A stereoselective synthesis of the C9-C19 subunit of (+)-peloruside A

Article abstract of DOI:10.1039/c3ob27508f

The stereoselective synthesis of a C9-C19 fragment of the potent antitumor agent peloruside A is disclosed. The C11 stereogenic centre was created by a vinylogous Mukaiyama aldol reaction following Carreira's protocol, with excellent stereocontrol. The C13 stereogenic centre was introduced by a substrate controlled reduction. The C15 stereocentre was fashioned using Noyori's asymmetric transfer hydrogenation while the Z-trisubstituted double bond was formed by a regioselective hydrostannation of an alkyne followed by methylation of the resultant vinyl stannane using Lipshutz's protocol. The C18 chiral centre was introduced by a chemoenzymatic route.

Full text of DOI:10.1039/c3ob27508f

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A stereoselective synthesis of the C9–C19 subunit of
(+)-peloruside A†
Cite this: Org. Biomol. Chem., 2013, 11,
2847
Sadagopan Raghavan* and V. Vinoth Kumar
The stereoselective synthesis of a C9–C19 fragment of the potent antitumor agent peloruside A is dis-
closed. The C11 stereogenic centre was created by a vinylogous Mukaiyama aldol reaction following Car-
reira’s protocol, with excellent stereocontrol. The C13 stereogenic centre was introduced by a substrate
controlled reduction. The C15 stereocentre was fashioned using Noyori’s asymmetric transfer hydrogen-
ation while the Z-trisubstituted double bond was formed by a regioselective hydrostannation of an
alkyne followed by methylation of the resultant vinyl stannane using Lipshutz’s protocol. The C18 chiral
centre was introduced by a chemoenzymatic route.
Received 28th December 2012,
Accepted 18th February 2013
DOI: 10.1039/c3ob27508f
www.rsc.org/obc
the remaining two by a substrate controlled reduction and
enzymatic resolution. The Z-trisubstituted alkene is created by
Introduction
Peloruside A (1), a 16-membered macrolide, was isolated from hydrostannation of an alkyne followed by reaction of the
the marine sponge Mycale hentscheli collected in Pelorus ensuing vinylstannane with dimethyl cuprate. Aldehyde 2 was
Sound of New Zealand by Northcote and co-workers.1 Peloru- envisioned to be obtained from alkenone 4 by a stereoselective
side A displays potent antitumor activity against P388 murine reduction followed sequentially by protection of the resulting
leukemia cells with an IC50 value of 10 ng mL−1.2 It is a micro- carbinol, selective deprotection to reveal the C9 hydroxy group
tubule stabilizing agent and arrests cells in the G2-M phase of and further oxidation. Alkenone 4 can be obtained from
the cell cycle.3 The clinical potential of peloruside A is high- Weinreb amide 5 and the alkenyl lithium prepared from 6.
lighted by its activity against Taxol® resistant cells, being less Compound 5 can be obtained from δ-lactone 7 which in turn
susceptible than paclitaxel to MDR-cell lines.4 Elucidation of was envisaged to be obtained by an asymmetric vinylogous
its structure by NMR studies revealed a polyoxygenated macro- Mukaiyama reaction of silyl ketene acetal 8 and aldehyde 9.
lide containing a pyranose ring with a Z-configured trisubsti-
tuted alkene.
The significant biological activity of peloruside A combined
with its scarcity in nature and densely functionalized structure
Results and discussion
have prompted numerous studies directed toward its syn-
thesis. To date, a number of total syntheses3,5–9 as well as syn-
thetic studies of peloruside A have been reported.10,11 Our
retrosynthesis of peloruside A involved the scission of the C8–
C9 bond and in the forward direction it was envisioned to
create this bond by addition of the acetylide derived from
alkyne 312 (C1–C8 subunit) to the aldehyde 2 (C9–C19
subunit), Scheme 1. Herein, we report a stereoselective syn-
thesis of the C9–C19 fragment of (+)-peloruside A adopting a
strategy wherein two of the four stereocentres were introduced
using metal complex-promoted catalytic asymmetric reactions;
The synthesis began with the selective monoprotection of 2,2-
dimethyl-1,3-propanediol 10 as its TBDPS ether 11. Oxidation
with IBX13 cleanly afforded aldehyde 9 (P = TBDPS). The C11
stereocentre was created while extending the carbon chain by
utilizing the vinylogous Mukaiyama aldol reaction pioneered
by Carreira and co-workers.14 Thus exposure of aldehyde 9 to
ketene acetal 815 in the presence of copper(II) fluoride/(R)-Tol-
binap furnished the alcohol 12 (93 : 7 er, 52% yield).16 It is
noteworthy that the reaction proceeds cleanly, though in
modest yield, on a sterically demanding aliphatic aldehyde as
9. To the best of our knowledge this is the first report on a
vinylogous Mukaiyama aldol reaction of 8 with an α-quaternary
carbon-containing aldehyde. Heating of 12 with methanol in
toluene at reflux14 provided a chromatographically separable
mixture of β-keto ester 13 and keto lactone 14 in a roughly 3 : 1
ratio. β-Keto ester 13 on anti-selective reduction following
Evans’ protocol17 furnished diol 15 (>95% dr, 78% yield).18
Division of Natural Product Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500007, India. E-mail: sraghavan@iict.res.in
†Electronic supplementary information (ESI) available: Experimental procedures
for the preparation of known compounds 11, 9, 8, anti-1,3-acetonide of com-
pounds 15, 23, 24, 25, 26, 33 and epi-33. Copies of 1H and 13C NMR spectra for
the compounds. See DOI: 10.1039/c3ob27508f
19
Lactonization of diol 15 promoted by anhydrous ZnCl2
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Scheme 1 Retrosynthetic analysis of (+)-peloruside A.
followed by treatment of the resulting hydroxy lactone 16 with The vinyl lithium reagent 20 functioned competitively as a
MeI in the presence of Ag2O furnished compound 7 (P = base rather than as a nucleophile.25 Since sp-hybridized
TBDPS), Scheme 2. The small quantity of keto lactone 14 was nucleophiles are less basic than sp2 nucleophiles, we
initially transformed into ene carbonate 17 by exposure to attempted the reaction between alkynyl lithium prepared from
dimethyl sulfate in the presence of K2CO3 and further reduced 31 and amide 18. The alkynyl ketone 32 was indeed obtained
with RANEY®-nickel20 under an atmosphere of hydrogen to though in poor yield (10%) along with amide 30 as the major
afford compound 7 diastereoselectively (>95% dr, 76% yield).
The introduction of a C16–C19 carbon chain and the crea-
product (60–70),26 Scheme 5.
The preparation of alkyne 31 commenced with the alkynation
tion of the C15 stereocentre were the next task. We initially of aldehyde 34, obtained from 22 by the same sequence of reac-
explored the reaction of alkenyl lithium 20, derived from iodo tions detailed in Scheme 4 except using TBDPS-Cl for monosilyl-
alkene 19, with the Weinreb amide 18, prepared from lactone ation of diol 23, using Ohira–Bestmann’s protocol27 to furnish
7, as a means to secure α,β-unsaturated ketone 21, expecting to alkyne 35. TBAF mediated deprotection followed by protection
reduce the keto group in 21 selectively via substrate control, of the resulting carbinol 36 using benzyl trichloroacetimidate in
Scheme 3.
the presence of catalytic triflic acid yielded alkyne 31, Scheme 6.
Alcohol epi-33 was also converted to alkyne 31 by an initial
The iodo alkene 19 was prepared from diethyl 2-ethyl propane-
dioate 22 following
a
reported chemoenzymatic route.21 benzyl ether formation to yield compound 37 that on TBAF
Reduction of the diester 22 to diol 23 followed by selective mediated deprotection yielded alcohol 38. Oxidation of 38
monoprotection with TBS-Cl furnished silyl ether 24. Resolu- under Swern conditions followed by alkynation of the ensuing
tion of 24 by lipase catalyzed transesterification using vinyl- aldehyde yielded alkyne 31.28,29
acetate yielded optically pure alcohol 25 and acetate 26.
Having been unsuccessful in introducing the C16–C19
Hydrolysis of the acetate 26 by treatment with a catalytic quan- subunit by reaction of Weinreb amide 18 with alkenyl or
tity of anhydrous K2CO3 in methanol yielded alcohol epi-25 alkynyl nucleophilic partners, we explored its introduction
that on oxidation employing Swern conditions22 furnished using Fukuyama’s methodology. Lactone 7 was transformed
aldehyde 27. Wittig olefination following Zhao’s protocol with under mild reaction conditions into thioester 39 by treatment
the ylide derived from the iodo compound23 28 yielded iodo with decanethiol30 and trimethylaluminum.31 Protection of
alkene 19 in modest yield, Scheme 4.
the carbinol under standard conditions furnished TBS ether
Lactone 7 was converted via Weinreb amide formation24 to 40. The alkyne 31 was coupled to thioester 40 under the con-
compound 29 that on treatment with TBS-OTf and 2,6-lutidine ditions reported by Fukuyama32 to furnish alkynone 32 in
furnished amide 18. Addition of alkenyl lithium 20, prepared good yield, Scheme 7. Stereoselective reduction of alkynone 32
from 19 via lithium iodine exchange, to amide 18 afforded using Noyori’s transfer-hydrogenation33 methodology afforded
none of the expected ketone 21, but the unsaturated amide 30. the (S)-propargylic alcohol 4134,35 (8 : 2 dr, 85% yield).
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Scheme 2 Preparation of δ-lactone 7.
Scheme 3 Proposed route to unsaturated ketone 21.
Scheme 4 Synthesis of iodo alkene 19.
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Scheme 5 Attempted preparation of unsaturated ketones 21 and 32.
Scheme 6 Synthesis of alkyne 31.
The major isomer 41 was separated and subjected to hydro- proton shows NOE with the methyl group on the double bond,
36
stannation with nBu3SnH in the presence of PdCl2(PPh3)2
one of the methylene protons of the ethyl residue and the
hoping to obtain the desired regioisomeric vinyl stannane 42 C19 methylene protons thus confirming its C17 location. The
stereoselectively as the major isomer via hydroxy directed methyl group on the double bond shows NOE with the olefinic
hydrostannation and also due to steric effects.37 In the event proton and one of the methylene protons at C14 proving its
hydrostannation of 41 in hexane afforded a 4 : 1 ratio of an C16 location.
inseparable mixture of vinyl stannanes 42 and 43 respecti-
vely.38 The regioisomeric mixtures of stannanes were
subjected to reaction with dimethylcopper cyanide following
Conclusion
Lipshutz’ protocol39 to furnish a separable mixture of allyl
alcohols 44 and 45.40 The structure of major product 44 was In summary, we have synthesized the C9–C19 fragment of
confirmed by 1H NMR and characteristic NOE signals.41 The peloruside A exploiting the vinylogous Mukaiyama aldol reac-
C15 methine proton shows strong NOE with the C18 methine tion, Noyori transfer-hydrogenation, anti-selective reduction
proton thus unambiguously establishing the Z-geometry of the and alkyne hydrostannation followed by cuprate addition as
trisubstituted alkene. It also reveals NOE with one of the key steps. The fragment has been prepared in 13 steps (longest
C14 methylene protons and C13 methine proton. The olefinic linear sequence) in 4.34% overall yield.
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Scheme 7 Synthesis of the C9–C19 fragment.
of the residue by column chromatography using hexanes–
EtOAc (8 : 2, v/v) as the eluent afforded pure aldol 12 (1.25 g,
2.6 mmol) in 52% yield as a viscous oil. TLC Rf = 0.22 (25%
Experimental section
Compound 12
A mixture of copper(II) trifluoromethanesulfonate (36 mg, EtOAc–hexanes). [α]3D5 = −11.5 (c 1, CHCl3). IR (KBr): 3474,
0.1 mmol) and (R)-Tol-BINAP (75 mg, 0.11 mmol) in THF 2959, 2933, 2859, 1752, 1635, 1391, 1274, 1108, 704, 505 cm−1
.
(20 mL) was stirred at rt for 10 minutes to yield a clear yellow 1H NMR (300 MHz, CDCl3): δ 7.68–7.58 (m, 4H), 7.48–7.32 (m,
solution. A solution of tetrabutylammonium triphenyldifluoro- 6H), 5.28 (s, 1H), 3.83 (dd, J = 11.1, 1.5 Hz, 1H), 3.51–3.42 (m,
silicate (TBAT) (110 mg, 0.2 mmol) in THF (2 mL) was added 2H), 2.35 (dd, J = 14.2, 2.4 Hz, 1H), 2.18 (dd, J = 14.2, 10.6 Hz,
and stirring was continued for 10 minutes. After cooling the 1H), 1.70 (s, 6H), 1.07 (s, 9H), 0.89 (s, 3H), 0.87 (s, 3H). 13C
reaction mixture to −78 °C the ketene acetal 8 (1.6 mL, NMR (75 MHz, CDCl3): δ 170.4, 161.1, 135.4, 134.6, 132.3,
7.5 mmol) was added dropwise followed by a solution of the 129.8, 127.9, 94.9, 74.3, 72.1, 38.8, 36.5, 26.6, 25.5, 24.1, 21.5,
aldehyde 9 (1.7 g, 5 mmol) in THF (5 mL). The color of the 19.2, 19.0. MS (ESI) 500 [M + NH4]+. HRMS (ESI) m/z calcd for
reaction mixture slowly changed to dark red color; the progress C28H38O5NaSi 505.23807; found 505.23918.
of the reaction was monitored by TLC. After 16 h, trifluoroace-
Compounds 13 and 14
tic acid (2 mL) was added at −78 °C and the solution was
allowed to warm to rt. Stirring was continued for an additional
hour. The reaction mixture was diluted with ether (50 mL) and
a saturated aqueous solution of NaHCO3 was added dropwise
until the evolution of gas ceased. The layers were separated
and the aqueous layer was extracted with ether (3 × 20 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification
A solution of aldol adduct 12 (4.82 g, 10 mmol) in anhydrous
methanol (8 mL, 200 mmol) and anhydrous toluene (20 mL)
was heated to 110 °C in a sealed vessel for 1 h. The solvent was
evaporated and the residue was purified by column chromato-
graphy using hexanes–EtOAc (8 : 2, v/v) to provide ketoester 13
(2.96 g, 6.5 mmol) in 65% yield as a viscous oil along with
ketolactone 14 (890 mg, 2.1 mmol) in 21% yield as a viscous
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oil. Ketoester 13: TLC Rf = 0.35 (30% EtOAc–hexanes). [α]D35
=
were evaporated and the crude residue was purified by column
−17.5 (c 1, CHCl3). IR (KBr): 3490, 3069, 2933, 2858, 1744, chromatography using hexanes–EtOAc (7 : 3, v/v) to yield pure
1716, 1428, 1262, 1108, 822, 704, 505 cm−1
.
1H NMR hydroxy lactone 16 (1.16 g, 2.7 mmol) in 90% yield as a viscous
(300 MHz, CDCl3): δ 7.90–7.72 (m, 4H), 7.48–7.36 (m, 6H), 4.11 oil. TLC Rf = 0.10 (30% EtOAc–hexanes). [α]3D5 = +5.1 (c 1,
(dd, J = 9.2, 3.0 Hz, 1H), 3.73 (s, 3H), 3.55 (s, 2H), 3.49–3.44 CHCl3). IR (KBr): 3423, 2923, 2853, 1731, 1462, 1108, 704,
(m, 2H), 2.73–2.59 (m, 2H), 1.06 (s, 9H), 0.90 (s, 3H), 0.83 (s, 504 cm−1 1H NMR (300 MHz, CDCl3): δ 7.70–7.61 (m, 4H),
.
3H). 13C NMR (75 MHz, CDCl3): δ 203.2, 167.5, 135.5, 132.8, 7.48–7.32 (m, 6H), 4.29 (dd, J = 12.1, 2.3 Hz, 1H), 4.26–4.17 (m,
132.7, 129.7, 127.7, 73.4, 71.8, 52.1, 49.7, 45.3, 38.7, 26.8, 23.3, 1H), 3.64 (d, J = 9.8 Hz, 1H), 3.38 (d, J = 9.8 Hz, 1H), 2.87 (dd,
21.5, 19.1. MS (ESI) 479 [M + Na]+. HRMS (ESI) m/z calcd for J = 16.6, 5.2 Hz, 1H), 2.42 (dd, J = 16.6, 7.5 Hz, 1H), 2.19–2.08
C26H36O5NaSi 479.22242; found 479.22133. Ketolactone 14: (m, 1H), 1.63–1.50 (m, 1H), 1.05 (s, 9H), 0.96 (s, 3H), 0.92 (s,
TLC Rf = 0.15 (30% EtOAc–hexanes). [α]3D5 = −15.3 (c 1, CHCl3). 3H). 13C NMR (75 MHz, CDCl3): δ 171.0, 135.5, 133.4, 133.2,
IR (KBr): 2931, 1717, 1466, 1393, 1219, 1102, 822, 765, 700, 129.7, 127.7, 80.1, 69.3, 64.1, 39.4, 39.1, 32.4, 26.9, 20.4, 19.6,
503 cm−1 1H NMR (300 MHz, CDCl3): δ 7.64–7.61 (m, 4H), 19.3. MS (ESI) 444 [M + NH4]+. HRMS (ESI) m/z calcd for
.
7.46–7.36 (m, 6H), 4.71 (dd, J = 12.1 Hz, 3.1 Hz, 1H), 3.70 (d, C25H34O4NaSi 449.21186; found 449.21125.
J = 10.6 Hz, 1H), 3.52 (d, J = 18.9 Hz, 1H), 3.40 (d, J = 10.6 Hz,
Lactone 7
1H), 3.38 (d, J = 18.9 Hz, 1H), 2.63 (dd, J = 18.1, 3.1 Hz, 1H),
2.50 (dd, J = 18.1, 12.1 Hz, 1H), 1.06 (s, 9H), 0.99 (s, 3H), 0.97 A solution of 16 (4.26 g, 10 mmol) in anhydrous Et2O (10 mL)
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 200.7, 167.2, 135.5, 132.9, was added to a slurry of activated 4 Å MS (4 g) and silver oxide
129.8, 127.7, 78.3, 68.9, 60.3, 46.9, 38.7, 26.8, 20.4, 19.3, 19.2. (3.48 g, 15 mmol) in dry Et2O (20 mL). To this slurry freshly
MS (ESI) 447 [M
+
Na]+. HRMS (ESI) m/z calcd for distilled MeI (3.1 mL, 50 mmol) was added, heated to reflux
C25H32O4NaSi 447.1967; found 447.1974.
for 1 h, filtered through a pad of Celite and the filter cake
washed with Et2O (3 × 20 mL). The filtrate was concentrated
and the crude compound purified by column chromatography
Compound 15
To a solution of Me4NBH(OAc)3 (7.9 g, 30 mmol) in anhydrous using hexanes–EtOAc (9 : 1, v/v) to provide 7 (4.1 g, 9.3 mmol)
acetonitrile (15 mL) was added acetic acid (15 mL) dropwise. in 93% yield as a viscous oil. TLC Rf = 0.45 (25% EtOAc–
The mixture was stirred at rt for 30 min. The mixture was hexanes). [α]3D5 = +4.7 (c 1, CHCl3). IR (KBr): 2927, 2859, 1744,
cooled to −35 °C and a solution of keto ester 13 (2.28 g, 1468, 1247, 1102, 821, 702, 502 cm−1 1H NMR (500 MHz,
.
5 mmol) in anhydrous acetonitrile (5 mL) was added and stir- CDCl3): δ 7.72–7.68 (m, 4H), 7.49–7.38 (m, 6H), 4.33 (dd, J =
ring was continued for 18 h at −35 °C. The reaction mixture 12.3, 2.0 Hz, 1H), 3.81–3.75 (m, 1H), 3.69 (d, J = 9.6 Hz, 1H),
was quenched with aqueous sodium potassium tartrate and 3.43 (d, J = 9.6 Hz, 1H), 3.39 (s, 3H), 2.88 (dd, J = 17.1, 5.5 Hz,
the mixture was allowed to warm to rt. The mixture was 1H), 2.53 (dd, J = 17.1, 6.8 Hz, 1H), 2.32–2.26 (m, 1H),
diluted with DCM and washed with aqueous NaHCO3 solution. 1.57–1.54 (m, 1H), 1.11 (s, 9H), 1.02 (s, 3H), 0.98 (s, 3H). 13C
The layers were separated and the aqueous layer was re- NMR (75 MHz, CDCl3): δ 170.5, 135.5, 133.2, 133.1, 129.6,
extracted with DCM (4 × 40 mL). The combined organic layers 127.6, 79.7, 72.7, 69.3, 55.8, 39.1, 36.1, 29.4, 26.8, 20.3, 19.6,
were washed with water, brine, dried over anhydrous Na2SO4, 19.2. MS (ESI) 458 [M + NH4]+. HRMS (ESI) m/z calcd for
concentrated and the residue purified by column chromato- C26H36O4NaSi 463.22751; found 463.22851.
graphy using hexanes–EtOAc (7 : 3, v/v) to provide diol 15
Compound 17
(1.66 g, 3.9 mmol) in 78% yield as a highly viscous oil. TLC Rf
= 0.15 (30% EtOAc–hexanes). [α]3D5 = −2.6 (c 1, CHCl3). IR (KBr): To a solution of keto lactone 14 (848 mg, 2 mmol) in anhy-
3488, 3047, 2951, 2882, 1727, 1349, 833, 703, 502 cm−1 1H drous acetone (10 mL) was added freshly purified (MeO)2SO2
.
NMR (500 MHz, CDCl3): δ 7.74–7.62 (m, 4H), 7.52–7.37 (m, (227 mL, 2.4 mmol), and solid K2CO3 (332 mg, 2.4 mmol) por-
6H), 4.42–4.37 (m, 1H), 3.92 (dd, J = 9.3, 2.8 Hz, 1H), 3.75–3.71 tionwise over 2 h. After further stirring at rt for 3 h, TLC exam-
(m, 4H), 3.52 (d, J = 5.6 Hz, 1H), 2.58 (d, J = 6.5 Hz, 2H), ination revealed complete consumption of keto lactone. The
1.63–1.57 (m, 2H), 1.07 (s, 9H), 0.90 (s, 3H), 0.81 (s, 3H). 13C reaction mixture was diluted with ether (50 mL) and washed
NMR (75 MHz, CDCl3): δ 173.1, 135.6, 133.2, 129.7, 127.7, 75.2, with water (2 × 20 mL). The aqueous layer was extracted with
73.6, 65.8, 51.7, 41.4, 37.2, 30.9, 26.8, 19.3, 19.1, 18.7. MS (ESI) ether (2 × 25 mL). The combined organic layers were washed
481 [M + Na]+. HRMS (ESI) m/z calcd for C26H38O5NaSi with brine, dried over anhydrous Na2SO4 and concentrated.
481.23807; found 481.23625.
Purification of the residue by column chromatography using
hexanes–EtOAc (8 : 2, v/v) afforded enol ether 17 (850 mg,
1.94 mmol) in 95% yield. TLC Rf = 0.3 (25% EtOAc–hexanes).
Compound 16
To a mixture of flame dried ZnCl2 (810 mg, 6 mmol) and acti- [α]3D6 = −1.8 (c 1, CHCl3). IR (KBr): 2956, 2802, 1761, 1441,
vated 4 Å molecular sieves (1.5 g) in anhydrous THF (12 mL) 1114, 887, 724, 512 cm−1 1H NMR (300 MHz, CDCl3): δ
.
was added a solution of diol 15 (1.35 g, 3 mmol) in anhydrous 7.68–7.61 (m, 4H), 7.44–7.36 (m, 6H), 5.15 (s, 1H), 4.46 (dd, J =
THF (6 mL) and the mixture was heated to reflux for 3 h. The 13.4, 3.3 Hz, 1H), 3.75 (s, 3H), 3.66 (d, J = 10.0 Hz, 1H), 3.40 (d,
mixture was filtered through a pad of Celite and the filter cake J = 10.0 Hz, 1H), 2.69–2.55 (m, 1H), 2.24 (dd, J = 16.9, 3.5 Hz,
washed with ethyl acetate (2 × 10 mL). The combined filtrates 1H), 1.04 (s, 9H), 0.99 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz,
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CDCl3): δ 173.5, 167.4, 135.4, 133.2, 133.0, 129.5, 127.6, 90.0, (300 MHz, CDCl3): δ 7.68–7.60 (m, 4H), 7.42–7.28 (m, 6H),
79.0, 68.9, 55.9, 38.7, 28.1, 26.7, 20.5, 19.7, 19.2. MS (ESI) 456 3.95–3.88 (m, 1H), 3.76 (d, J = 7.3 Hz, 1H), 3.69 (s, 3H), 3.49 (d,
[M
+
NH4]+. HRMS (ESI) m/z calcd for C26H34O4NaSi J = 9.6 Hz, 1H), 3.38–3.28 (m, 4H), 3.15 (s, 3H), 2.78 (dd, J =
461.21186; found 461.21228.
14.7, 5.8 Hz, 1H), 2.29 (dd, J = 14.9, 5.6 Hz, 1H), 1.87–1.74 (m,
1H), 1.49–1.38 (m, 1H), 1.07 (s, 9H), 0.93 (s, 3H), 0.82 (m,
12H), 0.01 (s, 3H), −0.07 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
Lactone 7
To a solution of compound 17 (219 mg, 0.5 mmol) in iso-pro- 172.2, 135.7, 133.8, 129.4, 127.5, 74.4, 74.1, 70.1, 61.1, 56.2,
panol (5 mL) was added a slurry of catalytic amount of 41.00, 39.6, 37.5, 32.1, 26.9, 26.2, 21.6, 20.4, 19.3, 18.4, −3.4,
RANEY®-nickel. The reaction mixture was stirred for 6 h under −4.0. MS (ESI) 638 [M + Na]+. HRMS (ESI) m/z calcd for
an atmosphere of hydrogen at rt. The mixture was filtered C34H57O5NNaSi2 638.36675; found 638.36774.
through Celite, and the filter cake washed with EtOAc (3 ×
Compound 19
10 mL). The combined filtrate was concentrated and the
residue purified by column chromatography using hexanes– To a cooled (−78 °C) solution of oxalyl chloride (1.75 mL,
EtOAc (8 : 2, v/v) to furnish compound 7 (172 mg, 0.39 mmol) 20 mmol) in anhydrous DCM (30 mL) was added dimethylsulf-
in 78% yield as a viscous oil.
oxide (4.7 mL, 40 mmol) dropwise. After 30 min a solution of
alcohol, epi-25 (2.18 g, 10 mmol) in DCM (30 mL) was added
dropwise. The reaction mixture was stirred for 1.5 h before
Weinreb amide 29
To an ice cooled solution of N,O-dimethylhydroxylamine·HCl adding triethylamine (9 mL, 60 mmol). The resulting suspen-
(588 mg, 6 mmol) in anhydrous CH2Cl2 (15 mL) was added sion was warmed slowly to rt, diluted with H2O (30 mL) and
Me3Al (3 mL, 6 mmol, 2 M in toluene) slowly at 0 °C. After extracted with DCM (3 × 50 mL). The combined organic
20 minutes compound 7 (2.2 g, 5 mmol) in anhydrous CH2Cl2 extracts were washed with brine, dried over Na2SO4, filtered
(10 mL) was added slowly and the mixture stirred at the same and concentrated under reduced pressure to afford the crude
1
temperature for 30 minutes. The reaction mixture was diluted aldehyde 27 as a light yellow oil. H NMR (300 MHz, CDCl3): δ
with CH2Cl2 (30 mL) and quenched with ice pieces carefully 9.67 (d, J = 1.9 Hz, 1H), 3.86 (d, J = 5.4 Hz, 2H), 2.35–2.26 (m,
followed by aq. 1 N HCl (12 mL). The layers were separated 1H), 1.79–1.65 (m, 1H), 1.59–1.46 (m, 1H), 0.95 (t, J = 7.5 Hz,
and the aqueous layer was extracted with DCM (3 × 25 mL). 3H), 0.87 (s, 9H), 0.04 (s, 6H). 13C NMR (75 MHz, CDCl3): δ
The combined organic layers were washed with aqueous 180.5, 63.5, 50.0, 25.7, 21.3, 18.1, 11.6, −5.6. The crude alde-
NaHCO3, water, brine, dried over Na2SO4 and concentrated. hyde was taken ahead to the next step without further purifi-
Purification of the residue by column chromatography using cation for fear of epimerization. To a suspension of EtPh3PBr
hexanes–EtOAc (7 : 3, v/v) afforded amide 29 (2.15 g, 4.3 mmol) (10.1 g, 22 mmol) in anhydrous THF (80 mL) cooled at −23 °C
in 86% yield as a viscous oil. TLC Rf = 0.15 (30% EtOAc– was added n-BuLi (8 mL, 20 mmol, 2.5 M in hexane) dropwise
hexanes). [α]3D6 = −13.1 (c 1, CHCl3). IR (KBr): 3485, 3070, 3049, over 10 minutes to form a dark red solution. After an
2961, 2933, 2859, 1724, 1469, 1427, 1254, 1189, 1107, 1002, additional 30 minutes, the ylide was added via cannula over
1
822, 744, 505 cm−1. H NMR (500 MHz, CDCl3): δ 7.68–7.6 (m, 20 minutes to a cooled (−78 °C) solution of iodine (5.4 g,
4H), 7.44–7.32 (m, 6H), 4.08–3.96 (m, 1H), 3.80 (dd, J = 7.9, 3.9 21 mmol) in anhydrous THF (80 mL). The resulting yellow
Hz, 1H), 3.68 (s, 3H), 3.53 (d, J = 9.8 Hz, 1H), 3.43–3.4 (m, 4H), slurry was stirred for 15 minutes and warmed to −23 °C.
3.17 (s, 3H), 2.86 (dd, J = 15.8, 4.9 Hz, 1H), 2.48 (dd, J = 15.8, NaHMDS (18 mL, 18 mmol, 1 M in THF) was added dropwise
5.9 Hz, 1H), 1.72–1.60 (m, 2H), 1.06 (s, 9H), 0.87 (s, 3H), 0.86 over 10 minutes, and the resulting orange suspension was
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 172.3, 135.5, 132.9, 129.6, stirred for 20 minutes and cooled to −78 °C. A solution of
127.6, 75.9, 73.7, 71.9, 61.1, 57.6, 38.9, 36.8, 35.9, 31.9, 26.7, crude aldehyde 27 (2.2 g, 10 mmol) in THF (20 mL) was added
21.8, 19.2, 19.1. MS (ESI) 524 [M + Na]+. HRMS (ESI) m/z calcd dropwise over 10 minutes and stirred for 2 h at the same temp-
for C28H44NO5Si 502.2988; found 502.3002.
erature. The reaction mixture was quenched with MeOH
(2.5 mL). The reaction mixture was filtered through a pad of
Celite and the filter cake washed with ether (4 × 50 mL). The
Compound 18
To a solution of amide 29 (2 g, 4 mmol) in anhydrous CH2Cl2 combined filtrates were washed with aqueous Na2S2O3, brine,
(20 mL) cooled at 0 °C was added anhydrous 2,6-lutidine dried over Na2SO4 and concentrated. The crude product was
(0.72 mL, 6 mmol) followed by TBS-OTf (1.1 mL, 4.8 mmol). purified by column chromatography using hexanes–EtOAc
After 15 min the reaction was quenched by the addition of (95 : 5, v/v) to furnish vinyl iodide 19 (1.33 g, 3.9 mmol) in 39%
water. The layers were separated and the aqueous layer was overall yield as an oil. TLC Rf = 0.15 (5% EtOAc–hexanes). [α]D35
extracted with CH2Cl2 (3 × 30 mL). The combined organic = +1.9 (c 1, CHCl3). IR (KBr): 2956, 2929, 2857, 1465, 1253,
1
layers were washed with brine, dried over anhydrous Na2SO4, 1105, 1059, 835, 775 cm−1. H NMR (500 MHz, CDCl3): δ 5.20
concentrated and the resulting residue was purified by column (dd, J = 9.0, 1.1 Hz, 1H), 3.58–3.52 (m, 1H), 3.50–3.42 (m, 1H),
chromatography using hexanes–EtOAc (9 : 1, v/v) to afford 18 2.52 (s, 3H), 2.38–2.28 (m, 1H), 1.66–1.52 (m, 1H), 1.40–1.32
(2.26 g, 3.68 mmol) in 92% yield as a viscous oil. TLC Rf = 0.25 (m, 1H), 0.94–0.86 (m, 12H), 0.03 (s, 6H). 13C NMR (75 MHz,
(20% EtOAc–hexanes). [α]3D4 = −13.9 (c 1, CHCl3). IR (KBr): CDCl3): δ 137.2, 101.4, 64.9, 50.9, 33.8, 25.9, 23.6, 18.3, 11.5,
3069, 2933, 1667, 1467, 1106, 833, 704 cm−1
.
1H NMR −5.3.
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Compound 35
chromatography using hexanes–EtOAc (95 : 5, v/v) to afford
pure product 31 (270 mg, 1.44 mmol) in 72% yield as a color-
less oil. TLC Rf = 0.4 (5% EtOAc–hexanes). [α]3D7 = +1.9 (c 1,
Aldehyde 34 was prepared in much the same way from 33 as
disclosed earlier for the preparation of aldehyde 27 from epi-
25. TLC Rf = 0.40 (10% EtOAc–hexanes). 1H NMR (300 MHz,
CDCl3): δ 9.73 (d, J = 2.26 Hz, 1H), 7.70–7.61 (m, 4H), 7.43–7.36
(m, 6H), 3.88 (d, J = 6.0 Hz, 2H), 2.39–2.32 (m, 1H), 1.77–1.65
(m, 1H), 1.56–1.47 (m, 1H), 1.03 (s, 9H), 0.87 (t, J = 7.5 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 204.6, 135.5, 134.7, 129.5, 127.7,
62.2, 55.8, 26.7, 19.2, 18.4, 11.4. Aldehyde 34 without purifi-
cation was employed in the next step. To the solution of the
crude aldehyde 34 (1.5 g, 4.4 mmol) in anhydrous MeOH
(22 mL) was added the Ohira–Bestmann reagent (1.02 g,
5.28 mmol) and solid K2CO3 (1.8 g, 13.2 mmol) at rt. The reac-
tion mixture was stirred for 8 h at the same temperature. The
reaction was quenched by addition of 10% aqueous HCl, and
the mixture was extracted with ether (4 × 50 mL). The com-
bined organic layers were washed with water, brine, dried over
anhydrous Na2SO4 and concentrated. Purification of the
residue by column chromatography using hexanes–EtOAc
(95 : 5, v/v) afforded alkyne 35 (1.12 g, 3.3 mmol) in 76%
overall yield for two steps as a colorless oil. TLC Rf = 0.44 (5%
EtOAc–hexanes). [α]3D7 = +2.1 (c 1.1, CHCl3). IR (KBr): 2961,
1
CHCl3). IR (KBr): 2961, 2928, 2873, 1456, 1097, 739 cm−1. H
NMR (300 MHz, CDCl3): δ 7.38–7.26 (m, 5H), 4.56 (s, 2H), 3.54
(dd, J = 9.0, 6.7 Hz, 1H), 3.45 (dd, J = 9.0, 6.7 Hz, 1H),
2.68–2.56 (m, 1H), 2.09 (d, J = 2.2 Hz, 1H), 1.73–1.63 (m, 1H),
1.56–1.42 (m, 1H), 1.02 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 138.0, 128.2, 127.4, 126.4, 84.9, 72.9, 72.1, 69.9, 33.7,
24.3, 11.1.
Compound 37
Compound 37 was prepared from epi-33 (2.72 g, 8 mmol) fol-
lowing the same procedure described for the preparation of
compound 31 from alcohol 36, in 92% yield (3.2 g, 7.36) after
column chromatography using hexanes–EtOAc (97 : 3, v/v) as
the eluent. TLC Rf = 0.6 (5% EtOAc–hexanes). [α]3D7 = +0.8 (c 1,
CHCl3). IR (KBr): 2931, 2908, 1792, 1767, 1214, 1110, 908,
702 cm−1 1H NMR (300 MHz, CDCl3) δ 7.77–7.58 (m, 4H),
.
7.43–7.22 (m, 11H), 4.48 (s, 2H), 3.75–3.46 (m, 4H), 1.77–1.68
(m, 1H), 1.48–1.38 (m, 2H), 1.03 (s, 9H), 0.86 (t, J = 7.6 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 140.9, 135.5, 133.8, 129.4, 128.2,
127.7, 127.5, 127.3, 127.2, 72.9, 70.3, 63.3, 43.0, 26.9, 20.9,
19.3, 11.6. MS (ESI) 455 [M + Na]+. HRMS (ESI) m/z calcd for
C28H36O2NaSi 455.23768; found 455.23761.
2931, 2860, 1427, 1110, 703 cm−1. H NMR (300 MHz, CDCl3):
1
δ 7.68–7.60 (m, 4H), 7.40–7.28 (m, 6H), 3.72 (dd, J = 9.8, 5.2
Hz, 1H), 3.58 (dd, J = 9.8, 7.5 Hz, 1H), 2.53–2.40 (m, 1H), 1.95
(d, J = 2.2 Hz, 1H), 1.77–1.67 (m, 1H), 1.52–1.41 (m, 1H), 1.05
(s, 9H), 0.99 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
135.6, 133.6, 129.6, 127.6, 85.3, 70.0, 65.8, 36.1, 26.8, 24.0,
19.3, 11.3. MS (ESI) 359 [M + Na]+. HRMS (ESI) m/z calcd for
C22H28ONaSi 359.18016; found 359.18121.
Compound 38
Compound 38 was prepared following the same procedure dis-
closed for preparation of 36. Compound 37 (2.6 g, 6 mmol)
provided product 38 (950 mg, 4.9 mmol) in 82% yield after
column chromatography using hexanes–EtOAc (95 : 5, v/v) as
the eluent. TLC Rf = 0.2 (10% EtOAc–hexanes). [α]3D7 = +3.2 (c
Compound 36
1.1, CHCl3). IR (KBr): 3302, 2964, 2930, 1455, 1097, 698 cm−1
.
1H NMR (300 MHz, CDCl3): δ 7.34–7.22 (m, 5H), 4.49 (s, 2H),
3.67 (dd, J = 10.7, 3.4 Hz, 1H), 3.62–3.54 (m, 2H), 3.43 (d, J =
8.8, 1.7 Hz, 1H), 1.80–1.68 (m, 1H), 1.38–1.23 (m, 2H), 0.92 (t, J
= 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 137.9, 127.9, 127.1,
72.8, 72.1, 63.9, 42.0, 20.5, 11.2. MS (ESI) 217 [M + Na]+. HRMS
(ESI) m/z calcd for C12H18O2Na 217.11990; found 217.11976.
To a solution of alkyne 35 (1 g, 3 mmol) in anhydrous THF
(9 mL) cooled at 0 °C was added TBAF (3.6 mL, 3.6 mmol, 1 M
in THF). After 1 h the reaction mixture was concentrated and
the crude compound was purified by column chromatography
using EtOAc–hexanes (1 : 9 to 2 : 8, v/v) to afford pure hydro-
xyalkyne 36 (255 mg, 2.6 mmol) in 87% yield as a colorless oil.
TLC Rf = 0.1 (10% EtOAc–hexanes). [α]3D7 = +2.8 (c 1, CHCl3). IR
1
(KBr): 3428, 2972, 2965, 2902, 1397, 1214, 703 cm−1. H NMR Compound 31
(300 MHz, CDCl3): δ 3.71–3.53 (m, 2H), 2.57–2.47 (m, 1H), 2.15
Compound 31 was prepared from alcohol 38 following the
(d, J = 2.3, 1H), 1.62–1.45 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 82.6, 73.0, 69.9, 33.7, 24.4, 11.2.
same two step sequence disclosed for the preparation of
alkyne 35 from alcohol 33. Compound 38 (776 mg, 4 mmol)
yielded alkyne 31 (540 mg, 2.9 mmol) in 72% overall yield after
column chromatography using hexanes–EtOAc (98 : 2, v/v) as
Compound 31
To a solution of hydroxy alkyne 36 (196 mg, 2 mmol) and the eluent. The physical characteristics were identical to those
freshly prepared benzyl imidate (582 mg, 3 mmol) in a mixture obtained from alcohol 36.
of anhydrous CH2Cl2 (5 mL) and cyclohexane (5 mL) cooled at
Compound 30
0 °C was added a catalytic amount of triflic acid (2 drops).
After 16 h, the reaction mixture was quenched with aqueous To a solution of iodo alkene 19 (57 mg, 0.3 mmol) in anhy-
NaHCO3. The mixture was filtered through a pad of Celite and drous THF (1 mL) cooled at 0 °C was added t-BuLi (0.19 mL,
the filter cake washed with a mixture of CH2Cl2 and cyclo- 0.3 mmol, 1.6 M in hexane) slowly. After 1 h the reaction
hexane. The combined organic layers were washed with water, mixture was cooled to −78 °C and the solution of amide 18
brine, dried over anhydrous Na2SO4 and concentrated to (154 mg, 0.25 mmol) in anhydrous THF (1 mL) was added
provide the crude product which was purified by column slowly. After 3 h of stirring at the same temperature the
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reaction mixture was quenched by the addition of aq. NH4Cl. organic layers were washed with brine, dried over Na2SO4, con-
The layers were separated and the aqueous layer was extracted centrated and the residue was purified by column chromato-
with ethyl acetate (3 × 5 mL). The combined organic layers graphy using hexanes–EtOAc (95 : 5, v/v) to afford silyl ether 40
were washed with water, brine, dried over anhydrous Na2SO4 (2.77 g, 3.8 mmol) in 95% yield as a viscous oil. TLC Rf = 0.24
and concentrated to provide the crude material. Purification (10% EtOAc–hexanes). [α]3D5 = −9.8 (c 1, CHCl3). IR (KBr): 2927,
by column chromatography using hexanes–EtOAc (85 : 15, v/v) 2856, 1689, 1466, 1086, 772, 702 cm−1 1H NMR (300 MHz,
.
provided compound 30 (118 mg, 0.2 mmol) in 80% yield as a CDCl3): δ 7.69–7.64 (m, 4H), 7.44–7.32 (m, 6H), 3.91–3.82 (m,
viscous oil. TLC Rf = 0.28 (30% EtOAc–hexanes). [α]3D5 = −8.1 (c 1H), 3.74 (d, J = 7.5 Hz, 1H), 3.49 (d, J = 9.8 Hz, 1H), 3.32–3.30
1, CHCl3). IR (KBr) 3052, 2948, 1672, 1552, 1153, 956, 833, (m, 4H), 2.90–2.83 (m, 2H), 2.53 (dd, J = 14.3, 6.0 Hz, 1H), 1.82
706 cm−1 1H NMR (400 MHz, CDCl3): δ 7.68–7.60 (m, 4H), (dd, J = 14.3, 10.5 Hz, 1H), 1.59–1.20 (m, 18H), 1.05 (s, 9H),
.
7.44–7.32 (m, 6H), 6.97 (ddd, J = 14.8, 8.3, 6.4 Hz, 1H), 6.32 (d, 0.92 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.82 (s, 9H), 0.80 (s, 3H),
J = 14.8 Hz, 1H), 3.75 (dd, J = 6.4, 4.6 Hz, 1H), 3.66 (s, 3H), 3.49 0.08 (s, 3H), −0.08 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 196.9,
(d, J = 9.2 Hz, 1H), 3.34 (d, J = 9.2 Hz, 1H), 3.29 (s, 3H), 135.7, 133.7, 129.4, 127.5, 74.6, 73.8, 70.1, 55.9, 48.9, 40.9,
2.58–2.50 (m, 1H), 2.38–2.30 (m, 1H), 1.09 (s, 9H), 0.97 (s, 3H), 39.2, 31.8, 29.5, 29.4, 29.3, 29.1, 29.0, 28.8, 26.9, 26.2, 22.6,
0.85 (s, 9H), 0.83 (s, 3H), 0.02 (s, 3H), −0.06 (s, 3H). 13C NMR 21.5, 20.7, 19.3, 18.4, 14.1, −3.4, −3.8. MS (ESI) 751 [M + Na]+.
(75 MHz, CDCl3): δ 166.7, 146.6, 135.6, 133.6, 129.5, 127.5, HRMS (ESI) m/z calcd for C42H72O4NaSSi2 751.45821; found
119.6, 76.0, 70.2, 61.5, 41.3, 36.7, 32.2, 26.9, 26.0, 21.3, 21.0, 751.45922.
19.3, 18.2, −3.5, −4.3. MS (ESI) 606 [M + Na]+. HRMS (ESI) m/z
calcd for C33H53O4NNaSi2 606.34053; found 606.34089.
Compound 32
To the mixture of thio ester 40 (1.57 g, 2 mmol), PdCl2(dppf)2
(163 mg, 0.2 mmol), CuI (950 mg, 5 mmol) triphenylpho-
Compound 39
To a solution of decanethiol (2.1 g, 12 mmol) in anhydrous sphine (262 mg, 1 mmol) and Et3N (0.8 mL) in anhydrous
CH2Cl2 (24 mL) cooled at 0 °C was added Me3Al (4.5 mL, DMF (4 mL) was added a solution of alkyne 31 (940 mg,
9 mmol, 2 M in toluene) dropwise over 5 minutes and the 5 mmol) in anhydrous DMF (6 mL) slowly over 6 h using a
mixture was stirred for another 30 minutes. A solution of syringe pump at 60 °C. The reaction mixture was stirred for an
lactone 7 (2.64 g, 6 mmol) in anhydrous CH2Cl2 (12 mL) was additional 3 h at the same temperature. The reaction mixture
added slowly over a period of 10 min. After 1 h the reaction was then diluted with ether (20 mL), quenched with water
mixture was diluted with CH2Cl2 (20 mL) and poured slowly (10 mL) and the solids filtered through a pad of Celite. The
into a 250 mL beaker containing ice cooled water (20 mL) with filter cake was washed with ether (5 × 20 mL). The layers were
stirring. Aq. 1 N HCl (10 mL) was added and layers were separ- separated and the aqueous layer was extracted with Et2O (3 ×
ated. The aqueous layer was extracted with DCM (3 × 20 mL). 30 mL). The combined organic layers were washed with brine,
The combined organic layers were washed with aqueous dried over Na2SO4 and concentrated. The crude product was
NaHCO3, water, brine, dried over Na2SO4 and concentrated. purified by column chromatography using hexanes–EtOAc
Purification of the residue by column chromatography using (95 : 5, v/v) to afford alkynone 32 (1.17 g, 1.58 mmol) in 79%
hexanes–EtOAc (9 : 1, v/v) furnished 39 (3.4 g, 5.5 mmol) in yield as a viscous oil. TLC Rf = 0.15 (10% EtOAc–hexanes). [α]D35
92% yield as a viscous oil. TLC Rf = 0.10 (20% EtOAc–hexanes). = −11.0 (c 1, CHCl3). IR (KBr): 2958, 2931, 2211, 1672, 1085,
[α]3D4 = −8.6 (c 1, CHCl3). IR (KBr): 3446, 3070, 2863, 1697, 769, 702 cm−1
.
1H NMR (300 MHz, CDCl3): δ 7.69–7.60 (m,
1086, 803, 616 cm−1. H NMR (300 MHz, CDCl3): δ 7.69–7.62 4H), 7.44–7.28 (m, 11H), 4.53 (s, 2H), 4.04–3.92 (m, 1H), 3.76
(m, 4H), 7.45–7.36 (m, 6H), 4.29 (dd, J = 12.2, 2.6 Hz, 1H), (d, J = 7.1 Hz, 1H), 3.58–3.48 (m, 3H), 3.35–3.30 (m, 4H), 2.86
3.79–3.72 (m, 1H), 3.65 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, (dd, J = 15.2, 6.6 Hz, 1H), 2.81–2.72 (m, 1H), 2.57 (dd, J = 15.2,
1H), 3.33 (s, 3H), 2.83 (dd, J = 16.8, 5.8 Hz, 1H), 2.54–2.44 (m, 5.4 Hz, 1H), 1.90–1.64 (m, 2H), 1.60–1.36 (m, 2H), 1.06 (s, 9H),
1
2H), 2.30–2.20 (m, 1H), 1.64–1.46 (m, 3H) 1.41–1.24 (m, 15H), 0.92 (s, 3H), 0.88–0.81 (m, 15H), 0.08 (s, 3H), −0.07 (s, 3H). 13
C
1.07 (s, 9H), 0.98 (s, 3H), 0.95 (s, 3H), 0.94 (t, J = 6.9 Hz, 3H). NMR (75 MHz, CDCl3): δ 185.4, 137.7, 135.6, 133.7, 129.4,
13C NMR (75 MHz, CDCl3): δ 170.4, 135.4, 133.2, 133.0, 129.6, 128.3, 127.6, 127.5, 94.6, 82.6, 73.7, 73.5, 73.0, 71.1, 70.0, 55.7,
127.6, 79.6, 72.7, 69.3, 55.8, 39.1, 36.1, 33.9, 31.7, 29.4, 29.2, 50.6, 40.8, 39.1, 34.3, 26.2, 25.9, 23.9, 21.4, 20.6, 19.3, 18.3,
28.9, 28.2, 26.8, 24.5, 22.5, 20.3, 19.6, 19.2, 14.0. MS (ESI) 637 11.4, −3.4, −3.9. MS (ESI) 765 [M + Na]+. HRMS (ESI) m/z calcd
[M + Na]+. HRMS (ESI) m/z calcd for C36H58O5NaSi2 637.37173; for C45H66O5NaSi2 765.43410; found 765.43494.
found 637.37226.
Compound 41
Compound 40
A solution of compound 32 (185 mg, 0.25 mmol) in ethyl
To a solution of 39 (2.4 g, 4 mmol) in anhydrous CH2Cl2 acetate (5 mL) was added to a suspension of [(S,S)-TsDPEN]Ru-
(12 mL) cooled at 0 °C was added anhydrous 2,6-lutidine (p-cymene)Cl (15.9 mg, 0.025 mmol), sodium formate
(0.71 mL, 6 mmol) followed by TBS-OTf (1.1 mL, 4.8 mmol). (272 mg, 4 mmol) and 1-butyl-3-methylimidazolium tetra-
After 15 minutes the reaction mixture was quenched by fluoroborate (23 mg, 0.1 mmol) in water (5 mL). The reaction
addition of water. The layers were separated and the aqueous mixture was stirred for 7 h at rt. The phases were separated
layer was extracted with CH2Cl2 (3 × 20 mL). The combined and the aqueous phase was extracted with ethyl acetate (2 ×
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10 mL). The combined organic layers were washed with brine, and aqueous NH4Cl added. The mixture diluted with ether fil-
dried over anhydrous Na2SO4 and concentrated. The crude tered through a pad of Celite to remove the insolubles and the
product obtained was purified by column chromatography filter cake washed with ether. The layers were separated, the
using hexanes–DCM–acetone (50 : 48 : 2, v/v) to furnish alcohol aqueous layer was extracted with ether (2 × 10 mL) and the
41 (126 mg, 0.17 mmol) in 68% yield as a viscous oil along combined organic layer was washed with brine and dried over
with a minor isomer (31.5 mg, 0.042 mmol) in 17% yield as a anhydrous Na2SO4. Removal of the solvent afforded the crude
viscous oil. Major isomer: TLC Rf = 0.45 (25% EtOAc–hexanes). product which was purified by column chromatography using
[α]3D5 = −16.3 (c 1, CHCl3). IR (KBr): 3431, 3067, 2957, 2928, hexanes–EtOAc (9 : 1, v/v) to furnish Z-trisubstituted alkene 44
2857, 1464, 1085, 830, 701 cm−1. 1H NMR (300 MHz, CDCl3): δ (42.5 mg, 0.056 mmol) and alkene 45 (9.1 mg, 0.012 mmol) in
7.78–7.68 (m, 4H), 7.57–7.26 (m, 11H), 4.70–4.52 (m, 3H), 3.78 68% combined yield. Compound 44: TLC Rf = 0.15 (10%
(dd, J = 6.8, 2.8 Hz, 1H), 3.76–3.33 (m, 8H), 2.76–2.64 (m, 1H), EtOAc–hexanes). [α]3D5 = −15.0 (c 1, CHCl3). IR (KBr): 3453,
2.16–1.90 (m, 2H), 1.88–1.60 (m, 2H), 1.56–1.28 (m, 2H), 1.08 2957, 2931, 2857, 1465, 1156, 831, 701 cm−1
.
1H NMR
(s, 9H), 0.98 (t, J = 7.4 Hz, 3H), 0.93 (s, 3H), 0.86–0.78 (m, (500 MHz, CDCl3): δ 7.74–7.68 (m, 4H), 7.47–7.27 (m, 11H),
12H), 0.06 (s, 3H), −0.06 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 4.95 (d, J = 10.3 Hz, 1H), 4.55–4.40 (m, 3H), 3.71 (dd, J = 5.7,
138.2, 135.4, 133.8, 129.5, 128.3, 127.6, 127.5, 85.6, 83.0, 75.9, 2.3 Hz, 1H), 3.66–3.59 (m, 1H), 3.51 (d, J = 9.1 Hz, 1H),
74.0, 73.0, 72.3, 70.1, 60.8, 55.0, 42.2, 41.1, 38.6, 33.9, 26.9, 3.39–3.21 (m, 6H), 2.75–2.69 (m, 1H), 1.97–1.82 (m, 2H), 1.72
26.2, 24.5, 21.6, 20.5, 19.3, 18.4, 11.4, −3.2, −4.0. MS (ESI) 762 (s, 3H), 1.58–1.21 (m, 4H), 1.06 (s, 9H), 0.92 (s, 3H), 0.88–0.77
[M + NH4]+. HRMS (ESI) m/z calcd C45H68O5NaSi2 767.44975; (m, 15H), 0.06 (s, 3H), −0.07 (s, 3H). 13C NMR (125 MHz,
1
found 767.45017. Minor isomer: H NMR (500 MHz, CDCl3): δ CDCl3): δ 139.1, 138.4, 135.7, 133.8, 129.4, 128.7, 128.4, 128.2,
7.71–7.61 (m, 4H), 7.48–7.22 (m, 11H), 4.55–4.43 (m, 3H), 127.5, 127.4, 76.3, 74.2, 73.8, 73.0, 70.2, 69.2, 54.2, 41.1, 39.5,
3.77–3.61 (m, 2H), 3.56–3.47 (m, 3H), 3.38–3.32 (m, 4H), 39.2, 38.5, 27.0, 26.2, 25.1, 21.6, 20.4, 19.4, 19.2, 18.4, 11.7,
2.83–2.75 (m, 1H), 1.97–1.87 (m, 2H), 1.63–1.53 (m, 2H), −3.3, −3.9. MS (ESI) 783 [M + Na]+. HRMS (ESI) m/z calcd for
1.42–1.31 (m, 2H), 1.07 (s, 9H), 0.93 (t, J = 7.0 Hz, 3H), C46H72O5NaSi2 783.48105; found 783.48105. Compound 45:
0.86–0.78 (m, 15H), 0.06 (s, 3H), −0.07 (s, 3H). 13C NMR TLC Rf = 0.14 (10% EtOAc–hexanes). [α]D36 = −13.8 (c 1, CHCl3).
(75 MHz, CDCl3): δ 138.2, 135.7, 133.8, 129.5, 128.3, 127.6, 1H NMR (500 MHz, CDCl3): δ 7.74–7.64 (m, 4H), 7.45–7.24 (m,
127.5, 85.4, 83.3, 76.0, 74.2, 72.9, 72.3, 70.4, 60.2, 55.8, 41.0, 11H), 4.92 (d, J = 10.3 Hz, 1H), 4.71 (d, J = 10.3 Hz, 1H),
40.7, 38.5, 33.9, 26.9, 26.1, 23.8, 21.6, 21.0, 19.3, 18.4, 11.4, 4.49–4.41 (m, 2H), 3.77 (d, J = 6.9 Hz, 1H), 3.74–3.70 (m, 1H),
−3.4, −4.0.
3.51 (d, J = 9.2 Hz, 1H), 3.39–3.19 (m, 6H), 2.71–2.63 (m, 1H),
2.00–1.86 (m, 2H), 1.75 (s, 3H), 1.53–1.20 (m, 4H), 1.07 (s, 9H),
Compounds 42 and 43
0.93 (s, 3H), 0.87–0.80 (m, 15H), 0.06 (s, 3H), −0.05 (s, 3H). 13
C
To a solution of alkyne 41 (74 mg, 0.1 mmol) and Pd(PPh3)4 NMR (125 MHz, CDCl3): δ 139.2, 135.7, 133.8, 129.4, 128.4,
(7 mg, 0.01 mmol) in anhydrous hexane (1 mL) was added 128.2, 127.5, 127.4, 75.8, 74.4, 73.8, 72.9, 70.2, 67.7, 55.3, 41.0,
nBu3SnH (0.06 mL, 0.2 mmol) in anhydrous hexane (1 mL) 39.5, 38.0, 37.9, 29.7, 26.9, 26.2, 25.1, 21.4, 20.5, 19.3, 19.0,
dropwise over a period of 1 h using a syringe pump. Removal 11.7, −3.3, −3.9. MS (ESI) 783 [M + Na]+. HRMS (ESI) m/z calcd
of the solvent afforded the crude product which was purified for C46H72O5NaSi2 783.4816; found 783.4828.
by column chromatography using hexanes–EtOAc (95 : 5, v/v)
to yield an inseparable mixture of regioisomers (72 mg,
0.07 mmol) as a viscous oil. TLC Rf = 0.45 (5% EtOAc–
Acknowledgements
hexanes), [α]3D3 = −12.6 (c 0.5, CHCl3). IR (KBr): 3411, 2896,
2975, 2953, 2857, 1465, 1136, 1068, 1011, 839, 705 cm−1 1H V. V. K. is thankful to the UGC, New Delhi, for a fellowship. We
.
NMR (300 MHz, CDCl3): 7.83–7.70 (m, 8H), 7.56–7.30 (m, thank the Ministry of Science and Technology for funding
22H), 5.32–5.24 (m, 1H), 4.88–4.76 (m, 1H), 4.62–4.50 (m, 5H), under the ORIGIN program. We thank Dr B. Jagadeesh, Head
3.88–3.74 (m, 4H), 3.68–3.58 (m, 2H), 3.52–3.28 (m, 12H), NMR center, for acquiring the NMR spectra and Dr R. Srinivas,
2.78–2.60 (m, 2H), 2.20–1.82 (m, 4H), 1.76–1.32 (m, 30H), 1.16 Head NCMS division, for acquiring the mass spectra.
(s, 18H), 1.06–0.84 (m, 68H), 0.16 (s, 6H), 0.00 (s, 6H). MS (ESI)
1037 [M + H]+. HRMS (ESI) m/z calcd for C57H96O5NaSi2Sn
1059.57105; found 1059.57064.
References
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Organic & Biomolecular Chemistry
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100, 3257.
regioisomeric alkene 45, see ESI.†
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This journal is © The Royal Society of Chemistry 2013