Stereoselective synthesis of the C5-C18 fragment of halichomycin

Article abstract of DOI:10.1021/jo202602n

An efficient and convergent synthesis of the C₅-C₁₈ fragment of halichomycin is reported. Butanolide fragment 6 was readily prepared stereoselectively from (R)-Roche ester through catalyst control; dienylic bromide domain 7 was synthesized from (S)-serine by substrate control. C ₅-C₁₈ fragment 2 was rapidly assembled through a stereoselective alkylation of the butanolide with the dienylic bromide, followed by functional group transformations.

Full text of DOI:10.1021/jo202602n

Note
pubs.acs.org/joc
Stereoselective Synthesis of the C5−C18 Fragment of Halichomycin
Qingjiang Li,† Shiyong Mao,† Yuxin Cui,† and Yanxing Jia*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing 100191, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: An efficient and convergent synthesis of the
C5−C18 fragment of halichomycin is reported. Butanolide
fragment 6 was readily prepared stereoselectively from (R)-
Roche ester through catalyst control; dienylic bromide domain
7 was synthesized from (S)-serine by substrate control. C5−
C18 fragment 2 was rapidly assembled through a stereoselective
alkylation of the butanolide with the dienylic bromide,
followed by functional group transformations.
alichomycin, a structurally unique tricyclic macrolactam,
is produced by a strain of Streptomyces hygroscopicus
which was isolated from the gastrointestinal tract of the marine
fish Halichoeres bleekeri by Numata and colleagues in 1994
(Figure 1).1 Halichomycin exhibits potent cytotoxicity (ED50
halichomycin, a concise and scalable synthesis of its backbone is
needed. Herein, we report a synthetic strategy for the C5−C18
fragment (2), which includes six contiguous stereocenters.
Our retrosynthetic analysis of halichomycin (1) is outlined in
Scheme 1. The key compound 2 could be generated from an
Evans asymmetric aldol reaction between aldehyde 3 and
acylated oxazolidinone 4 followed by reduction. In order to
introduce with stereocontrol the C8 and C25 vicinal carbon
substituents of 3, butenolide 8 was used as the chiral template.5
The lactone 5 could be obtained through stereoselective α-
alkylation of 6 with bromide 7 from the β-face. Butyrolactone 6
could be accessed by conjugate addition of lithium
dimethylcuprate to butenolide 8, which would be available
from the Pu asymmetric addition of methyl propiolate to
aldehydes,6 followed by Lindlar reduction. Dienylic bromide 7
would be obtained in optically pure form by manipulation of
chiron derived originally from (S)-serine.
The synthesis of the known lactone 6 has been reported by
many other groups.7 We developed a new method for the
synthesis of 6 (Scheme 2). The known aldehyde 12 was
prepared in 95% yield starting from the commercially available
(R)-Roche ester 9.8 According to the standard conditions
reported by Pu, the (S)-BINOL-catalyzed asymmetric addition
of ethyl propiolate 10 to aldehyde 12 led to the desired product
13 in 94% yield with a diastereomeric ratio of 11:1, which was
impossible to separate by column chromatography.9 Lindlar
reduction of alkyne 13 gave the corresponding cis-alkene, which
was automatically converted into butenolide 8 during
purification by flash column chromatography. Conjugate
addition of Me2CuLi to butenolide 8 gave the known exclusive
product lactone 62b,7e as a single stereoisomer in 85% yield.
The synthesis of C9−C15 dienylic bromide 7 is shown in
Scheme 3. The known alcohol 15 was prepared from (S)-serine
H
Figure 1. Structure of halichomycin (relative configuration).
0.13 μg/mL) against a murine P388 lymphocytic leukemia cell
line, which is of potential use as an anticancer drug.
Halichomycin represents a significant challenge to chemical
synthesis owing to its extraordinary molecular architecture,
embodying three intersecting ring systems which include a fully
functionalized 11-membered ether ring (C ring) and a
structurally unique 13/11-membered bicyclic hemimacrolactam
(AB ring), 10 stereocenters including six contiguous stereo-
centers, and five double bonds. However, the absolute
configuration of halichomycin has not been reported until
now. The unique structural features and powerful biological
activity of 1 make it an attractive target for total synthesis.2
Wood reported the synthesis of the C1−C7 segment of
halichomycin.2a Hale proposed a biosynthetic route for ring
formation in halichomycin and synthesized the AB-carbon
backbone of halichomycin.2b However, no total synthesis has
been accomplished up to now. As part of our interest directed
toward the total synthesis of bioactive natural products,3 we
have embarked on the synthesis of halichomycin. In order to
test the formation of the “strange”4 hemimacrolactam of
Received: January 11, 2012
Published: March 26, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Retrosynthetic Analysis of Halichomycin (1)
Scheme 3. Synthesis of Dienylic Bromide 7
to bromination following Roush’s procedure to afford the
dienylic bromide 7 in 99% yield.15
With the two fragments 6 and 7 in hand, the stage was set for
the key α-alkylation reaction (Scheme 4). It smoothly afforded
the desired coupling product 5 as a nearly 4.2:116 inseparable
diastereomers. It is worth mentioning that HMPA played an
important role in this reaction, giving a higher conversion.
Lactone 5 was reductively ring-opened with lithium borohy-
dride to produce the diol 22 in 60% overall yield. Selective
protection of the primary alcohol in 22 by using Ac2O/DMAP,
followed by protection the remaining secondary hydroxy group
by using TBSOTf/2,6-lutidine, furnished fully protected
compound 23 in 94% overall yield. Removal of the acetyl
group in 23 employing K2CO3 in CH3OH followed by IBX
oxidation of the derived alcohol 24 provided aldehyde 3 in 96%
yield. In order to promote the complete conversion of aldehyde
3 in the Evans aldol reaction,17 it was essential to use the excess
of propionimide enolate (see the Experimental Section).
Finally, reductive removal of the oxazolidinone unit from 25
with LiBH4 furnished the diol 2 in 95% yield.18
Scheme 2. Synthesis of Lactone 6
In conclusion, we have accomplished the synthesis of the
C5−C18 fragment (2) of halichomycin. The approach is highly
convergent. The longest linear sequence is 20 steps, and the
overall yield is an impressive 8.8%. The synthesis features an
(S)-BINOL-catalyzed asymmetric addition of ethyl propiolate
to aldehyde followed by reduction to form the butenolide 8,
and stereocontrolled introduction of C8 and C25 functional
groups by using butenolide 8 as the chiral template.
(11) in 57% overall yield.10 Methylation of alcohol 15 with
iodomethane and Ag2O in Et2O afforded 16 in 90% yield.11,12
DIBAL reduction of the ester moiety in 16 followed by Swern
oxidation of the derived alcohol provided aldehyde 17 in 80%
yield, which further underwent a Horner−Wadsworth−
Emmons olefination to afford 18 in 92% yield. DIBAL
reduction of ester 18 followed by Swern oxidation provided
the aldehyde 19 in 93% yield. (Z)-Selective olefination of
aldehyde 19 using Still−Gennari’s protocol provided diene 20
in quantitative yield.13,14 Reduction of ester 20 with DIBAL
gave the corresponding allylic alcohol 21, which was subjected
EXPERIMENTAL SECTION
■
General Remarks. Flash column chromatography (FCC) was
performed using silica gel (200−300 mesh) with solvents distilled
prior to use. Petroleum ether is abbreviated to PE.
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Note
1.07 (s, 9H), 0.90 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.0, 155.3, 135.6, 135.5, 133.1, 133.0, 129.9, 129.8, 127.8, 121.9,
84.6, 65.1, 39.2, 26.9, 19.3, 11.7; [α]D26 −37.6 (c 1.07, MeOH); HRMS
(ESI) m/z calcd for C23H32NO3Si (M + NH4)+ 398.2146, found
398.2149; IR (KBr) 2959, 2931, 2858, 1784, 1757, 1471, 1428, 1162,
1110, 1089, 1029, 820, 742, 704, 614, 505 cm−1.
Scheme 4. Synthesis of Fragment 2
Compound 6. To a slurry of CuI (1.72 g, 9.05 mmol) in Et2O (25
mL) was added MeLi·LiBr (10.9 mL, 1.5 M in ether, 16.2 mmol) at 0
°C under Ar. The solution was cooled to −30 °C, and then 8 (686 mg,
1.81 mmol) in Et2O (5 mL) was added. The mixture was stirred at
−20 °C for 1 h and quenched with saturated NH4Cl. Ammonium
hydroxide was added, and the aqueous layers were extracted with
ether. The combined organic extracts were washed with brine, dried
over Na2SO4, and evaporated. The residue was purified by FCC (PE/
1
EtOAc, 6:1) to give 6 (609 mg, 85%). The data of H and 13C NMR
are consistent with that reported by Hale:2b 1H NMR (400 MHz,
CDCl3) δ 7.69−7.66 (m, 4H), 7.46−7.37 (m, 6H), 4.15 (t, J = 6.4 Hz,
1H), 3.70 (dd, J = 1.6, 5.2 Hz, 2H), 2.68 (dd, J = 8.8, 17.2 Hz, 1H),
2.49 (m, 1H), 2.18 (dd, J = 8.0, 17.6 Hz, 1H), 1.99 (m, 1H), 1.17 (d, J
= 6.8 Hz, 3H), 1.08 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 176.4, 135.5, 133.4, 133.3, 129.7, 127.7, 88.3, 64.9,
39.4, 37.1, 32.2, 26.8, 19.3, 19.2, 13.0; [α]D26 +23.9 (c 0.50, MeOH);
HRMS (ESI) m/z calcd for C24H36NO3Si (M + NH4)+ 414.2459,
found 414.2453; IR (KBr) 2960, 2929, 2857, 1779, 1463, 1427, 1214,
1173, 1110, 1007, 823, 742, 704, 614, 505 cm−1.
Compound 16. To a solution of 15 (5.86 g, 25.0 mmol), MeI (31
mL, 500 mmol) in Et2O (300 mL) was added Ag2O (17.4 g, 75.0
mmol). The reaction mixture was stirred for 10 h at rt, filtered, and
concentrated, and the residue was purified by FCC (PE/EtOAc, 8:1)
to give 16 (5.6 g, 90%): 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H),
3.72 (s, 3H), 3.41 (s, 3H), 0.84 (s, 9H), 0.02 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 171.2, 82.0, 64.0, 58.5, 51.7, 25.7, 18.2, −5.5, −5.6;
[α]D23 −24.3 (c 0.40, CH2Cl2), the optical rotation of its enantiomer [lit.11
[α]D28 +20.3 (c 1.9, CH2Cl2)]; HRMS (ESI) m/z calcd for
C11H24O4SiNa (M + Na)+ 271.1336, found 271.1333; IR (KBr)
2954, 2931, 2858, 1756, 1464, 1257, 1201, 1121, 839, 779 cm−1.
Compound 17. To a solution of 16 (4.02 g, 16.2 mmol) in Et2O
(110 mL) at −78 °C was added DIBAL-H (19.5 mL, 1 M in hexane,
19.5 mmol). After the starting material was consumed via TLC
analysis, the reaction was quenched with MeOH, warmed to rt, and
poured into satd aq potassium sodium tartrate solution. The mixture
was vigorously stirred until the phase separation occurred and
extracted with Et2O. The combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated to give the
corresponding alcohol.
Compound 13. To a solution of (S)-BINOL (458 mg, 1.6 mmol),
HMPA (1.4 mL, 8.0 mmol), and ethyl propiolate (1.63 mL, 16.0
mmol) in dry CH2Cl2 (48 mL) at rt under Ar was added Et2Zn (16
mL, 1 M in hexane, 16.0 mmol). After the solution had been stirred for
16 h, Ti(O-i-Pr)4 (1.2 mL, 4.0 mmol) was added and stirred for
another 1 h. Then, 12 (1.30 g, 4.0 mmol) was added, and the reaction
was allowed to proceed at rt for 4 h. The mixture was quenched with
saturated NH4Cl and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified by FCC
To a solution of (COCl)2 (2.9 mL, 32.4 mmol) in CH2Cl2 (120
mL) at −78 °C was added DMSO (4.6 mL, 64.8 mmol). After being
stirred for 10 min, the alcohol was added to CH2Cl2 (15 mL). After 45
min, Et3N (13.6 mL, 97.2 mmol) was added, and the solution was
warmed to rt. After 30 min, the reaction was quenched with water and
extracted with CH2Cl2. The combined organic phase was washed with
brine, dried over Na2SO4, filtered, and concentrated. The residue was
purified by FCC (PE/EtOAc, 20:1) to give the aldehyde 17 (2.83 g,
1
(PE/EtOAc, 12:1) to give the product 13 (1.59 g, 94%): H NMR
(400 MHz, CDCl3) δ 7.71−7.67 (m, 4H), 7.46−7.39 (m, 6H), 4.65 (t,
J = 6.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.96 (dd, J = 4.0, 10.4 Hz,
1H), 3.63 (dd, J = 6.0, 10.4 Hz, 1H), 3.49 (d, J = 5.2 Hz, 1H), 2.07 (m,
1H), 1.33 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.3, 135.6, 135.5, 132.7, 132.6,
129.9, 127.8, 86.8, 77.4, 66.8, 66.1, 62.0, 40.4, 26.8, 19.1, 14.0, 12.9;
HRMS (ESI) m/z calcd for C25H33O4Si (M + H)+ 425.2143, found
425.2138; IR (KBr) 3032, 2961, 2859, 2234, 1713, 1470, 1427, 1390,
1366, 1246, 1110, 1037, 823, 742, 704, 614, 505 cm−1.
Compound 8. To a solution of 13 (936 mg, 2.21 mmol) in
methanol (30 mL) was added Lindlar catalyst (221 mg) at rt, and then
the flask was evacuated and filled with hydrogen three times. The
suspension was stirred under H2 at rt for 11 h and then filtered
through a pad of Celite and concentrated. The residue was purified by
FCC (PE/EtOAc, 10:1) to give butenolide 8 (805 mg, 96%): 1H
NMR (400 MHz, CDCl3) δ 7.67−7.63 (m, 4H), 7.47−7.38 (m, 7H),
6.11 (dd, J = 1.6, 5.6 Hz, 1H), 5.23 (dt, J = 1.6, 6.0 Hz, 1H), 3.81 (dd,
J = 4.4, 10.4 Hz, 1H), 3.59 (dd, J = 6.0, 10.4 Hz, 1H), 2.16 (m, 1H),
1
80%): H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 3.91 (d, J = 4.4
Hz, 2H), 3.66 (t, J = 4.4 Hz, 1H), 3.50 (s, 3H), 0.88 (s, 9H), 0.06 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 202.9, 86.5, 62.5, 58.6, 25.8,
18.3, −5.5; [α]D22 −32.0 (c 0.40, CH2Cl2); HRMS (ESI) m/z calcd for
C10H23O3Si (M + H)+ 219.1411, found 219.1411; IR (KBr) 2954,
2931, 2858, 1737, 1467, 1256, 1114, 838, 778 cm−1.
Compound 18. To a solution of NaH (524 mg, 13.1 mmol, 60%
in mineral oil) in THF (25 mL) at 0 °C was added triethyl
phosphonoacetate (2.62 mL, 13.2 mmol). After being stirred for 10
min, aldehyde 17 (2.62 g, 12.0 mmol) in THF (5 mL) was added. The
reaction mixture was warmed to rt and then heated at reflux for 1 h.
The solution was cooled to rt, diluted with water, and extracted with
EtOAc. The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by FCC
1
(PE/EtOAc, 40:1) to give 18 (3.18 g, 92%): H NMR (400 MHz,
CDCl3) δ 6.81 (dd, J = 5.6, 16.0 Hz, 1H), 6.02 (dd, J = 1.2, 16.0 Hz,
1H), 4.18 (q, J = 7.2 Hz, 2H), 3.82 (m, 1H), 3.67 (dd, J = 6.0, 10.4 Hz,
4113
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Note
1H), 3.58 (dd, J = 5.6, 10.4 Hz, 1H), 3.35 (s, 3H), 1.26 (t, J = 7.2 Hz,
3H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.0, 145.4, 122.8, 81.5, 65.3, 60.3, 57.7, 25.8, 18.2, 14.2,
−5.4, −5.5; [α]D25 −8.0 (c 0.43, CH2Cl2); HRMS (ESI) m/z calcd for
C14H32NO4Si (M + NH4)+ 306.2095, found 306.2089; IR (KBr) 2955,
2931, 2859, 1724, 1660, 1467, 1366, 1303, 1261, 1172, 1137, 1114,
1041, 984, 839, 779 cm−1.
C15H33NBrO2Si (M + NH4)+ 366.1458, found 366.1463; IR (KBr)
2954, 2928, 2856, 1254, 1134, 1110, 838, 777 cm−1.
Compound 22. To a solution of 6 (522 mg, 1.32 mmol) and
HMPA (0.46 mL, 2.64 mmol) in THF (30 mL) under Ar at −78 °C
was added LHMDS (2.64 mL, 1.0 M in THF, 2.64 mmol). The
solution was stirred at −78 °C for 1 h, and 7 (552 mg, 1.58 mmol) in
THF (5 mL) was added. After 45 min, the reaction mixture was
quenched with saturated NaHCO3, and extracted with EtOAc. The
combined organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by FCC (PE/
EtOAc, 15:1) to give the inseparable coupling product 5 and its
Compound 19. The ester 18 (1.37 g, 4.76 mmol) was converted
into aldehyde 19 (1.08 g, 93% for two steps) by DIBAL reduction and
Swern oxidation of the corresponding alcohol as described for
compound 17.
Corresponding alcohol S2: [α]D23 −15.7 (c 0.38, CH2Cl2);
HRMS (ESI) m/z calcd for C12H27O3Si (M + H)+ 247.1724, found
247.1724; IR (KBr) 3416, 2954, 2930, 2858, 1464, 1255, 1096, 838,
777 cm−1.
isomers (781 mg, 89% overall yield): H NMR (400 MHz, CDCl3) δ
1
7.66−7.63 (m, 4H), 7.44−7.36 (m, 6H), 6.44 (dd, J = 12.0, 14.0 Hz,
1H), 5.97 (d, J = 10.8 Hz, 1H), 5.48 (dd, J = 6.4, 14.8 Hz, 1H), 4.03 (t,
J = 7.2 Hz, 1H), 3.69−3.56 (m, 5H), 3.29 (s, 3H), 2.68 (m, 1H),
2.51−2.37 (m, 2H), 2.12−1.96 (m, 2H), 1.79 (s, 3H), 1.11 (d, J = 6.0
Hz, 3H), 1.05 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 178.1, 135.5, 135.4, 133.5,
133.4, 130.1, 129.7, 128.5, 127.7, 127.6, 85.8, 83.2, 66.4, 65.0, 56.8,
46.7, 39.7, 38.7, 32.0, 26.9, 25.9, 23.7, 19.3, 18.4, 18.1, 13.1, −5.2,
−5.3; HRMS (ESI) m/z calcd for C39H64NO5Si2 (M + NH4)+
682.4318, found 682.4329.
To a stirred solution of 5 (781 mg, 1.17 mmol) in THF (20 mL)
and MeOH (0.2 mL) at 0 °C was added LiBH4 (257 mg, 11.7 mmol).
The reaction mixture was warmed to rt, stirred for 1.5 h, cooled to 0
°C, carefully quenched with HCl (1.0 M), and extracted with EtOAc.
The extract was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by FCC (PE/EtOAc, 8:1) to
give 22 (530 mg, 67%): 1H NMR (400 MHz, CDCl3) δ 7.70−7.68 (m,
4H), 7.47−7.39 (m, 6H), 6.51 (dd, J = 11.2, 14.8 Hz, 1H), 5.93 (d, J =
11.2 Hz, 1H), 5.42 (dd, J = 7.2, 14.8 Hz, 1H), 3.93 (dd, J = 3.2, 10.4
Hz, 1H), 3.74−3.41 (m, 8H), 3.32 (s, 3H), 2.36−2.16 (m, 3H), 2.06−
1.92 (m, 3H), 1.86 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H), 0.91
(s, 9H), 0.86 (d, J = 7.2 Hz, 3H), 0.07 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 139.4, 135.6, 135.5, 132.6, 132.5, 129.9, 129.5, 128.5, 127.8,
127.7, 126.0, 83.3, 79.3, 67.2, 66.5, 64.0, 56.7, 39.4, 36.8, 35.9, 30.1,
26.8, 25.9, 24.0, 19.0, 18.4, 15.3, 12.5, −5.2, −5.3; [α]D23 −21.6 (c 0.43,
CH2Cl2); HRMS (ESI) m/z calcd for C39H64O5Si2Na (M + Na)+
691.4184, found 691.4199; IR (KBr) 2956, 2928, 2857, 1469, 1428,
1256, 1110, 1084, 837, 747, 703, 505 cm−1.
Compound 23. To a solution of 22 (339 mg, 0.51 mmol),
pyridine (82 μL, 1.02 mmol), and DMAP (12 mg, 0.010 mmol) in
CH2Cl2 (8 mL) at 0 °C was added Ac2O (73 μL, 0.77 mmol). The
reaction mixture was stirred at rt for 1 h, quenched with saturated
NH4Cl, and extracted with EtOAc. The extract was washed with brine,
dried over Na2SO4 and concentrated. The residue was purified by
FCC (PE/EtOAc, 10:1) to give the primary alcohol Ac-protected
product S3 (349 mg, 97%): [α]D23 −13.2 (c 0.26, CH2Cl2); HRMS
(ESI) m/z calcd for C41H66O6Si2Na (M + Na)+ 733.4290, found
733.4282; IR (KBr) 2961, 2928, 2857, 1338, 1260, 1109, 751, 704
cm−1.
To a stirred solution of S3 (304 mg, 0.43 mmol) and 2,6-lutidine
(0.30 mL, 2.58 mmol) in CH2Cl2 (8 mL) at 0 °C was added TBSOTf
(0.30 mL, 1.29 mmol). The reaction mixture was stirred at rt for 1.5 h,
quenched with saturated NH4Cl, and extracted with EtOAc. The
extract was washed with brine, dried over Na2SO4, and concentrated.
The residue was purified by FCC (PE/EtOAc, 20:1) to give 23 (342
mg, 97%): 1H NMR (400 MHz, CDCl3) δ 7.68−7.64 (m, 4H), 7.42−
7.33 (m, 6H), 6.40 (dd, J = 11.2, 15.2 Hz, 1H), 5.92 (d, J = 11.2 Hz,
1H), 5.42 (dd, J = 7.2, 15.2 Hz, 1H), 3.94 (dd, J = 3.6, 11.2 Hz, 1H),
3.84−3.58 (m, 6H), 3.44 (dd, J = 8.4, 9.2 Hz, 1H), 3.33 (s, 3H), 2.35−
2.21 (m, 2H), 2.11 (m, 1H), 2.01 (m, 1H), 1.97 (s, 3H), 1.87 (m, 1H),
1.78 (s, 3H), 1.06 (s, 9H), 1.00 (dd, J = 3.2, 6.8 Hz, 3H), 0.91 (dd, J =
1.2, 7.2 Hz, 3H), 0.89 (s, 9H), 0.79 (s, 9H), 0.06−0.02 (9H), −0.09 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 137.7, 135.6 (2C), 134.0,
133.9, 129.5 (2C), 129.0, 128.8, 127.6, 126.9, 83.3, 77.8, 66.6 (2C),
64.9, 56.8, 40.2, 36.4, 35.5, 30.5, 26.9, 26.1, 25.9, 23.8, 20.9, 19.3, 18.4,
18.2, 14.5, 13.2, −3.8, −4.4, −5.2, −5.3; [α]D23 +18.2 (c 0.22, CH2Cl2);
HRMS (ESI) m/z calcd for C47H80O6Si3Na (M + Na)+ 847.5155,
19: 1H NMR (400 MHz, CDCl3) δ 9.54 (dd, J = 1.2, 8.0 Hz, 1H),
6.72 (dd, J = 5.6, 16.0 Hz, 1H), 6.26 (ddd, J = 1.2, 8.0, 16.0 Hz, 1H),
3.92 (dd, J = 5.2, 10.8 Hz, 1H), 3.72 (m, 1H), 3.59 (dd, J = 6.0, 10.4
Hz, 1H), 3.34 (s, 3H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 193.0, 154.4, 132.9, 81.3, 64.8, 57.8, 25.7, 18.1, −5.5,
−5.6; [α]D22 +14.4 (c 0.32, CH2Cl2); HRMS (ESI) m/z calcd for
C12H28NO3Si (M + NH4)+ 262.1833, found 262.1831; IR (KBr) 2957,
2931, 2858, 1724, 1696, 1468, 1256, 1117, 980, 839, 779 cm−1.
Compound 20. To a solution of ethyl 2-[bis(2,2,2-trifluoroethyl)
phosphono]propionate (1.15 g, 3.33 mmol) and 18-crown-6 (3.38 g,
12.8 mmol) in THF (50 mL) at −78 °C was added KHMDS (6.15
mL, 0.5 M in toluene, 3.07 mmol) under Ar. After the solution was
stirred for 1 h, aldehyde 19 (624 mg, 2.56 mmol) in THF (5 mL) was
added. The reaction mixture was stirred for another 1 h, quenched
with saturated NH4Cl, and extracted with EtOAc. The extract was
washed with brine, dried over Na2SO4, and concentrated. The residue
was purified by FCC (PE/EtOAc, 30:1) to give 20 (840 mg, quant,
1
Z:E > 30:1): H NMR (400 MHz, CDCl3) δ 7.25 (dd, J = 11.2, 15.2
Hz, 1H), 6.37 (d, J = 11.2 Hz, 1H), 5.69 (dd, J = 7.2, 15.2 Hz, 1H),
4.18 (q, J = 7.2 Hz, 2H), 3.72 (m, 1H), 3.64 (dd, J = 6.4, 10.4 Hz, 1H),
3.56 (dd, J = 5.2, 10.4 Hz, 1H), 3.29 (s, 3H), 1.93 (s, 3H), 1.28 (t, J =
7.2 Hz, 3H), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 167.3, 138.8, 137.0, 130.0, 126.9, 82.7, 66.0, 60.2,
56.9, 25.8, 20.6, 18.2, 14.1, −5.3, −5.4; [α]D23 −23.0 (c 0.49, CH2Cl2);
HRMS (ESI) m/z calcd for C17H36NO4Si (M + NH4)+ 346.2408,
found 346.2416; IR (KBr) 2954, 2929, 2858, 1712, 1464, 1377,1255,
1209, 1162, 1108, 838, 777 cm−1.
Compound 21. DIBAL reduction of 20 (867 mg, 2.64 mol) gave
21 (624 mg, 83%) described as above: 1H NMR (400 MHz, CDCl3) δ
6.51 (dd, J = 11.2, 15.2 Hz, 1H), 5.93 (d, J = 11.2 Hz, 1H), 5.47 (dd, J
= 7.2, 15.2 Hz, 1H), 4.24 (d, J = 2.8 Hz, 2H), 3.70−3.62 (m, 2H), 3.55
(dd, J = 4.8, 10.4 Hz, 1H), 3.31 (s, 3H), 1.86 (s, 3H), 1.75 (brs, 1H),
0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 137.4, 130.6, 128.1, 127.1, 83.0, 66.2, 61.5, 56.9, 25.9, 21.4, 18.3,
−5.3 (2C); [α]D24 −28.6 (c 0.48, CH2Cl2); HRMS (ESI) m/z calcd for
C15H31O3Si (M + H)+ 287.2037, found 287.2034; IR (KBr) 3418,
2953, 2929, 2858, 1466, 1254, 1111, 1007, 969, 838, 778 cm−1.
Compound 7. To a stirred solution of 21 (572 mg, 2.0 mmol) and
triethylamine (0.44 mL, 3.0 mmol) in CH2Cl2 (4 mL) at 0 °C was
added Me2O (453 mg, 2.6 mmol). After 15 min, the reaction was
diluted with acetone (4 mL) and charged with LiBr (1.05 g, 12.0
mmol). After the mixture was stirred for 1.5 h at 25 °C, the solvents
were removed in vacuo. The concentrate was then rinsed out of the
flask and partitioned between saturated NH4Cl and EtOAc. The
aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with brine, dried over Na2SO4, filtered, and
evaporated. The residue was purified by FCC (PE/EtOAc, 20:1) to
1
give 7 (691 mg, 99%): H NMR (400 MHz, CDCl3) δ 6.48 (dd, J =
11.2, 15.2 Hz, 1H), 5.99 (d, J = 10.8 Hz, 1H), 5.61 (dd, J = 7.2, 15.2
Hz, 1H), 4.11 (dd, J = 10.0, 13.2 Hz, 2H), 3.76−3.65 (m, 2H), 3.58
(dd, J = 4.8, 10.0 Hz, 1H), 3.34 (s, 3H), 1.92 (s, 3H), 0.88 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 133.6,
132.5, 129.5, 127.6, 82.9, 66.0, 57.1, 31.9, 25.9, 22.1, 18.4, −5.2, −5.3;
[α]D21 −24.0 (c 0.20, CH2Cl2); HRMS (ESI) m/z calcd for
4114
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The Journal of Organic Chemistry
Note
found 847.5152; IR (KBr) 2927, 2856, 1730, 1466, 1262, 1108, 752
cm−1.
Compound 2. Compound 2 was prepared from 25 (23 mg, 0.023
mmol) as described for compound 22 in Et2O/H2O (160:1): FCC
(PE/EtOAc, 6:1), yield (18.3 mg, 95%); 1H NMR (400 MHz, CDCl3)
δ 7.67−7.64 (m, 4H), 7.42−7.35 (m, 6H), 6.50 (dd, J = 10.8, 14.8 Hz,
1H), 5.87 (d, J = 10.8 Hz, 1H), 5.44 (dd, J = 6.8, 14.8 Hz, 1H), 3.80
(dd, J = 6.0, 10.0 Hz, 1H), 3.72−3.56 (m, 7H), 3.45 (t, J = 8.8 Hz,
1H), 3.33 (s, 3H), 2.41−2.01 (m, 7H), 1.82 (s, 3H), 1.77 (m, 1H),
1.06 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H), 0.94−0.89 (m, 15H), 0.79 (s,
9H), 0.06−0.05 (9H), −0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
139.6, 135.6, 133.9 (2C), 129.5, 129.2, 128.8, 127.6, 126.1, 83.0, 78.9,
75.9, 67.5, 66.8, 66.7, 56.9, 41.2, 37.4, 36.9, 34.4, 30.6, 26.9, 26.2, 26.0,
24.0, 19.3, 18.5, 18.4, 13.6 (2C), 11.1, −3.3, −4.2, −5.2, −5.3; [α]D22
+20.0 (c 0.37, CH2Cl2); HRMS (ESI) m/z calcd for C48H84O6Si3Na
(M + Na)+ 863.5468, found 863.5470; IR (KBr) 3447, 2956, 2929,
2857, 1468, 1254, 1110, 1084, 1026, 836, 776, 703 cm−1.
Compound 24. To a solution of 23 (313 mg, 0.38 mmol) in
MeOH (5 mL) was added K2CO3 (262 mg, 1.90 mmol) at rt. After
being stirred for 5 h, the reaction was diluted with EtOAc and washed
with 0.1 M NaOH (aq) solution. The aqueous layer was extracted with
EtOAc, and the combined organic layer was dried over Na2SO4 and
concentrated. The residue was purified by FCC (PE/EtOAc, 15:1) to
give 24 (290 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 7.68−7.65 (m,
4H), 7.43−7.34 (m, 6H), 6.47 (dd, J = 11.2, 15.2 Hz, 1H), 5.93 (d, J =
10.8 Hz, 1H), 5.42 (dd, J = 7.2, 15.2 Hz, 1H), 3.85 (dd, J = 5.2, 10.0
Hz, 1H), 3.73−3.43 (m, 6H), 3.35 (dd, J = 6.0, 11.2 Hz, 1H), 3.32 (s,
3H), 2.33 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.92−1.90 (m, 2H),
1.80 (s, 3H), 1.07 (s, 9H), 1.03 (d, J = 6.8 Hz, 3H), 0.90 (s, 12H), 0.79
(s, 9H), 0.07−0.03 (9H), −0.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 139.2, 135.7, 134.1, 134.0, 129.5, 129.4, 128.9, 127.6, 126.4,
83.3, 78.1, 66.7, 66.5, 63.7, 56.7, 40.2, 38.9, 36.6, 31.0, 27.0, 26.1, 26.0,
24.0, 19.3, 18.4, 18.2, 14.8, 13.6, −3.7, −4.4, −5.2, −5.3; [α]D23 +10.7 (c
0.21, CH2Cl2); HRMS (ESI) m/z calcd for C45H82NO5Si3 (M +
NH4)+ 800.5495, found 800.5479; IR (KBr) 2955, 2923, 2856, 1463,
1254, 1109, 1033, 1006, 836, 774, 702 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of spectra for compounds 2, 3, 5−8, 12, 13, and 15−25,
and related compounds S1, S2, and S3. This material is
available free of charge via the Internet at http://pubs.acs.org.
Compound 3. To a solution of 24 (221 mg, 0.28 mmol) in DMSO
(6 mL) was added IBX (118 mg, 0.42 mmol) at rt. After 2.5 h, the
reaction mixture was diluted with water (20 mL), filtered, and
extracted with EtOAc. The combined organic extracts were washed
with water, brine, dried over Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by FCC (PE/EtOAc, 30:1)
to give 3 (216 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J =
2.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 4H), 7.44−7.35 (m, 6H), 6.46 (dd, J
= 11.2, 15.2 Hz, 1H), 5.89 (d, J = 11.2 Hz, 1H), 5.44 (dd, J = 7.2, 15.2
Hz, 1H), 3.79−3.56 (m, 5H), 3.44 (dd, J = 8.0, 10.0 Hz, 1H), 3.33 (s,
3H), 2.67−2.58 (m, 2H), 2.31 (m, 1H), 2.15 (m, 1H), 1.96 (m, 1H),
1.77 (s, 3H), 1.06 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 7.6
Hz, 3H), 0.89 (s, 9H), 0.81 (s, 9H), 0.06−0.03 (9H), −0.07 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 204.1, 135.9, 135.6, 133.9, 133.8,
129.7, 129.6 (2C), 128.7, 127.6, 126.9, 83.2, 77.2, 66.5, 66.2, 56.9, 50.8,
40.1, 36.7, 29.4, 26.9, 26.0, 25.9, 23.9, 19.2, 18.4, 18.2, 14.3, 13.9, −3.9,
−4.4, −5.2, −5.3; [α]D24 +14.2 (c 0.16, CH2Cl2); HRMS (ESI) m/z
calcd for C45H80NO5Si3 (M + NH4)+ 798.5339, found 798.5343; IR
(KBr) 2955, 2926, 2855, 1729, 1463, 1256, 1110, 837, 774 cm−1.
Compound 25. To a solution of (4R,5S)-4-methyl-5-phenyl-3-
propionyl-2-oxazolidinone (4) (378 mg, 1.62 mmol) in CH2Cl2 (5.5
mL) at 0 °C under Ar were successively added Bu2BOTf (1.62 mL, 1
M in CH2Cl2, 1.62 mmol) and triethylamine (0.28 mL, 1.94 mmol).
After the solution was stirred at 0 °C for 45 min, 3 (158 mg, 0.202
mmol) in CH2Cl2 (2 mL) was added at −78 °C. The resulting mixture
was stirred for 1 h, warmed to rt, stirred overnight, and quenched with
phosphate buffer (4 mL, pH = 7) followed by addition of MeOH (1
mL). To the resulting slurry was then added slowly 3 mL of a 2:1 v/v
mixture of MeOH/30% aq H2O2, and the mixture was stirred
vigorously for 4 h. The reaction was then extracted with EtOAc, and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and evaporated under reduced pressure. The residue
was purified by FCC (PE/EtOAc, 12:1) to give 25 (121 mg, 59%): 1H
NMR (400 MHz, CDCl3) δ 7.68−7.65 (m, 4H), 7.42−7.34 (m, 9H),
7.22 (d, J = 6.8 Hz, 2H), 6.61 (dd, J = 11.2, 15.2 Hz, 1H), 5.97 (d, J =
10.8 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 5.47 (dd, J = 7.2, 15.2 Hz, 1H),
4.72 (m, 1H), 3.88−3.80 (m, 3H), 3.76−3.58 (m, 4H), 3.45 (t, J = 9.2
Hz, 1H), 3.34 (s, 3H), 2.64 (t, J = 12.8 Hz, 1H), 2.30−2.03 (m, 5H),
1.86 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H), 1.02 (d, J = 7.2
Hz, 3H), 1.00 (d, J = 7.6 Hz, 3H), 0.90 (s, 9H), 0.84 (d, J = 6.4 Hz,
3H), 0.80 (s, 9H), 0.07−0.06 (9H), −0.08 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 176.7, 152.1, 139.4, 135.6, 135.5, 133.9 (2C), 133.2,
129.5, 129.3, 128.7 (3C), 127.6, 126.7, 125.5, 83.2, 79.2, 78.7, 73.3,
67.0, 66.6, 56.8, 54.6, 41.2, 41.1, 36.1, 34.3, 30.4, 27.0, 26.2, 26.0, 23.7,
19.3, 18.4, 18.3, 14.2 (2C), 14.0, 13.5, −3.3, −4.2, −5.1, −5.3; [α]D24
+21.2 (c 0.44, CH2Cl2); HRMS (ESI) m/z calcd for C58H95N2O8Si3
(M + NH4)+ 1031.6391, found 1031.6410; IR (KBr) 2956, 2930,
2857, 1786, 1697, 1462, 1345, 1254, 1194, 1112, 1091, 1027, 836, 774,
702 cm−1.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yxjia@bjmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Nos. 20972007, 20802005), the National
Basic Research Program of China (973 Program, NO.
2010CB833200), and NCET.
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