oil (77%, >98% ee determined by chiral GC). The crude
product was used without further purification for the further syntheses. For
analytical purposes 90.0 mg of the crude product was purified by column
chromatography on silica gel which had been pretreated with NEt3
(cyclohexane/EtOAc 9/1 to 7/3) to obtain 52.0 mg of the pure desired
product as a colorless wax. Rf = 0.15 (cyclohexane/EtOAc 7/3). [R]20
=
D
5.27° (c = 0.64, CHCl3 filtered over basic Al2O3). 1H NMR (400 MHz,
CDCl3 filtered over basic Al2O3): δ 4.57 (s, br, 1H, H-12), 4.20 (m, 2H,
1
(cyclohexane/EtOAc 7/3). H NMR (400 MHz, CDCl3): δ 2.75 (m,
2H, H-13), 2.58 (m, 2H, H-12), 2.22 (m, 3H, H-18) ppm. 13C NMR
(100.7 MHz, CDCl3): δ 203.7 (Cq, C14), 179.8 (Cq, C11), 102.8 (Cq,
C10), 34.4 (CH2, C13), 33.3 (CH2, C12), 22.2 (CH3, C18) ppm.
HRMS (EI): m/z [M]+ calcd for [C6H7OI]+ 221.9536, obsd 221.9533.
6-Iodo-7-methyl-1,4-dioxaspiro[4.4]non-6-ene (8b). To a
solution of 2-iodo-3-methylcylopent-2-enone (1.00 g, 4.5 mmol, 1.00
equiv) in triethyl orthoformate (5.30 mL, 31.5 mmol, 7.00 equiv) were
added ethylene glycol (1.80 mL, 31.5 mmol, 7.00 equiv) and
p-toluenesulfonic acid (8.60 mg, 45.0 μmol, 0.01 equiv). The reaction
mixture was stirred for 22 h at room temperature until conversion was
complete (GC/MS), purged into 50.0 mL of 2.00 M NaOH solution,
and extracted three times with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and evaporated to dryness
to yield the crude product as a black oil. Purification by column
chromatography on alumina (pH 10, Brockmann activity 2) yielded
574 mg (2.16 mmol, 48%) of 8b as a slightly yellow oil. Rf = 0.53
2
3
CH2-ketal), 3.99 (m, 2H, CH2-ketal), 2.62 (dd, J = 14.0, J = 7.0, 1H,
H-13), 2.02 (dd, 2J = 13.9, 3J = 3.7, 1H, H-13), 1.90 (dd, 4J = 0.9, 3H, H-18)
ppm. 13C NMR (100.6 MHz, CDCl3 filtered over basic Al2O3) δ153.4 (Cq,
C11), 116.4 (Cq, C14), 103.6 (Cq, C10), 75.6 (CH, C12), 66.2 (CH2-
ketal), 65.9 (CH2-ketal), 45.4 (CH2, C13), 16.72 (CH3, C18) ppm. HRMS
(EI): m/z [M]+ calcd for [C8H11O3I]+ 281.9747, obsd 281.9748.
(S)-2-Iodo-4-(4-methoxybenzyloxy)-3-methylcyclopent-
2-enone (5b). To a suspension of NaH (157 mg, 3.92 mmol, 2.00
equiv) in a flame-dried two-necked round-bottom flask in 10.0 mL of
THF under argon was added dropwise a solution of crude 10b (553
mg, 1.96 mmol, 1.00 equiv) in 10.0 mL of THF within 10 min at 0 °C.
The reaction mixture was stirred for 30 min at room temperature,
HMPA (1.40 mL, 7.84 mmol, 4.00 equiv) and p-methoxybenzyl
bromide (583 μL, 3.92 mmol, 2.00 equiv) were added, and the mixture
was stirred overnight at room temperature. After it was cooled with an
ice bath, the mixture was carefully diluted with water and extracted
three times with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, and evaporated to dryness to yield
1.35 g of crude (S)-8-(benzyloxy)-6-iodo-7-methyl-1,4-dioxaspiro-
[4.4]non-6-ene as a yellow liquid. The crude product was used for
the next reaction without further purification.
A solution of 1.35 g of crude (S)-8-(benzyloxy)-6-iodo-7-methyl-1,4-
dioxaspiro[4.4]non-6-ene and a small amount of TosOH in 39.0 mL
acetone/water (25/1) was stirred for 20 h under argon at room
temperature (conversion was monitored by GC/MS). The reaction
mixture was diluted with water and extracted three times with EtOAc.
The combined organic layers were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification by column chromatog-
raphy on silica gel (cyclohexane/EtOAc 9/1) provided 205 mg of 5b
(573 μmol, 27% over four steps) as a yellow, viscous oil, Rf = 0.52
(cyclohexane/EtOAc 7/3). [R]20D = 39.4° (c = 0.85, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 7.27 (m, 2H, Ph), 6.90 (m, 2H, Ph), 4.63À4.55
1
(cyclohexane/EtOAc 7/3). H NMR (400 MHz, CDCl3 filtered over
basic Al2O3): δ 4.20 (m, 2H, CH2-ketal), 3.98 (m, 2H, CH2--ketal), 2.44
(m, 2H, H-12), 2.18 (m, 2H, H-13), 1.85 (t, 4J = 0.9, 3H, H-18) ppm.
13C NMR (100.6 MHz, CDCl3 filtered over basic Al2O3): δ 151.4 (Cq,
C11), 120.0 (Cq, C14), 98.2 (Cq, C10), 65.8 (CH2-ketal), 34.6 (CH2,
C12/13), 34.6 (CH2, C12/13, 19.8 (CH3, C18) ppm. HRMS (EI): m/z
[M]+ calcd for [C8H11O2I]+ 265.9798, obsd 265.9790.
9-Iodo-8-methyl-1,4-dioxaspiro[4.4]non-8-en-7-one (9b).
To a mixture of 8b (574 mg, 2.16 mmol, 1.00 equiv), molecular sieves (4
Å), and 4.60 mL of a 34% solution of TBHP in C2H4Cl2 (21.6 mmol,
10.0 equiv) was added Cr(CO)6 (47.5 mg, 216 μmol, 0.10 equiv) under
argon, and the reaction mixture was stirred at 40 °C for 22 h. At this time
GC/MS analysis showed ca. 33% conversion. A solution of 1.00 mL of
TBHP in C2H4Cl2 (4.74 mmol, 2.20 equiv) was added, and the mixture
was stirred for a further 46 h at 40 °C until all starting material had been
consumed. The reaction mixture was filtered, water was added to the
filtrate, and the mixture was extracted three times with EtOAc. The
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ARTICLE
(m, 2H, CH2PhOMe, H-12), 4.49 (d, 3J = 11.3, 1H, CH2PhOMe), 3.82
(s, 3H, OCH3), 2.81 (dd, 2J = 18.1, 3J = 5.9, 1H, H-13), 2.51 (dd, 2J =
18.0, 3J = 2.2, 1H, H-13), 2.22 (d, 4J = 0.4, 3H, H-18) ppm. 13C NMR
(100.6 MHz, CDCl3): δ 199.2 (Cq, C14), 177.7 (Cq, C11), 129.8 (2CH,
PhOMe), 129.5 (Cq, Ph), 129.3 (Cq, Ph), 114.2 (2CH, Ph), 113.9 (Cq,
C10), 79.0 (CH, C12), 71.9 (CH2PhOMe), 55.5 (CH3, OMe), 40.4
(CH2, C13), 19.4 (CH3, C18) ppm. HRMS (EI): m/z [M]+ calcd for
[C14H15O3I]+ 358.0060, obsd 358.0054.
CH2PhOMe), 4.43 (d, 2J = 11.3, 1H, CH2PhOMe), 4.27 (ddd, 3J = 7.3,
4.8, 4J = 1.0, 1H, H-12), 3.78 (s, 3H, OCH3), 3.36 (dd, 2J = 10.7, 3J = 4.0,
1H, H-19), 3.03 (dd, 2J = 10.7, 3J = 8.3, 1H, H-19), 2.73 (dd, 2J = 13.9,
3J = 7.4, 1H, H-13), 1.99 (m, 1H, H-15), 1.83 (d, 4J = 1.0, 3H, H-18),
1.73 (dd, 4J = 13.8, 3J = 4.7, 1H, H-13), 1.09 (d, 3J = 6.8, 3H, H-20) ppm.
13C NMR (100.6 MHz, MeOD): δ 178.1 (Cq), 148.0 (Cq, C11), 131.7
(Cq), 130.6 (2CH, PhOMe), 114.8 (2CH, PhOMe), 112.7 (Cq, C14),
86.4 (Cq, C10), 83.7 (CH, C12), 71.6 (CH2PhOMe), 64.1 (CH2, C19),
55.7 (CH3, OMe), 44.0 (CH, C15), 41.1 (CH2, C12), 17.1 (CH3, C18),
11.6 (CH3, C20) ppm. HRMS (ESI): m/z [M]+ calcd for [C17H23-
O4INa]+ 441.0533, obsd 441.0525.
(1S,4S)-2-Iodo-4-(4-methoxybenzyloxy)-3-methyl-1-(prop-
1-en-2-yl)cyclopent-2-enol (12b). A water-free suspension of
CeCl3 in THF (4.10 mL, 0.10 g/mL, 1.66 mmol, 3.00 equiv; for the
preparation, see ref 24) was added via a transfer cannula to a solution of
5b (199 mg, 554 μmol, 1.00 equiv) in 8.80 mL of THF in a flame-dried
Schlenk tube under positive argon pressure. The suspension was stirred
for 3 h at room temperature, and a solution of isopropylmagensium
bromide in THF (3.30 mL, 0.50 M, 1.66 mmol, 3.00 equiv) was added
dropwise within 20 min. The reaction mixture was stirred at room
temperature until all starting material was consumed (determined by
GC/MS and by TLC control; 30 min). After it was cooled with an ice
bath, the reaction mixture was carefully diluted with water and extracted
three times with diethyl ether. The combined organic layers were
washed with brine, dried over MgSO4, and evaporated to dryness.
Purification by column chromatography on silica gel (cyclohexane/
EtOAc 9/1) yielded 193 mg (483 μmol, 87%, >87% de by NMR) of 12b
(1S,4S)-2-Iodo-4-(4-methoxybenzyloxy)-1-((R)-1-(4-meth-
oxybenzyloxy)propan-2-yl)-3-methylcyclopent-2-enol (14b).
In a flame-dried Schlenk tube NaH (5.80 mg, 60%, 145.5 μmol, 1.25
equiv) was suspended under positive argon pressure in 300 μL of THF.
At 0 °C a solution of 13b (48.7 mg, 116 μmol, 1.00 equiv) in 300 μL of
THF was slowly added dropwise. The mixture was stirred for 20 min at
0 °C, HMPA (28.6 μL, 233 μmol, 2.00 equiv) and p-methoxybenzyl
bromide (17.3 μL, 116 μmol, 1.00 equiv) were added, and stirring was
continued for 1.5 h at 0 °C and for an additional 20 min at room
temperature, after which the starting material was completely consumed.
After the mixture was cooled with an ice bath, water was added, the
aqueous phase was extracted three times with EtOAc, and the combined
organic layers were washed with brine, dried over MgSO4, and evapo-
rated to dryness. Purification by column chromatography on silica
yielded 29.4 mg of 14b as a colorless oil (54.6 μmol, 47%, 80% de by
NMR). Rf = 0.36 (cyclohexane/EtOAc 7/3). [R]20D = 3.87° (c = 0.31,
MeOH). 1H NMR (400 MHz, CDCl3): δ 7.25À7.19 (m, 4H, PhOMe),
6.88À6.85 (m, 4H, PhOMe), 4.44 (dd, 2J = 11.3, 9.8, 2H, CH2PhOMe),
4.36 (d, 2J = 11.4, 1H, CH2PhOMe), 4.30 (d, 2J = 11.4, 1H,
as a slightly yellow oil. Rf = 0.61 (cyclohexane/EtOAc 7/3). [R]20
=
D
13.0° (c = 0.05, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.27 (m, 2H,
PhOMe), 6.89 (m, 2H, PhOMe), 5.14 (dd, 4J = 0.7, 1.4, 1H, H-19), 4.97
(p, 4J = 1.4, 1H, H-19), 4.51 (d, 2J = 11.3, 1H, CH2PhOMe), 4.44 (d, 2J =
11.4, 1H, CH2PhOMe), 4.35 (ddq, 4J = 0.9, 3J = 4.3, 7.2, 1H, H-12), 3.81,
(s, 3H, OCH3), 2.64 (dd, 2J = 13.9, 3J = 7.2, 1H, H-13), 2.20 (s, br, 1H,
OH), 2.09 (dd, 2J = 13.9, 3J = 4.3, 1H, H-13), 1.89 (d, 4J = 0.9, 3H, H-18),
1.57 (dd, 4J = 0.7, 1.4, 3H, H-20) ppm. 13C NMR (100.6 MHz, CDCl3):
δ 159.5 (Cq, PhOMe), 148.6 (Cq, C14), 146.6 (Cq, C11), 130.3 (Cq,
PhOMe), 129.5 (2CH, PhOMe), 114.0 (Cq), 111.8 (2CH, PhOMe),
110.6 (Cq, C10), 87.4 (Cq, C15), 83.1 (CH, C12), 70.7 (CH2PhOMe),
55.4 (CH3, OMe), 43.2 (CH2, C13), 18.6 (CH3 C20), 17.2 (CH3, C18)
ppm. HRMS (ESI): m/z [M]+ calcd for [C17H21O3INa]+ 423.0428,
obsd 423.0425.
3
4
CH2PhOMe), 4.21 (ddd, J = 7.0, 4.4, J = 0.9, 1H, H-12), 3.80 (s,
6H, 2OCH3), 3.46 (dd, 2J = 9.5, 3J = 5.8, 1H, H-19), 3.15 (dd, 2J = 9.5,
3J = 5.8, 1H, H-19), 2.86 (s, 1H, OH), 2.64 (dd, 2J = 13.8, 3J = 7.1, 1H,
H-13), 2.18 (m, 1H, H-15), 1.88 (dd, 2J = 13.8, 3J = 4.4, 1H, H-13), 1.82
4
3
(d, J = 0.8, 3H, H-18), 1.03 (d, J = 6.9, 3H, H-20) ppm. 13C NMR
(100.6 MHz, CDCl3): δ 159.4 (2Cq, PhOMe), 148.1 (Cq, C11), 130.5
(Cq), 130.3 (Cq), 129.5 (2CH, PhOMe), 129.5 (2CH, PhOMe), 114.0
(2CH, PhOMe), 113.9 (2CH, PhOMe), 110.3 (Cq, C10), 86.2 8 (Cq,
C14), 82.4 (CH, C12), 73.0 (CH2, CH2PhOMe), 72.1 (CH2, C19),
70.5 (CH2, CH2PhOMe), 55.4 (2CH3, 2OMe), 41.9 (CH2, C13), 41.5
(CH, C15), 17.3 (CH3, C18), 12.0 (CH3, C20) ppm. HRMS (ESI):
m/z [M]+ calcd for [C25H31O5INa]+ 561.1108, obsd 561.1102.
(1S,4S)-1-((R)-1-Hydroxypropan-2-yl)-2-iodo-4-(4-meth-
oxybenzyloxy)-3-methylcyclopent-2-enol (13b). Freshly pre-
pared (+)-(Ipc)2BH (186 mg, 651 μmol, 1.50 equiv) was suspended in
2.10 mL of THF in a flame-dried Schlenk tube under positive argon
pressure. At 0 °C a solution of 12b (174 mg, 434 μmol, 1.00 equiv) in
1.50 mL of THF was added dropwise within 15 min. The reaction
mixture was stirred for 60 min at room temperature, and since GC/MS
monitoring revealed that the starting material had not been consumed
completely, (+)-(Ipc)2BH (124 mg, 434 μmol, 1.00 equiv) was added as
a solid on cooling with an ice bath. The reaction mixture was stirred until
conversion was complete (60 min) with warming to room temperature.
At 0 °C aqueous NaOH (2.80 mL, 2.00 M, 5.69 mmol, 13.3 equiv) and
an aqueous H2O2 solution (277 μL, 30%, 2.71 mmol, 6.30 equiv) were
added dropwise to the reaction mixture, and the mixture was stirred for
3 h at room temperature. Water was added, the mixture was extracted
three times with diethyl ether, and the combined organic layers were
washed with brine, dried over MgSO4, and evaporated to dryness at
room temperature (caution! the product is very acid and temperature
sensitive). After purification by column chromatography on deactivated
silica gel (cyclohexane/EtOAc 7/3) 69.7 mg of 12b was obtained as a
slightly yellow oil (165 μmol, 38%). To calculate the diastereomeric
excess, an analytical sample of the product was dissolved in N,O-
bis(trimethylsilyl)acetamide and stirred at 80 °C for 30 min. Monitoring
by GC/MS revealed a de of 80%. Rf = 0.07 (cyclohexane/EtOAc 7/3).
[R]20D = 13.6° (c = 0.75, MeOH). 1H NMR (400 MHz, MeOD): δ 7.28
(m, 2H, PhOMe), 6.89 (m, 2H, PhOMe), 4.50 (d, 2J = 11.3, 1H,
(1S,4S)-2-Iodo-4-(4-methoxybenzyloxy)-1-((R)-1-(4-meth-
oxybenzyloxy)propan-2-yl)-3-methylcyclopent-2-enyl Di-
ethylcarbamate (3b). To a suspension of NaH (3.20 mg, 60%, 80
μmol, 2.00 equiv) in 300 μL of THF in a flame-dried flask was added
dropwise a solution of 14b (21.5 mg, 40 μmol, 1.00 equiv) in 300 μL of
THF at room temperature, and the mixture was stirred for 30 min.
4-DMAP (4.90 mg, 40.0 μmol, 1.00 equiv) and diethylcarbamoyl
chloride (52.2 μL, 399 μmol, 10.0 equiv) were added, and the reaction
mixture was stirred overnight at 45 °C. After it was cooled to room
temperature, the mixture was quenched by the addition of water and
extracted three times with EtOAc. The combined organic layers were
washed once with brine, dried over MgSO4, and evaporated to dryness.
Purification on deactivated silica gel (NEt3, cyclohexane/EtOAc 9/1)
yielded 6.3 mg of 3b as a slightly yellow oil (9.90 μmol, 25%, >95% de by
NMR). Rf = 0.41 (cyclohexane/EtOAc 7/3). [R]20D = 5.32° (c = 0.55,
MeOH). 1H NMR (400 MHz, CDCl3): δ 7.26À7.18 (m, 4H, PhOMe),
2
6.86À6.84 (m, 4H, PhOMe), 4.50 (d, J = 11.8, 1H, CH2PhOMe),
4.42 (d, 2J = 11.8, 1H, CH2PhOMe), 4.35 (d, 2J = 11.6, 1H,
CH2PhOMe), 4.30À4.26 (m, 2H, CH2PhOMe, H-12), 3.80À3.80
(m, 6H, 2OCH3), 3.34 - 3.12 (m, 6H, 2CH2-carbamate, 2H-19), 2.77
(dd, 2J = 13.3, 3J = 7.3, 1H, H-13), 2.63 (dd, 2J = 13.3, 3J = 5.6, 1H, H-13),
4
2.53À2.49 (m, 1H, H-15), 1.84 (d, J = 1.0, 3H, H-18), 1.13À1.10
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The Journal of Organic Chemistry
ARTICLE
(m, 6H, CH3-carbamate), 1.08 (d, 3J = 6.8, 3H, H-29). ppm. 13C NMR
(100.6 MHz, CDCl3): δ 159.2 (2Cq), 153.9 (Cq), 148.8 (Cq, C11),
130.6 (2Cq), 129.4 (2CH, PhOMe), 129.3 (2CH, PhOMe), 113.9
(4CH, PhOMe), 104.4 (Cq, C10), 92.3 (Cq, C14), 82.3 (CH, C12),
72.8 (CH2, CH2PhOMe), 70.9 (CH2, C19), 69.7 (CH2, CH2PhOMe),
55.4 (2CH3, 2OMe), 41.6 (CH2, C13), 41.0 (2CH2, CH2-carbamate),
39.1 (CH, C15), 17.1 (CH3, C18), 14.0 (2CH3, CH3-carbamate), 12.8
(CH3, C20) ppm. HRMS (ESI): m/z [M]+ calcd for [C30H40O6NINa]+
660.1793, obsd 660.1789.
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’ ASSOCIATED CONTENT
S
Supporting Information. Text, figures, and a table giving
b
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an explanation of the Mosher ester analysis, an exploration of
different methods for the allylic oxidation of 8a, and 1H and 13
C
spectra of all compounds synthesized. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: herbert.waldmann@mpi-dortmund.mpg.de. Tel:
+492311332401. Fax: +492311332499.
’ ACKNOWLEDGMENT
This research was supported by the Max Planck Society and
the Fonds der Chemischen Industrie (Kekulꢀe-stipend to A.R.).
The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC Grant
Agreement No. 268309 (H.W.)
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