Step-economic synthesis of (+)-crocacin C: A concise crotylboronation/[3,3] -sigmatropic rearrangement approach

Article abstract of DOI:10.1021/jo301210f

The step-economic total synthesis of (+)-crocacin C has been achieved in 20% yield from commercially available starting materials. This approach requires the isolation of only 8 intermediates and can provide a reliable supply of (+)-crocacin C for the development of new antifungal and crop protection agents.

Full text of DOI:10.1021/jo301210f

Article
pubs.acs.org/joc
Step-Economic Synthesis of (+)-Crocacin C: A Concise
Crotylboronation/[3,3]-Sigmatropic Rearrangement Approach†
Adele E. Pasqua,‡ Frank D. Ferrari,‡ Chris Hamman,§ Yanzhou Liu,§ James J. Crawford,§
and Rodolfo Marquez*,‡,∥
‡School of Chemistry, University of Glasgow, Glasgow G12 8QQ, U.K.
§Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
S
* Supporting Information
ABSTRACT: The step-economic total synthesis of (+)-cro-
cacin C has been achieved in 20% yield from commercially
available starting materials. This approach requires the
isolation of only 8 intermediates and can provide a reliable
supply of (+)-crocacin C for the development of new
antifungal and crop protection agents.
he crocacins are a family of four antifungal and cytotoxic
residue. Crocacin C 3 is the free carboxamide unit. The
promising biological activity, together with their low natural
abundance and interesting structural features, has made them
attractive synthetic targets. This interest has resulted in a
number of formal and total syntheses.4−11
T
antibiotics, isolated in 1994 from two different strains of
Chondromyces bacteria by Hofle and co-workers (Figure 1).1
̈
As part of our efforts toward the development of stable
crocacin analogues starting from (+)-crocacin C as a synthetic
platform, we have recently reported our initial modular
synthetic approach to the formal synthesis of (+)-crocacin C
3.11 However, despite the fact that our approach was successful
in completing the formal synthesis of (+)-crocacin C 3, it was
deemed unsuitable for scale-up due to the number of steps
required and its low overall efficiency. Challenged by this
outcome, we sought to develop an alternative route, and in this
contribution we report our efficient, step-economic, and cost-
effective second generation synthesis of (+)-crocacin C 3 from
commercially available starting materials.
Figure 1. Crocacins A−D.
Biologically, the crocacins exhibit a range of activities. Crocacin
A 1 has shown remarkable activity as a growth inhibitor of fungi
and yeasts through inhibition of the electron flow within the
cytochrome bc1 segment (complex III) of the respiratory chain,
while crocacin D 4 has shown a MIC of 1.4 ng/mL against S.
cerevisiae.2
RESULTS AND DISCUSSION
■
In planning our current approach, we envisioned that crocacin
C 3 could be derived following a route featuring a concise
crotylboronation, cross-metathesis, and [3,3]-sigmatropic re-
arrangement (Scheme 1).
Crucial for this bioactivity is the highly reactive enamide
moiety. It has been postulated that the enamide unit is
protonated, and the resultant N-acyliminium ion can then be
trapped by a nucleophile to generate the enzyme complex
responsible for activity.2
Scheme 1. Second Generation Retrosynthetic Analysis of
(+)-Crocacin C 3
Despite their relative instability, the crocacins have been the
subject of industrial antifungal research as they inhibit strains of
yeast that have been genetically modified for antifungal
resistance,3 as well as vine downy mildew (Phytophthora
infestans) and wheat brown rust (Puccinia recondite). Crocacins
A 1, B 2, and D 4 are unusual dipeptides incorporating glycine
and a 6-aminohexenoic or 6-aminohexadienoic acid in which
the nitrogen is protected by a complex polyketide derived acyl
Received: June 11, 2012
Published: July 17, 2012
© 2012 American Chemical Society
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Scheme 2. Synthesis of Enone 13
a
Table 1. Cross-Metathesis Studies for the Synthesis of Enone 13
entry
equiv 10
equiv 11
X
conditions
13 (%)
1
1.0
1.0
1.0
1.0
1.0
1.0
5.0
10.0
1.0
1.0
1.0
1.0
1.5
1.5
3.0
3.0
1.0
3.0
1.0
1.0
4.0
5.0
5.0
5.0
H, OAc
H, OAc
H, OAc
H, OAc
H, OH
H, OH
H, OAc
H, OAc
O
HGII, 0.1 MDCM, 40 °C, 12 h
GII, 0.1 MDCM, 40 °C, 12 h
GII, 0.1 MDCM, 45 °C, 24 h
only poor homodimerization
2
only poor homodimerization
3
only poor homodimerization
4
HGII, 0.05 M DCM, 80 °C, MW, 12 h
GII, 0.05 M DCM, 80 °C, MW, 12 h
HGII, 0.1 MDCM, 80 °C, 2 h
GII, 0.1 MDCM, 45 °C, 72 h
GII, 0.1 M toluene, 45 °C, 72 h
HGII, 0.2 M DCM, 50 °C, 120 h
HGII, 0.25 M DCM, 40 °C,, MW, 48 h
HGII, 0.3 MDCM, 40 °C, 48 h
Zhan 1B, 0.3 M DCM, 40 °C, 48 h
no rxn, SM epimerized
5
decomposition
6
decomposition
7
decomposition/epimerization
8
decomposition/epimerization
9
21
43
40
65
10
11
12
O
O
O
a
GII = Grubbs second generation; HGII = second generation Hoveyda−Grubbs.
Our synthesis of (+)-crocacin C 3 began with the
Subsequent Corey−Bakshi−Shibata reduction of enone 13
afforded the desired allylic alcohol 14 in excellent yield and in
>99% d.e.14 Interestingly, we observed a long-range influence
exerted by the homoallylic alcohol on the outcome of this
reduction (Table 2). For example, when the alcohol was
acetylated, the epimeric alcohol 14a was observed as the major
diastereomer in poor yield. However, when the allylic alcohol
was methylated, the yield was improved significantly, but no
stereocontrol was observed during the reduction. In the case of
commercially available Roche ester 5 (Scheme 2). Silyl
protection and reduction−oxidation of the resultant methyl
ester 6 gave aldehyde 8 (Scheme 2). Diastereoselective
crotylboronation of aldehyde 8 under Roush’s conditions
yielded the desired anti,anti-adduct 10.12 It is worth noting that
alcohol 10 is the first intermediate in the synthesis that required
purification. The pivotal crotylboronation allowed the insertion
of two stereocenters to generate the required anti,anti
stereotriad in a single transformation and provided us with an
olefinic handle from which a cross-metathesis could be
explored.
Table 2. Long-Range Neighboring Group Effects Observed
during CBS Reductions
Despite extensive experimentation, the cross-metathesis of
olefin 10 with either vinyl acetophenone 11 or its reduced form
proved extremely difficult, most likely due to the low reactivity
of both coupling partners (Table 1). However, application of
the cross-metathesis methodology recently reported by
Donohoe13 using the Zhan 1B catalyst 12 successfully coupled
the two olefins in good yield and with excellent stereocontrol to
give the desired E-enone 13.
entry
R
T (°C)
isolated yield (%)
(R)/(S)
1
2
3
Ac 13a
Me 13b
H 13
−40
−10
−40
40
99
93
14a
14b
14
1.0/2.0
1.1/1.0
>99.0/1.0
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Scheme 3. Synthesis of Alcohol 19
the unprotected alcohol 13, the reduction proceeded with
complete stereocontrol to generate the desired diol 14.
Although the reasons for this remarkable change in behavior
are not completely clear, it is possible that coordination
between the free alcohol and the oxazaborolidine is responsible
for the enhancement in stereoselectivity observed.
Scheme 5. Preliminary Stille Coupling
The newly generated diol 14 was acetylated to generate the
bis-acetate 15, allowing us to implement the key [3,3]-
sigmatropic rearrangement. Gratifyingly, when treated with
PdCl2(CH3CN)2, bis-acetate 15 gave the desired anti,anti,syn-
product 16 as a single diastereomer in excellent yield (Scheme
3).15 Hydrolysis of the bis-acetate 16 afforded the free diol 17
together with triol 18, which could be recycled to afford diol 17
in very good overall yield. Methylation of diol 17 followed by
silyl-group removal provided the desired alcohol 19 in near
quantitative yield over the two steps.
With alcohol 19 in hand, the final steps of the synthesis were
explored. Careful oxidation of alcohol 19 produced aldehyde
20, which upon Horner−Wadsworth−Emmons olefination
gave the expected dienoate ester 22 as a single diastereomer
(Scheme 4).5a Unfortunately, all attempts to hydrolyze ester 22
resulted in degradation.
coupling afforded (+)-crocacin C 3 in poor yield, an exciting
mixture of products containing two novel isomeric crocacin
analogues 25 and 26 was also obtained.
Scheme 4. Horner−Wadsworth−Emmons Approach
The promising Stille coupling results prompted us to
consider a reverse coupling strategy for the completion of the
synthesis whereby the enamide unit is introduced as the vinyl
halide and the C4−C11 framework of (+)-crocacin C 3 is
brought forward as the vinyl stannane.4a Hodgson olefination of
aldehyde 20 provided us with the key E-vinyl stannane unit 27
in moderate yield (Scheme 6).17,4a Microwave-assisted Stille
coupling of vinyl stannane 27 with the vinyl iodide bearing
amide 28 yielded (+)-crocacin C 3 as a single double bond
isomer in much improved yield.
Although the Stille coupling of vinyl stannane 27 with vinyl
iodide 28 yielded (+)-crocacin C 3 as a single alkene isomer,
the process was not amenable to scale-up, often resulting in
protodestannylation during purification of vinyl stannane 27.
In a variant of the highly promising Stille coupling, which
would allow us to circumvent the protodestannylation issues,
aldehyde 20 was subjected to Ohira−Bestmann homologation
conditions to generate alkyne 30 in quantitative yield (Scheme
7).18 To our delight, in situ conversion of alkyne 30 into the E-
vinyl stannane with concomitant Stille coupling (with vinyl
As a consequence of this initial setback, an alternative end
game was required for the synthesis of (+)-crocacin C 3. In
order to introduce the amide functionality without necessitating
a final functional group interconversion, a strategy involving a
metal-mediated coupling with the amide unit already in place
was pursued.6a Treatment of aldehyde 20 under Takai
conditions afforded the desired E-iodo-alkene 23 in excellent
yield and with complete stereocontrol (Scheme 5).16 With the
E-iodo-alkene 23 in hand, a Stille coupling with the known
stannyl enamide 246a was then performed. Although the
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Scheme 6. Reverse Stille Coupling Strategy
Scheme 7. End-Game Strategy to (+)-Crocacin C 3
iodide 28) using Bressy and Pons’ conditions9 afforded
(+)-crocacin C 3 in high yield and as a single isomer.
were used. The plates were visualized by the quenching of UV
fluorescence (λmax 254 nm) and/or by staining with potassium
permanganate or p-anisaldehyde followed by heating.
(S)-Methyl 3-(tert-Butyldiphenylsilyloxy)-2-methylpropa-
noate, 6. To a 0 °C solution of (S)-methyl 3-hydroxy-2-
methylpropanoate 5 (7.0 g, 59.3 mmol) and imidazole (4.8 g, 71.1
mmol) in CH2Cl2 (300 mL) was added TBDPSCl (17.0 mL, 65.2
mmol) in small portions, and the reaction mixture was allowed to
warm to room temperature and stir until completion as indicated by
TLC analysis (12 h). The reaction was then quenched with satd aq
NaHCO3 (200 mL) and extracted with CH2Cl2 (3 × 150 mL). The
organic layers were collected, dried over Na2SO4, filtered, and
concentrated under vacuum to afford 21.15 g of the desired ester 6
CONCLUSIONS
■
In conclusion, we have developed a reliable, flexible, and highly
efficient synthesis of (+)-crocacin C 3 from commercially
available starting materials that compares favorably with
previous syntheses. Our approach is amenable to scale-up and
is able to generate (+)-crocacin C 3 in 14 steps (8 isolated
intermediates) and 20% overall yield from commercially
available Roche ester 5. Efforts are currently underway to
develop new antifungal agents based on the frameworks of
(+)-crocacin C and the structurally isomeric analogues 25 and
26.
1
as colorless oil (quant) which required no further purification. H
NMR (400 MHz, CDCl3): δ 7.70−7.65 (m, 4H), 7.45−7.37 (m, 6H),
3.86 (1H, dd, J = 9.8, 6.9 Hz), 3.76 (1H, dd, J = 9.8, 5.9 Hz), 3.71 (3H,
s), 2.79−2.68 (1H, m), 1.18 (3H, d, J = 7.0 Hz), 1.06 (9H, s). 13C
NMR (100 MHz, CDCl3): δ 175.5, 135.7, 133.6, 129.8, 127.8, 66.0,
EXPERIMENTAL SECTION
■
51.7, 42.5, 26.8, 19.4, 13.6. Rf 0.44 (hexane/EtOAc, 9:1); [α]22 +6.8
D
General. All reactions were performed in oven-dried glassware
under an inert argon atmosphere unless otherwise stated. Tetrahy-
drofuran (THF) and toluene were purified through a solvent
purification system. Anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU), dimethylformamide (DMF), and
methanol (MeOH) were obtained commercially. Dichloromethane
(CH2Cl2) was freshly distilled over CaH2. All reagents were used as
received, unless otherwise stated. Solvents were evaporated under
reduced pressure at 40 °C unless otherwise stated. IR spectra were
recorded as neat films using a Fourier Transform spectrometer. Only
significant absorptions (νmax) are reported in wavenumbers (cm−1).
Proton magnetic resonance spectra (1H NMR) and carbon magnetic
resonance spectra (13C NMR) were recorded at, respectively, 400/500
MHz and 100/125 MHz. Chemical shifts (δ) are reported in parts per
million (ppm) and are referenced to the residual solvent peak. The
order of citation in parentheses is (1) number of equivalent nuclei (by
integration), (2) multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, quint = quintet, sext = sextet, sept = septet, m = multiplet, b =
broad), (3) and coupling constant (J) quoted in Hertz to the nearest
0.1 Hz. High resolution mass spectra were recorded by electrospray
(ESI), fast atom bombardment (FAB), electron impact (EI), or
chemical ionization (CI) using a mass spectrometer operating at a
resolution of 15,000 full widths at half height. Flash chromatography
was performed using silica gel (40−63 μm) as the stationary phase.
TLC was performed on aluminum sheets precoated with silica (silica
gel 60 F254) unless otherwise stated where aluminum oxide plates
(c 1.0, CHCl3); IR νmax (film) 3073−2859, 1740, 1472, 1427, 1389,
1362, 1258, 1198, 1177, 1106, 824, 739, 702 cm−1. HRMS (CI+/ISO)
calcd for C21H29O3Si [M + H]+: 357.1886, found 357.1888.
(R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropan-1-ol, 7. A
0 °C solution of ester 6 (22.0 g, 61.7 mmol) in dry CH2Cl2 (300 mL)
was treated with the dropwise addition of DIBAL-H (1 M in CH2Cl2,
135.7 mL, 135.7 mmol), and the resulting reaction mixture was
allowed to stir at 0 °C until completion by TLC analysis (3 h). The
reaction mixture was quenched at 0 °C by the careful addition of satd
aq Rochelle’s salt (250 mL), and the biphasic system was allowed to
stir at room temperature for 12 h. The phases were separated, and the
aqueous layer was extracted with EtOAc (3 × 150 mL). The combined
organic extracts were washed with brine (300 mL), dried over Na2SO4,
filtered, and concentrated under vacuum to afford 20.1 g of alcohol 7
as colorless oil (99% yield) The crude product was clean enough and
1
could be used without the need of any further purification. H NMR
(400 MHz, CDCl3): δ 7.71−7.66 (m, 4H), 7.47−7.37 (m, 6H), 3.74
(1H, dd, J = 9.9, 4.5 Hz), 3.68 (2H, m), 3.61 (1H, dd, J = 10.1, 7.7
Hz), 2.56 (1H, bs), 2.06−1.95 (1H, m), 1.07 (9H, s), 0.84 (3H, d, J =
7.0 Hz). 13C NMR (100 MHz, CDCl3): δ 135.7, 134.9, 133.3, 129.9,
127.9, 68.9, 67.8, 37.4, 26.9, 19.3, 13.3. Rf 0.29 (hexane/EtOAc, 9:1),
[α]25 +4.0 (c 1.0, CHCl3); IR νmax (film) 3387, 3073−2859, 1472,
D
1427, 1391, 1362, 1111, 1086, 1028, 939, 822, 802, 739, 698 cm−1.
HRMS (CI+/ISO) calcd for C20H29O2Si [M + H]+: 329.1937, found
329.1933.
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(S)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropanal, 8. A sol-
ution of oxalyl chloride (2.15 mL, 24.5 mmol) in freshly distilled
CH2Cl2 (195 mL) was cooled to −78 °C and treated dropwise with a
solution of dimethylsulfoxide (3.5 mL, 49.0 mmol) in CH2Cl2 (8 mL),
and the resulting mixture was stirred under argon at −78 °C for 30
min. A solution of (R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropan-
1-ol 7 (4.02 g, 12.25 mmol) in CH2Cl2 (8 mL) was added dropwise,
and the reaction was allowed to stir at −78 °C for 1 h. The reaction
mixture was quenched at −78 °C by the addition dropwise of
triethylamine (13.7 mL, 98.0 mmol), and the obtained solution was
stirred at −78 °C for 10 min and then at room temperature for a
further 30 min. The reaction mixture was washed with satd aq
NaHCO3 (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with brine (100 mL), dried over
Na2SO4, filtered, and concentrated under vacuum to afford 4.02 g of
aldehyde 8 as a yellow oil in quantitative yield (4.02 g, 12.3 mmol).
The crude product was taken straight onto the next step without any
cm−1. HRMS (EI+) calcd for C9H10O [M]+: 134.0732, found
134.0733.
1-Phenylprop-2-en-1-one, 12. A solution of 1-phenylprop-2-en-
1-ol (6.23 g, 47.1 mmol) in anhydrous CH2Cl2 (500 mL) was treated
with TEMPO (147 mg, 0.94 mmol) and iodobenzene diacetate (38.0
g, 118 mmol) at room temperature. The resulting mixture was stirred
at room temperature until completion as indicated by TLC analysis
(12 h). The reaction mixture was quenched by the addition of satd aq
Na2S2O3 (200 mL) and left to stir for 1 h. The organic phase was
separated, and the aqueous phase was extracted with Et2O (3 × 200
mL). The combined organic layers were dried over Na2SO4 and
concentrated under vacuum to afford an orange-yellow residue.
Purification of the crude product by flash column chromatography
(silica gel, 80:20 hexane/Et2O) gave 5.3 g (85%) of enone 12 as
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.97−7.93 (2H, m), 7.60−
7.56 (1H, m), 7.49−7.47 (2H, m), 7.16 (1H, dd, J = 17.1, 10.6 Hz),
6.45 (1H, dd, J = 17.1, 1.7 Hz), 5.94 (1H, dd, J = 10.6, 1.7 Hz). 13C
NMR (125 MHz, CDCl3): δ 191.2, 137.5, 133.1, 132.6, 130.3, 128.8,
128.7. Rf 0.37 (hexane/Et2O, 8:2); IR νmax (film) 2967, 2932, 2874,
1768, 1668, 1618, 1449, 1364, 1252, 1215, 1090, 1015, 916, 775, 735
cm−1. HRMS (CI+/ISO) calcd for C9H9O [M + H]+: 133.0653, found
133.0650.
1
further purification. H NMR (400 MHz, CDCl3): δ 9.77 (1H, d, J =
1.7 Hz), 7.68−7.62 (4H, m), 7.45−7.38 (6H, m), 3.95−3.82 (2H, m),
2.65−2.50 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 1.05 (9H, s). 13C NMR
(100 MHz, CDCl3): δ 204.6, 135.7, 129.9, 127.9, 64.2, 48.9, 26.9, 19.3,
10.4. Rf 0.38 (hexane/Et2O, 9:1); [α]26 +5.0 (c 2.0, CHCl3); IR νmax
D
(4R,5R,6S,E)-7-(tert-Butyldiphenylsilyloxy)-5-hydroxy-4,6-di-
methyl-1-phenylhept-2-en-1-one, 13. A 0.5 − 2 mL microwave
vial, fitted with a magnetic follower, was charged with Zhan 1B catalyst
(15 mg, 5 mol %). The vial was sealed with a rubber septum and
purged with argon. A solution of alcohol 10 (145 mg, 0.38 mmol) and
1-phenylprop-2-en-1-one 12 (250 mg, 1.89 mmol) in freeze−thaw
degassed CH2Cl2 (1.5 mL) was added, and the resulting green solution
was heated at 40 °C for 12 h. After this period, a further portion of
Zhan 1B catalyst (15 mg, 5 mol %) in 1.5 mL of freeze−thaw degassed
CH2Cl2 was added, and the resulting brown solution was subjected to
an additional heating cycle at 40 °C for 12 h. The reaction mixture was
then allowed to cool to room temperature and concentrated under
vacuum to afford a dark brown crude oil. Purification of the crude
residue by flash column chromatography (silica gel, 80:20 hexane/
(film) 3073−2720, 2114, 1738−1713, 1472, 1428, 1111, 1026, 1008,
808, 826, 739, 698, 689, 615 cm−1. HRMS (CI+/ISO) calcd for
C20H27O2Si [M + H]+: 327.1780, found 327.1774.
(2S,3R,4R)-1-(tert-Butyldiphenylsilyloxy)-2,4-dimethylhex-5-
en-3-ol, 10. A slurry of 300 mg of 4 Å powdered molecular sieves
(previously dried under vacuum using a heatgun) in dry toluene (15
mL) was treated with (4S,5S)-diisopropyl 2-((E)-but-2-enyl)-1,3,2-
dioxaborolane-4,5-dicarboxylate, 912b (13.8 mL, 13.8 mmol, 1.0 M
solution in dry toluene). The heterogeneous solution was stirred at
room temperature for 10 min and was then cooled to −78 °C. A
solution of (S)-3-(tert-butyldiphenylsilyloxy)-2-methylpropanal 8 (3.0
g, 9.2 mmol) in dry toluene (15 mL) was then added dropwise to the
mixture via a cannula over a 20 min period. Once the addition was
complete, the solution was maintained at −78 °C for 16 h. Excess
ethanolic NaBH4 (200 mg in 3 mL of absolute EtOH) was then
introduced dropwise via a pipet, and the resulting solution was allowed
to warm to 0 °C. The reaction mixture was then diluted with 1 N
NaOH (25 mL) and stirred vigorously for 2 h. The phases were
separated, and the aqueous phase was extracted with diethyl ether (5 ×
150 mL). The combined organic layers were dried over K2CO3 and
concentrated under vacuum to afford yellow oil as crude product.
Purification of the crude residue (90:10 hexane/Et2O) yielded 2.3 g
(65%) of alkene 10 as colorless oil.1 1H NMR (500 MHz, CDCl3): δ
7.59−7.56 (4H, m), 7.36−7.24 (6H, m), 5.86 (1H, ddd, J = 10.5, 8.4,
2.1 Hz), 5.00−4.94 (2H, m), 3.66−3.58 (2H, m), 3.39 (1H, dd, J =
3.3, 0.6 Hz), 3.36−3.32 (1H, m), 2.33−2.22 (1H, m), 1.77−1.70 (1H,
m), 1.02 (3H, d, J = 7.0 Hz), 0.97 (9H, s), 0.72 (3H, d, J = 7.0 Hz).
13C NMR (125 MHz, CDCl3): δ 139.9, 135.7, 132.9, 129.9, 127.8,
1
EtOAc) afforded 120 mg (65%) of enone 13 as a pale yellow oil. H
NMR (500 MHz, CDCl3): δ 7.95−7.91 (2H, m), 7.69−7.65 (4H, m),
7.49−7.36 (9H, m), 7.20 (1H, dd, J = 15.8, 8.6 Hz), 6.86 (1H, d, J =
15.7 Hz), 3.96 (1H, d, J = 2.7 Hz), 3.74 (1H, dd, J = 10.4. 4.0 Hz),
3.68−3.64 (1H, m), 3.61−3.58 (1H, m), 2.69−2.61 (1H, m), 1.88−
1.80 (1H, m), 1.23 (3H, d, J = 6.9 Hz), 1.05 (9H, s), 0.80 (3H, d, J =
6.9 Hz). 13C NMR (125 MHz, CDCl3): δ 191.5, 151.2, 138.2, 135.8,
135.7, 132.7, 130.1, 130.0, 128.8, 128.6, 128.0, 127.9, 126.9, 80.2, 69.6,
40.7, 38.0, 26.9, 19.2, 17.4, 13.6. Rf 0.29 (hexane/EtOAc, 8:2); [α]25
D
+188.6 (c 0.1, CHCl3); IR νmax (film) 3450, 2974, 2931, 2857, 1670,
1618, 1473, 1428, 1112, 998, 823, 741, 700 cm−1. HRMS (EI+) calcd
for C31H37O2Si [M − OH]+: 469.2563, found 469.2557.
(1R,4R,5R,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
1-phenylhept-2-ene-1,5-diol, 14. A room temperature solution of
(S)-CBS (348 mg, 1.25 mmol) dry THF (15 mL) was treated with the
dropwise addition of BH3·THF (1 M solution in THF, 1.25 mL, 1.25
mmol). The resulting mixture was stirred vigorously at room
temperature for 30 min and then cooled to −40 °C before being
treated dropwise with a solution of (4R,5R,6S,E)-7-(tert-butyldiphe-
nylsilyloxy)-5-hydroxy-4,6-dimethyl-1-phenylhept-2-en-1-one 13 (500
mg, 1.03 mmol) in dry THF (15 mL). The reaction mixture was
stirred at −40 °C until complete disappearance of the starting material
by TLC (5 h). The reaction was quenched with MeOH (10 mL) and
concentrated under vacuum to afford a yellow crude oil. Purification of
the crude residue by flash column chromatography (silica gel, 60:40
hexane/EtOAc) yielded 467 mg (93%) of diol 14 as clear yellow oil.
1H NMR (500 MHz, CDCl3): δ 7.69−7.65 (4H, m), 7.46−7.43 (2H,
79.7, 68.9, 41.2, 37.9, 26.9, 19.1, 17.8, 13.6. Rf 0.32 (hexane/Et2O,
9:1); [α]28 +14.6 (c 4.0, CHCl3); IR νmax (film) 3050, 2062, 1430,
D
1210, 1010, 915, 864, 702, 610, 420, 350 cm−1. HRMS (CI+/ISO)
calcd for C24H35O2Si [M + H]+: 383.2406, found 383.2410.
1-Phenylprop-2-en-1-ol. Vinylmagnesium bromide (1.0 M in
THF, 47.1 mL, 47.1 mmol) was added dropwise to a solution of
benzaldehyde (5.0 g, 47.1 mmol) in dry THF (250 mL) at 0 °C. After
stirring for 10 min the reaction mixture was allowed to warm to room
temperature and was stirred for 4 h. The reaction was then quenched
by addition of satd aq NH4Cl (200 mL) and extracted with diethyl
ether (3 × 150 mL). The combined organic layers were washed with
brine (200 mL), dried over Na2SO4, and concentrated under vacuum
to afford 6.23 g (quant) of 1-phenylprop-2-en-1-ol as crude yellow oil,
which was taken directly onto the next step without any further
purification. 1H NMR (400 MHz, CDCl3): δ 7.38−7.36 (5H, m), 6.05
(1H, ddd, J = 17.1, 10.3, 6.1 Hz, 1H), 5.38−5.33 (1H, m), 5.22−5.17
(1H, m), 4.66 (1H, bs). 13C NMR (100 MHz, CDCl3): δ 142.7, 140.3,
128.7, 128.6, 127.8, 126.4, 115.2, 75.4. Rf 0.21 (hexane/Et2O, 8:2); IR
νmax (film) 3371, 1667, 1451, 1119, 950, 865, 780, 706, 630, 410, 360
m), 7.42−7.37 (6H, m), 7.36−7.32 (2H, m), 7.29−7.25 (1H, m), 5.93
(1H, ddd, J = 15.6, 8.5, 0.9 Hz), 5.69 (1H, ddd, J = 15.6, 7.1, 0.7 Hz),
5.22 (1H, dd, J = 6.9, 3.4 Hz), 3.72−3.64 (3H, m), 3.46−3.43 (1H,
m), 2.40−2.36 (1H, m), 2.03 (1H, d, J = 3.6 Hz), 1.81−1.75 (1H, m),
1.13 (3H, d, J = 7.0 Hz), 1.06 (9H, s), 0.74 (3H, d, J = 7.0 Hz). 13C
NMR (125 MHz, CDCl3): δ 143.5, 135.7, 133.6, 133.3, 132.9, 130.1,
130.0, 128.6, 128.0, 127.9, 127.6, 126.2, 80.2, 75.3, 69.2, 39.8, 37.9,
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26.9, 19.2, 18.1, 13.6. Rf 0.19 (hexane/EtOAc, 8:2); [α]25D −4.8 (c 0.1,
CHCl3); IR νmax (film) 2974, 2931, 2859, 1473, 1428, 1383, 1112, 986,
823, 741, 699 cm−1. HRMS (ESI+) calcd for C31H41O2Si [M − OH]+:
473.2870, found 473.2868.
extracted with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (20 mL) and concentrated under vacuum to afford
100 mg (60%) of the desired silyl ether 17 as colorless oil. The total
yield for the silyl ether over the two steps was 133 mg (80%).
(3S,4R,5S,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
(1R,4R,5R,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
1-phenylhept-2-ene-1,5-diyl diacetate, 15. A solution of diol 14
(500 mg, 0.87 mmol) in dry CH2Cl2 (50 mL) was treated with acetic
anhydride (1.0 mL, 10.47 mmol) followed by DMAP (11 mg, 0.09
mmol), and the resulting reaction mixture was stirred at room
temperature until completion as indicated by TLC analysis (12 h).
The solvent was then removed under vacuum to afford a yellow-brown
crude product. Purification of the crude residue by flash column
chromatography (silica gel, 80:20 hexane/EtOAc) yielded 495 mg
(99%) of diacetate 15 as colorless oil. 1H NMR (500 MHz, CDCl3): δ
7.66−7.61 (4H, m), 7.45−7.27 (11H, m), 6.18 (1H, bd, J = 4.6 Hz),
5.59 (2H, bd, J = 6.8 Hz), 4.76 (1H, t, J = 6.2 Hz), 3.61 (1H, dd, J =
10.0, 4.5 Hz), 3.46−3.39 (1H, m), 2.59−2.46 (1H, m), 2.08 (3H, s),
1.99−1.89 (1H, m), 1.73 (3H, s), 1.04 (9H, s), 0.95 (3H, d, J = 6.8
Hz), 0.91 (3H, d, J = 6.8 Hz). 13C NMR (125 MHz, CDCl3): δ 170.7,
139.8, 135.8, 135.4, 133.8, 133.7, 129.7, 129.4, 128.7, 128.1, 127.8,
127.7, 127.6, 126.9, 77.9, 76.2, 64.9, 39.0, 37.2, 26.9, 21.5, 20.7, 19.3,
1
1-phenylhept-1-ene-3,5-diol, 17. H NMR (400 MHz, CDCl3): δ
7.70−7.67 (4H, m), 7.49−7.40 (8H, m), 7.34−7.19 (3H, m), 6.66
(1H, dd, J = 15.9, 1.2 Hz), 6.26 (1H, dd, J = 15.9, 5.4 Hz), 4.78 (1H, d,
J = 2.8 Hz), 4.73−4.68 (1H, m), 4.28 (1H, d, J = 2.8 Hz), 3.87 (1H,
dd, J = 10.3, 3.7 Hz), 3.75−3.70 (1H, m), 3.67 (1H, dd, J = 10.3, 7.6
Hz), 2.14−2.04 (1H, m), 1.99−1.89 (1H, m), 1.07 (9H, s), 1.04 (3H,
d, J = 7.2 Hz), 0.86 (3H, d, J = 7.2 Hz). 13C NMR (125 MHz, CDCl3):
δ 137.4, 135.8, 135.7, 132.6, 132.5, 131.2, 130.2, 130.1, 129.9, 128.6,
128.1, 128.0, 127.4, 126.6, 82.2, 73.0, 69.5, 39.9, 36.9, 26.9, 19.2, 13.9,
11.9. Rf 0.60 (hexane/EtOAc, 7:3); [α]27D +3.6 (c 1.0, CHCl3); IR νmax
(film) 3418, 3072, 2963, 2932, 2855, 1427, 1111 cm−1. HRMS (ESI+)
calcd for C31H37OSi [M − 2OH]+: 453.2608, found 453.2609. Triol
18 matched the literature data: Org. Lett. 2001, 3, 395−3954.
tert-Butyl((2S,3S,4R,5S,E)-3,5-dimethoxy-2,4-dimethyl-7-
phenylhept-6-enyloxy)diphenylsilane. A suspension of NaH (85
mg, 2.13 mmol) in dry THF (2 mL) was treated with a solution of diol
17 (130 mg, 266 μmol) in dry THF (2 mL), and the resulting mixture
was stirred at room temperature for 10 min. The solution was then
treated sequentially with MeI (0.3 mL, 4.26 mmol) and TBAI (8 mg,
21.3 μmol), and the resulting reaction mixture was stirred at 60 °C
until TLC analysis indicated reaction completion (12 h). The reaction
was quenched with satd aq solution of NH4Cl (5 mL), and the layers
were separated. The organic layer was washed with brine (5 mL), and
the aqueous layer was extracted with diethyl ether (3 × 5 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under vacuum to afford the fully protected triol as pale
17.5, 14.5. Rf 0.46 (hexane/EtOAc, 8:2); [α]25 −8.4 (c 0.1, CHCl3);
D
IR νmax (film) 2974, 2963, 2928, 2857, 2360, 2343, 1739, 1472, 1428,
1370, 1233, 1112, 10018, 964, 824, 756, 699 cm−1. HRMS (ESI+)
calcd for C31H37OSi [M − 2OAc]+: 453.2608, found 453.2606.
(3S,4R,5S,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
1-phenylhept-1-ene-3,5-diyl diacetate, 16. A solution of
diacetate 15 (420 mg, 0.73 mmol) in anhydrous THF (30 mL) was
treated with PdCl2(CH3CN)2 (10 mg, 0.03 mmol, 5 mol %), and the
resulting mixture was allowed to stir at room temperature until
reaction completion as indicated by TLC analysis (12 h). The solution
was filtered through Celite, and the Celite was washed using EtOAc
(50 mL) as the eluent. The EtOAc washings were then concentrated
under vacuum to afford a yellow-brown crude oil, which upon
purification by flash column chromatography (silica gel, 80:20 hexane/
EtOAc) afforded 399 mg (95%) of the desired 1,3-diacetate 16 a
yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.70−7.65 (4H, m), 7.42−
7.37 (6H, m), 7.35−7.21 (5H, m), 6.46 (1H, dd, J = 16.1, 1.0 Hz),
6.06 (1H, dd, J = 15.9, 5.8 Hz), 5.53−5.49 (1H, m), 4.94 (1H, dd, J =
9.7, 3.2 Hz), 3.76 (1H, dd, J = 10.2, 6.1 Hz), 3.47 (1H, dd, J = 10.3, 6.8
Hz), 2.32−2.25 (1H, m), 2.21−2.13 (1H, m), 2.08 (3H, s), 1.99 (3H,
s), 1.04 (9H, s), 0.96 (3H, d, J = 6.9 Hz), 0.94 (3H, d, J = 6.9 Hz). 13C
NMR (125 MHz, CDCl3): δ 170.8, 170.6, 136.6, 135.6, 133.8, 133.7,
131.8, 129.8, 129.7, 128.7, 127.9, 127.8, 126.9, 126.6, 76.3, 73.0, 64.7,
38.9, 36.8, 26.9, 21.3, 20.9, 19.3, 15.3, 11.1. Rf 0.54 (hexane/EtOAc,
1
yellow oil, which could be used without any further purification. H
NMR (400 MHz, CDCl3): δ 7.71−7.66 (4H, m), 7.45−7.23 (11H,
m), 6.54 (1H, d, J = 16.0 Hz), 6.14 (1H, dd, J = 16.0, 7.2 Hz), 4.03
(1H, dd, J = 7.2, 2.0 Hz), 3.77 (1H, dd, J = 10.0, 5.3 Hz), 3.58 (1H, dd,
J = 9.9, 7.9 Hz), 3.47 (3H, s), 3.33 (3H, s), 3.23−3.19 (1H, m), 2.09−
1.99 (1H, m), 1.81−1.71 (1H, m), 1.15 (3H, d, J = 7.0 Hz), 1.05 (9H,
s), 0.83 (3H, d, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3): δ 137.1,
135.8, 135.7, 134.2, 134.1, 131.9, 131.8, 129.8, 129.7, 129.6, 128.7,
127.7, 127.6, 126.5, 85.6, 81.5, 64.9, 61.5, 56.6, 41.8, 38.1, 27.0, 19.4,
16.0, 10.5.
(2S,3S,4R,5S,E)-3,5-Dimethoxy-2,4-dimethyl-7-phenylhept-
6-en-1-ol, 19. A 0 °C solution of tert-butyl((2S,3S,4R,5S,E)-3,5-
dimethoxy-2,4-dimethyl-7-phenylhept-6-enyloxy)diphenylsilane (138
mg, 0.266 mmol) in THF (5 mL) was treated with TBAF (1 M in
THF, 0.8 mL, 0.798 mmol), and the resulting reaction mixture was
allowed to warm and stir at room temperature until completion as
indicated by TLC analysis (12 h). The reaction was quenched with
distilled water (5 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic phases were washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated under vacuum to afford a crude
pale yellow oil. The crude product was purified by flash column
chromatography (silica gel, 60:40 hexane/EtOAc) to afford 73 mg of
8:2); [α]25 −7.6 (c 0.1, CHCl3); IR νmax (film) 3071, 2961, 2932,
D
2857, 1739, 1237, 1112 cm−1. HRMS (ESI+) calcd for C35H44O5NaSi
[M + Na]+: 595.2850, found 595.2852.
(3S,4R,5S,6S,E)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
1-phenylhept-1-ene-3,5-diol, 17 and (2S,3S,4R,5S,E)-2,4-Di-
methyl-7-phenylhept-6-ene-1,3,5-triol, 18. A solution of diac-
etate 16 (195 mg, 0.34 mmol) in MeOH (10 mL) was treated
dropwise with a 1.0 M K2CO3 solution in H2O (1.7 mL), and the
resulting mixture was allowed to stir at room temperature until
completion of reaction as indicated by TLC analysis (12 h). The
reaction was quenched with satd aq NH4Cl solution (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic layers were
dried over Na2SO4 and concentrated under vacuum to afford crude
pale yellow oil. The crude product was purified by flash column
chromatography (silica gel, elution gradient 80:20 hexane/EtOAc,
then 60/40 hexane/EtOAc) to yield 33 mg (20%) of the desired diol
17 as a colorless oil as well as 51 mg of the known triol 18 as a pale
yellow oil.
Triol 18 (51 mg, 0.21 mmol) was dissolved in anhydrous CH2Cl2
(1 mL) and treated with imidazole (18 mg, 0.27 mmol), and the
resulting mixture was cooled to −5 °C. A solution of TBDPSCl (62
mg, 0.23 mmol) in dry CH2Cl2 (1 mL) was then added dropwise to
the reaction mixture, and the resulting solution was allowed to stir at
−5 °C until complete disappearance of the starting material by TLC
analysis (30 min). The reaction was quenched with H2O (5 mL) and
1
alcohol 19 (99%) as colorless oil. H NMR (500 MHz, CDCl3): δ
7.43−7.39 (2H, m), 7.36−7.31 (2H, m), 7.27−7.23 (1H, m), 6.58
(1H, d, J = 16.3 Hz), 6.19 (1H, dd, J = 15.8, 7.1 Hz), 4.08−4.05 (1H,
m), 3.89−3.82 (1H, m), 3.57−3.51 (1H, m), 3.53 (3H, s), 3.32 (3H,
s), 3.29 (1H, dd, J = 9.4, 2.7 Hz), 2.92−2.87 (1H, m), 1.92−1.82 (2H,
m), 1.21 (3H, d, J = 7.2 Hz), 0.91 (3H, d, J = 7.2 Hz). 13C NMR (125
MHz, CDCl3): δ 136.9, 132.3, 129.5, 128.8, 127.8, 126.6, 88.6, 81.3,
64.7, 61.8, 56.5, 42.5, 35.9, 16.4, 10.5. Rf 0.14 (hexane/EtOAc, 8:2);
[α]22 −5.2 (c 1.0, CHCl3); IR νmax (film) 3440, 2972, 2935, 2831,
D
1497, 1449, 1100 cm−1. HRMS (ESI+) calcd for C17H26O3Na [M +
Na]+: 301.1774, found 301.1772.
(2R,3R,4R,5S,E)-3,5-Dimethoxy-2,4-dimethyl-7-phenylhept-
6-enal, 20. A solution of (2S,3S,4R,5S,E)-3,5-dimethoxy-2,4-dimeth-
yl-7-phenylhept-6-en-1-ol 19 (30 mg, 0.11 mmol) in dry CH2Cl2 (2
mL) was treated with Dess−Martin periodinane (92 mg, 0.22 mmol),
and the resulting mixture was stirred at room temperature until
completion as indicated by TLC analysis (40 min). The reaction was
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quenched by the sequential addition of satd aq Na2S2O3 (2 mL) and
satd aq NaHCO3 (2 mL) and diluted with diethyl ether (5 mL). The
resulting mixture was stirred for 20 min at room temperature, and the
layers were separated. The aqueous phase was extracted with diethyl
ether (3 × 5 mL), and the combined organic layers were dried over
Na2SO4 and concentrated under vacuum to afford 29.8 mg (quant.) of
the desired aldehyde 20 as pale yellow oil, which was taken straight
temperature, before being cooled back down to 0 °C. A solution of
(E)-ethyl 3-(tributylstannyl)but-2-enoate (343 mg, 0.86 mmol) in dry
toluene (5 mL) was then added, and the resulting reaction mixture was
warmed and heated at 50 °C for 16 h. The reaction was then allowed
to cool and was then diluted with EtOAc (10 mL) and quenched at 0
°C by addition of 10% HCl in a saturated NaCl aqueous solution (20
mL total volume). The organic phase was washed with satd aq
NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered,
and concentrated under vacuum to afford a thick pale yellow oil.
Purification of the crude product by flash column chromatography
(silica gel, hexane/EtOAc, 20/80) gave 124 mg (78%) of amide 24 as
1
onto the next step without any further purification. H NMR (400
MHz, CDCl3): δ 9.77 (1H, d, J = 1.8 Hz), 7.43−7.23 (5H, m), 6.57
(1H, d, J = 16.0 Hz), 6.15 (1H, dd, J = 16.0, 7.3 Hz), 4.11−4.06 (1H,
m), 3.55 (1H, dd, J = 9.3, 2.6 Hz), 3.49 (3H, s), 3.33 (3H, s), 2.73−
2.65 (1H, m), 1.93−1.82 (1H, m), 1.20 (3H, d, J = 7.1 Hz), 0.87 (3H,
d, J = 7.1 Hz). Rf 0.37 (hexane/EtOAc, 8:2).
1
a pure white solid. Mp: 33 °C. H NMR (400 MHz, CDCl3): δ 5.92
(1H, q, J = 1.7 Hz), 5.64 (1H, bs), 5.39 (1H, bs), 2.35 (3H, d, J = 1.8
Hz), 1.54−1.44 (6H, m), 1.35−1.27 (6H, m), 0.96−0.92 (6H, m),
0.88 (9H, t, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 167.6, 162.9,
130.5, 29.1, 27.5, 22.2, 13.8, 9.5. Rf 0.62 (EtOAc); IR νmax (film) 3402,
3202, 2955, 2924, 2847, 2361, 1659, 1597, 1458, 1397, 1312, 1072,
1312, 1072, 1003, 872, 733, 687 cm−1. HRMS (ESI+) calcd for
C16H34ONSn [M + H]+: 376.1657, found 376.1651.
Tributyl(diiodomethyl)stannane. A solution of Bu3SnCHBr2
(300 mg, 0.65 mmol) in anhydrous acetone (4 mL) was treated
with NaI (390 mg, 2.60 mmol), and the reaction mixture was stirred at
room temperature in te absence of light for 24 h. The reaction mixture
was concentrated and then diluted with hexane (10 mL) and the solids
filtered off. The resultant solution was concentrated under vacuum in
absence of light, diluted with chloroform (10 mL) and the newly
precipitated solids were filtered off. The solution was concentrated
once again under vacuum in the absence of light to afford 361 mg
(quant) of the desired diiodomethylstannane as light yellow oil, which
required no further purification. 1H NMR (500 MHz, CDCl3): δ 4.25
(1H, s), 1.64−1.58 (6H, m), 1.33 (6H, sext, J = 7.2 Hz), 1.12−1.09
(6H, m), 0.92 (9H, t, J = 7.2 Hz). 13C NMR (125 MHz, CDCl3): δ
28.6, 27.5, 15.7, 13.8, 13.1. Rf 0.50 (PE).
Tributyl((1E,3S,4S,5R,6S,7E)-4,6-dimethoxy-3,5-dimethyl-8-
phenylocta-1,7-dienyl)stannane, 27. A 0 °C bright green
suspension of anhydrous CrCl2 (135 mg, 1.1 mmol, previously gently
flame-dried under vacuum) in freeze−thaw degassed DMF (1 mL) in
the absence of light was treated via cannula with a solution of aldehyde
20 (21.8 mg, 0.08 mmol) and freshly prepared diiodomethyltributyltin
(120 mg, 0.22 mmol) in freeze−thaw degassed DMF (1 mL). The
resulting reaction mixture was allowed to warm to room temperature
in the dark until completion as indicated by TLC analysis (10 h). The
reaction mixture was quenched by addition of H2O (5 mL), and the
phases were separated. The aqueous phase was extracted with diethyl
ether (3 × 10 mL), and the combined organic layers were washed with
brine (10 mL), dried over Na2SO4, and concentrated under vacuum to
afford the crude product as yellow oil. The crude product was purified
by fast vacuum filtration on silica gel (90:10 hexane/EtOAc + 1%
Et3N) to afford 22.3 mg (50%) of stannane 27 as a pale yellow oil. 1H
NMR (500 MHz, CDCl3): δ 7.40−7.20 (5H, m), 6.57 (1H, d, J = 16.2
Hz), 6.17 (1H, dd, J = 16.2, 6.9 Hz), 5.96 (1H, dd, J = 19.2, 7.2 Hz),
5.86 (1H, d, J = 19.2 Hz), 4.11 (1H, dd, J = 7.2, 1.1 Hz), 3.53 (3H, s),
3.34 (3H, s), 3.14 (1H, dd, J = 10,2, 2.4 Hz), 2.46 (1H, m), 1.63 (1H,
m), 1.51−1.41 (6H, m), 1.33−1.21 (12H, m), 1.15 (3H, d, J = 7.0
Hz), 0.85 (3H, d, J = 7.2 Hz), 0.84 (12H, t, J = 7.2 Hz). 13C NMR
(125 MHz, CDCl3): δ 150.5, 137.1, 131.8, 129.7, 128.7, 127.5, 127.2,
126.5, 86.4, 81.4, 61.3, 56.7, 44.9, 42.7, 29.3, 27.4, 18.5, 13.8, 9.6, 9.5.
Rf 0.47 (PE/EtOAc, 40:1, 1% Et3N).
(E)-Methyl 3-iodobut-2-enoate. A mixture of (E)-3-iodobut-2-
enoic acid and (Z)-3-iodobut-2-enoic acid4a (E/Z ratio 1.7/1.0) (984
mg, 4.64 mmol) in anhydrous THF (50 mL) was treated with Cs2CO3
(1.51 g, 4.64 mmol), and the resulting mixture was stirred at room
temperature for 5 min. Iodomethane (0.6 mL, 9.28 mmol) was then
added, and the resulting reaction mixture was stirred at room
temperature until completion as indicated by TLC analysis (12 h).
The reaction was quenched with satd aq NH4Cl (30 mL), and the
resulting layers were separated. The aqueous phase was extracted with
diethyl ether (2 × 30 mL), and the combined organic layers were
washed with brine (30 mL) and concentrated under vacuum to afford
thick brown-yellow oil as crude product. Interestingly, 1H NMR
((1E,3S,4R,5S,6S,7E)-8-Iodo-3,5-dimethoxy-4,6-dimethyloc-
ta-1,7-dienyl)benzene, 23. A stirred suspension of anhydrous CrCl2
(226 mg, 1.84 mmol, previously gently flame-dried under vacuum) in
dry THF (2 mL) at room temperature was treated carefully with a
solution of aldehyde 20 (29.8 mg, 0.11 mmol) and iodoform (255 mg,
0.65 mmol) in dry THF (1 mL) transferred via cannula. The resulting
brown mixture was stirred in the dark at room temperature until
completion as indicated by TLC analysis (30 min). The reaction
mixture was quenched by addition of H2O (5 mL), and the phases
were separated. The aqueous phase was extracted with diethyl ether (3
× 10 mL), and the combined organic layers were washed with brine
(10 mL), dried over Na2SO4, and concentrated under vacuum to
afford a crude yellow solid. Purification of the crude residue by flash
column chromatography (silica gel, 95:5 hexane/EtOAc) yielded 43
1
mg (99%) of iodoolefin 23 as a white solid. H NMR (500 MHz,
C6D6): δ 7.24−7.04 (5H, m), 6.77 (1H, dd, J = 14.5, 9.2 Hz), 6.44
(1H, d, J = 16.0 Hz), 6.04 (1H, dd, J = 16.0, 7.0 Hz), 5.74 (1H, d, J =
14.6 Hz), 4.10−4.07 (1H, m), 3.31 (3H, s), 3.16 (3H, s), 3.02 (1H, dd,
J = 9.9, 2.1 Hz), 2.23−2.12 (1H, m), 1.71−1.60 (1H, m), 0.94 (3H, d,
J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz). 13C NMR (125 MHz, C6D6): δ
147.9, 137.2, 132.1, 129.5, 128.6, 128.4, 128.2, 126.7, 85.9, 80.9, 75.1,
61.1, 55.9, 43.5, 42.7, 18.2, 9.8. Rf 0.64 (hexane/EtOAc, 7.5:2.5);
[α]24 +1.84 (c 1.0, CHCl3); IR νmax (film) 2963, 2924, 2361, 2334,
D
1728, 1651, 1585, 1597, 1497, 1451, 1335, 1188, 1088, 972, 748, 694
cm−1.
(E)-Ethyl 3-(tributylstannyl)but-2-enoate. A 0 °C solution of
diisopropylamine (0.3 mL, 1.87 mmol) in dry THF (1 mL) was
treated dropwise with n-BuLi (1.6 M in hexanes, 1.2 mL, 1.87 mmol),
and the resulting mixture was allowed to stir for 10 min. The solution
was then treated with tributyltin hydride (0.5 mL, 1.78 mmol), and the
reaction was cooled at −50 °C. At this point, the mixture was added to
a suspension of CuBr·Me2S (368 mg, 1.78 mmol) in anhydrous THF
(2 mL) at −50 °C, and the newly formed suspension was stirred at
−50 °C for 30 min. The solution was then cooled to −95 °C and
treated with a precooled solution of ethyl-2-butynoate (100 mg, 0.89
mmol) and dry MeOH (0.01 mL, 1.52 mmol) in anhydrous THF (3
mL). Once the addition was complete, the resulting mixture was
stirred for 30 min at −95 °C, followed by warming up to −78 °C,
where the reaction was stirred for an additional 2 h. The reaction was
quenched with 5% aq NH4OH (5 mL), and the phases were separated.
The aqueous phase was then extracted with Et2O (3 × 5 mL), and the
combined organic layers dried over Na2SO4, filtered, and concentrated
under vacuum to afford a crude yellow oil. Purification of the crude
product by flash column chromatography (silica gel, hexanes) gave 343
mg (96%) of (E)-ethyl 3-(tributylstannyl)but-2-enoate as a colorless
1
oil. H NMR (400 MHz, CDCl3): δ 5.96 (1H, q, J = 1.8 Hz), 4.16
(2H, q, J = 7.1 Hz), 2.39 (3H, d, J = 1.9 Hz), 1.54−1.45 (6H, m),
1.34−1.27 (9H, m), 0.97−0.93 (6H, m), 0.91−0.87 (9H, t, J = 7.3
Hz). 13C NMR (100 MHz, CDCl3): δ 169.4, 164.6, 128.2, 59.7, 29.1,
27.5, 22.5, 14.5, 13.8, 9.5. Rf 0.08 (hexane); IR νmax (film) 2957, 2925,
2852, 1714, 1599, 1464, 1377, 1366, 1338, 1258, 1164, 1099, 1039,
960, 862, 689, 664 cm−1. HRMS (ESI+) calcd for C18H37O2Sn [M +
H]+: 405.1810, found 405.1813.
(E)-3-(Tributylstannyl)but-2-enamide, 24. A 0 °C suspension of
NH4Cl (170 mg, 3.18 mmol) in dry toluene (10 mL) was treated
dropwise with a solution of AlMe3 (2 M in toluene, 1.6 mL, 3.18
mmol), and the resulting mixture was allowed to warm to room
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analysis of the crude mixture indicated that the product was a mixture
of (E)-methyl 3-iodobut-2-enoate and (Z)-methyl 3-iodobut-2-enoate
in a 15:1 E/Z ratio in favor of the desired E-isomer. Purification of the
crude product by flash column chromatography (silica gel, 95:5 PE/
EtOAc) yielded 210 mg (32%) of the E-iodo-butenoate as a white
autosampler, and a model 701 fraction collector. Mobile phase A was
water with 0.1% ammonium hydroxide and mobile phase B was
acetonitrile. The flow rate was 60 mL/min. The method started at 40%
B for 1 min, then raised to 80% B over the next 9 min, was held at 80%
B for another minute, then raised to 95% B in 0.2 min, held at 95% for
1.5 min, then lowered back to 40% B in 0.2 min, and held at 40% B for
an additional 1.5 min. The column was a 30 mm × 100 mm, 10 μm
Gemini-NX from Phenomenex (Torrance, CA, USA). The UV
collection was done using a wavelength of 254 nm. (+)-Crocacin C
3 eluted at 6.2 min. (+)-Crocacin C and the two isomeric (Z)
analogues 25 and 26 were isolated in a 1.54/1.00/1.27 ratio, in a total
yield of 11% (4.2 mg total weight).
1
solid. H NMR (500 MHz, CDCl3): δ 6.64 (1H, q, J = 1.5 Hz), 3.70
(3H, s), 2.98 (3H, d, J = 1.5 Hz). 13C NMR (125 MHz, CDCl3): δ
164.6, 131.0, 120.7, 51.4, 31.0. Rf 0.6 (PE:EtOAc, 9.5:0.5); IR νmax
(film) 2954, 2922, 2853, 1718, 1617, 1456, 1444, 1331, 1263, 1176,
1073, 907 cm−1. HRMS (CI+/ISO) calcd for C5H8O2I [M + H]+:
226.9569, found 226.9566.
(E)-3-Iodobut-2-enamide, 28. A 0 °C suspension of NH4Cl (488
mg, 9.1 mmol) in dry toluene (8.5 mL) was treated by the dropwise
addition of AlMe3 (2.0 M solution in toluene, 4.55 mL, 9.1 mmol),
and the resulting solution was allowed to warm to room temperature.
The reaction was cooled back down to 0 °C, and (E)-methyl 3-
iodobut-2-enoate (206 mg, 0.91 mmol) was added. The resulting
mixture was stirred at 50 °C until completion as indicated by TLC
analysis (16 h). The reaction mixture was allowed to cool to room
temperature and diluted with EtOAc (10 mL). The solution was then
cooled to 0 °C and quenched by addition of 10% HCl in brine (10 mL
total volume). The phases were separated, and the organic layer was
washed with satd aq NaHCO3 (20 mL) and brine (20 mL), dried over
Na2SO4, and concentrated under vacuum to afford a crude pale yellow
oil. The crude product was purified by flash column chromatography
(silica gel, 1:1 PE/EtOAc) to afford 97 mg (50%) of iodo-amide 28 as
a white solid. Mp: 105−106 °C. 1H NMR (500 MHz, CDCl3): δ 6.58
(1H, q, J = 1.5 Hz), 5.31 (2H, bs), 2.99 (3H, d, J = 1.5 Hz). 13C NMR
(125 MHz, CDCl3): δ 165.7, 132.5, 117.6, 30.7. Rf 0.27 (PE:EtOAc,
1:1); IR νmax (film) 3354, 3181, 2359, 2330, 1651, 1597, 1397, 1364,
1302, 1067 cm−1. HRMS (CI+/ISO) calcd for C4H7NOI [M + H]+:
211.9572, found 211.9574.
Method B. In a flame-dried 2−5 mL MW vial, stannane 27 (22.3
mg, 39.6 μmol) and the vinyl iodide (13 mg, 43.6 μmol) were
dissolved in freeze−thaw degassed THF (2 mL), and the resulting
homogeneous solution was treated with PdCl2(PPh3)2 (1.4 mg, 2
μmol, 5 mol %). The vial was submitted to MW irradiation (15 min,
100 °C), and then the reaction was filtered and concentrated under
vacuum to afford a crude brown oily residue. The crude product was
purified by flash column chromatography (silica gel 1:1 PE/EtOAc) to
afford 7 mg (50%) of (+)-crocacin C 3 as a white solid.
Method C. In a flame-dried 5 mL microwave vial under an inert
atmosphere, a solution of alkyne 30 (50 mg, 183.5 μmol) in anhydrous
THF (2.5 mL) was degassed by three freeze−pump−thaw cycles.
PdCl2(Ph3P)2 (7.0 mg, 10.3 μmol) was then incorporated, and the
solution was cooled to 0 °C before Bu3SnH (56 μL, 203 μmol) was
added dropwise. The resultant brown solution was stirred at 0 °C until
the starting material was consumed as indicated by TLC (25 min).
Vinyl iodide 28 (42 mg, 197 μmol) was added, and the solution was
heated to 100 °C in a microwave reactor for 15 min. The reaction
mixture was filtered through a small pad of silica using EtOAc as the
eluent, and the filtrate was concentrated in vacuo to give crude yellow
oil. Purification of the crude residue by flash column chromatography
(silica gel, elution gradient 1:1 PE/EtOAc to 2:3 PE/EtOAc) afforded
46 mg (70%) of (+)-crocacin C 3 as a white solid.
((3S,4R,5S,6S,E)-3,5-dimethoxy-4,6-dimethyloct-1-ene-7-
ynyl)benzene, 30. A −78 °C solution of Ohira−Bestmann’s reagent
(138 mg, 0.72 mmol) in dry THF (2.5 mL) was treated dropwise with
NaOMe (25% solution in MeOH 0.17 mL, 0.72 mmol). After 20 min
of stirring, a solution of aldehyde 20 (50 mg, 0.18 mmol) in dry THF
(2.5 mL) was incorporated dropwise. The reaction mixture was
allowed to slowly warm to room temperature over 30 min and was
then quenched with satd aq NH4Cl (5 mL). The mixture was diluted
with H2O (10 mL) and extracted with diethyl ether (3 × 20 mL). The
combined organic extracts were washed with brine (20 mL), dried
over Na2SO4, and concentrated under vacuum to afford the crude
product as yellow oil. Initial purification by flash column
chromatography (silica gel, elution gradient 100% hexanes to 9:1
hexane/EtOAc) followed by a second flash column purification (silica
gel, 1:1 PE/dichloromethane) afforded 49 mg (99%) of alkyne 30 as a
1
(+)-Crocacin C, 3. H NMR (500 MHz, acetone-d6): δ 7.48−7.47
(2H, m), 7.34−7.31 (2H, m), 7.25−7.22 (1H, m), 6.70 (1H, bs), 6.59
(1H, d, J = 16.0 Hz), 6.26 (1H, dd, J = 16.1, 7.3 Hz), 6.13 (1H, bs),
6.12−6.04 (2H, m), 5.80 (1H, s), 4.09−4.07 (1H, m), 3.52 (3H, s),
3.29 (3H, s), 3.16 (1H, dd, J = 9.6, 2.0 Hz), 2.61−2.56 (1H, m), 2.22
(3H, d, J = 1.1 Hz), 1.58−1.52 (1H, m), 1.17 (3H, d, J = 6.9 Hz), 0.85
(3H, d, J = 7.0 Hz). 13C NMR (125 MHz, acetone-d6): δ 169.0, 148.1,
137.9, 137.0, 135.1, 132.6, 130.5, 129.4, 128.3, 127.3, 122.1, 87.1, 81.8,
61.5, 56.5, 43.5, 40.8, 19.3, 13.5, 10.1. Rf 0.25 (PE:EtOAc, 1:1); [α]26
D
+54.0 (c 0.1, MeOH); IR νmax (film) 3479, 3395, 3343, 3184, 2963,
2926, 1655, 1601, 1449, 1368, 1261, 1088, 972 cm−1. HRMS (FAB+)
calcd for C22H31O3NNa [M + Na]+: 380.2202, found 380.2207. Mp:
95−100 °C.
1
white solid. H NMR (500 MHz, CDCl3) δH 7.42−7.40 (2H, m),
(2Z,4E,6S,7S,8R,9S,10E)-7,9-Dimethoxy-3,6,8-trimethyl-11-
phenylundeca-2,4,10-trienamide, 25. 1H NMR (500 MHz,
acetone-d6): δ 7.82 (1H, d, J = 16.3 Hz), 7.51−7.47 (2H, m), 7.38−
7.29 (2H, m), 7.25−7.21 (1H, m), 6.71 (1H, bs), 6.59 (1H, d, J = 16.0
Hz), 6.26 (1H, dd, J = 15.9, 7.1 Hz), 6.07 (1H, bs), 6.05 (1H, dd, J =
16.2, 9.0 Hz), 5.69 (1H, bs), 4.09−4.07 (1H, m), 3.54 (3H, s), 3.30
(3H, s), 3.18 (1H, dd, J = 9.6, 2.1 Hz), 2.65−2.55 (1H, m), 1.90 (3H,
d, J = 1.0 Hz), 1.58−1.52 (1H, m), 1.18 (3H, d, J = 7.2 Hz), 0.86 (3H,
d, J = 7.2 Hz). 13C NMR (125 MHz, acetone-d6): δ 169.0, 146.9,
137.9, 137.8, 132.7, 130.5, 129.4, 129.3, 128.3, 127.3, 120.1, 87.2, 81.9,
61.5, 56.5, 43.5, 41.2, 21.0, 19.3, 10.1. [α]26D +32.0 (c 0.1, MeOH); IR
νmax (film) 3460, 3391, 3339, 3086, 2972, 2928, 1659, 1595, 1456,
1321, 1261, 1085, 1024, 750, 694, 677 cm−1.
(2Z,4Z,6S,7S,8R,9S,10E)-7,9-Dimethoxy-3,6,8-trimethyl-11-
phenylundeca-2,4,10-trienamide, 26. 1H NMR (500 MHz,
acetone-d6): δ 7.50−7.47 (2H, m), 7.35−7.31 (2H, m), 7.26−7.23
(1H, m), 6.83 (1H, bs), 6.60 (1H, d, J = 16.0 Hz), 6.26 (1H, dd, J =
16.1, 7.4 Hz), 6.14 (1H, bs), 5.89 (1H, d, J = 12.1 Hz), 5.84 (1H, s),
5.60 (1H, t, J = 11.3 Hz), 4.05−4.02 (1H, m), 3.52 (3H, s), 3.29 (3H,
s), 3.10 (1H, dd, J = 9.6, 2.2 Hz), 3.07−2.98 (1H, m), 2.20 (3H, d, J =
1.1 Hz), 1.58−1.50 (1H, m), 1.18 (3H, d, J = 7.3 Hz), 0.79 (3H, d, J =
7.3 Hz). 13C NMR (125 MHz, acetone-d6): δ 168.7, 148.9, 137.8,
7.34−7.31 (2H, m), 7.26−7.23 (1H, m), 6.59 (1H, d, J = 16.0 Hz),
6.20 (1H, dd, J = 16.0, 7.2 Hz), 4.15 (1H, ddd, J = 7.2, 2.2, 1.1 Hz),
3.57 (3H, s), 3.33 (3H, s), 3.15 (1H, dd, J = 9.9, 2.5 Hz), 2.77 (1H, qt,
J = 7.0, 2.5 Hz), 2.06 (1H, d, J = 2.5 Hz), 1.99−1.93 (1H, m), 1.35
(3H, d, J = 7.1 Hz), 0.93 (3H, d, J = 7.1 Hz). 13C NMR (125 MHz,
CDCl3) δC 136.9, 132.2, 129.4, 128.7, 127.7, 126.5, 85.1, 84.9, 81.1,
70.1, 61.5, 56.6, 42.9, 29.6, 18.4, 10.1. [α]27 +24.4 (c 1.0, CHCl3).
D
(+)-Crocacin C, 3; (2Z,4E,6S,7S,8R,9S,10E)-7,9-Dimethoxy-
3,6,8-trimethyl-11-phenylundeca-2,4,10-trienamide, 25, and
(2Z,4Z,6S,7S,8R,9S,10E)-7,9-Dimethoxy-3,6,8-trimethyl-11-
phenylundeca-2,4,10-trienamide, 26. Method A. A room temper-
ature solution of iodoolefin 23 (43 mg, 0.11 mmol) and (E)-3-
(tributylstannyl)but-2-enamide 24 (45 mg, 0.12 mmol) in anhydrous
THF (7 mL) was treated with CuI (3.4 mg, 0.65 mmol), AsPh3 (4.5
mg, 15 μmol), and Pd2(dba)3 (6 mg, 6 μmol), and the resulting
reaction mixture was stirred at 60 °C until completion as indicated by
TLC analysis (6 h). The reaction was quenched with H2O (5 mL), and
the phases were separated. The organic layer was washed with brine
(10 mL), dried over Na2SO4, filtered, and concentrated under vacuum
to afford a crude yellow residue. The sample was purified on a Varian
HPLC from Agilent Technologies (Santa Clara, CA, USA) equipped
with SD-1 pumps, a model 325 UV−vis detector, a model 410
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134.9, 133.0, 132.8, 130.6, 129.4, 128.4, 127.3, 121.3, 86.9, 81.9, 61.6,
56.4, 43.8, 36.0, 19.7, 19.5, 10.0. [α]26D −44.0 (c 0.1, MeOH); IR νmax
(film) 3460, 3391, 3339, 3086, 2972, 2928, 1659, 1595, 1456, 1368,
1296, 1088, 1017, 747, 669 cm−1.
Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339−
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ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data of the described compounds and
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rudi.marquez@glasgow.ac.uk.
■
Notes
The authors declare no competing financial interest.
(18) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
̈
1996, 521−522. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem.
ACKNOWLEDGMENTS
1982, 47, 1837−1845.
■
We thank Dr. Ian Sword for postgraduate support (A.E.P.).
The authors also thank Dr. Ian Sword and the EPSRC for
funding.
DEDICATION
■
†Dedicated to Professor Philip S. Beauchamp.
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