Asymmetric synthesis of gonioheptolide A analogues via an organocatalytic aldol reaction as the key step

Article abstract of DOI:10.1055/s-0032-1316803

An efficient asymmetric synthesis of the potential antitumor agent (-)-gonioheptolide A derivatives is described. By employing an (S)-proline-catalyzed aldol reaction, the RAMP hydrazone α-alkylation methodology, and a diastereoselective reduction with zinc borohydride five stereocenters are established in the target compound. 4-epi-Methoxy- gonioheptolide A was obtained in ten steps in 15% overall yield and excellent diastereo- and enantiomeric excesses (de95%, ee 99%). Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316803

PAPER
▌3483
paper
Asymmetric Synthesis of Gonioheptolide A Analogues via an Organocatalytic
Aldol Reaction as the Key Step
Asymmetric Synthesis of Gonioheptolide A Analogues
Dieter Enders,* Sarah David, Kristina Deckers, Andreas Greb, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received: 21.09.2012; Accepted: 24.09.2012
The first semi-synthesis of 1 was accomplished by
Abstract: An efficient asymmetric synthesis of the potential antitu-
McLaughlin et al. starting from (–)-goniofupyron (2), by
mor agent (–)-gonioheptolide A derivatives is described. By em-
opening the lactone moiety under acidic conditions to the
ploying an (S)-proline-catalyzed aldol reaction, the RAMP
hydrazone α-alkylation methodology, and a diastereoselective re-
corresponding methyl ester.6
duction with zinc borohydride five stereocenters are established in
the target compound. 4-epi-Methoxy-gonioheptolide A was ob-
has been published by Hudson et al. in 2007.7 Starting
tained in ten steps in 15% overall yield and excellent diastereo- and
To the best of our knowledge, the only total synthesis of 1
from L-(+)-tartaric acid, 1 was synthesized in 18 steps and
an overall yield of 3%. The same group synthesized four
different stereoisomers of 1. These isomers showed even
enantiomeric excesses (de ≥95%, ee ≥99%).
Key words: dihydroxyacetone, aldol reaction, organocatalysis,
proline, styryllactone
higher activity against breast cancer cells in biological
studies.8
For a new access to this interesting class of compounds we
envisaged a different route to synthesize new epimers and
derivatives of 1 and 2 (Figure 1). Based on our previous
experience in proline-catalyzed aldol reactions,9 RAMP-
hydrazone alkylations,10 previous total syntheses of natu-
ral products and bioactive compounds starting from diox-
anone,11 we hoped that the epimeric gonioheptolide 3
could be prepared from three basic building blocks: com-
mercially available methyl bromoacetate (5), 2,2-dimeth-
yl-1,3-dioxan-5-one (6, dioxanone),12 and aldehyde 7
(Scheme 1).
Styryllactones are secondary metabolites isolated from
plants of the family annonaceae, genus goniothalamus.1
Since the first isolation of goniothalamin in 1967,2 more
than 30 styryllactones3 were discovered showing interest-
ing cytotoxic, pesticidal, and antitumor activity.4 A char-
acteristic feature of the styryllactones is the presence of
mono- or bicyclic tetrahydrofuran ring systems, densely
decorated with oxygenated stereocenters.1
(–)-Gonioheptolide A (1) was first isolated in 1993 from
the bark of Goniothalamus giganteus by McLaughlin et
al.5 The initially published structure was revised by
McLaughlin and Hanaoka et al. in 1999.6 The generally
accepted structure of (–)-gonioheptolide A containing the
furan alkyl ester skeleton 1 is shown in Figure 1. (–)-Go-
nioheptolide A shows interesting antitumor activities
against lung, breast, and colon cancer cells.5
SN2 cyclization
HO
O
H
O
MeO
Ph
diastereoselective
RAMP-hydrazone alkylation
HO
OMe
organocatalytic
HO
O
anti-aldol reaction
HO
H
H
O
3
O
MeO
Ph
4-epi-methoxy-gonioheptolide A
Ph
O
HO
O
OH
OH
1
2
O
(–)-gonioheptolide A
(–)-goniofupyron
O
MeO
Br
Ph
+
+
HO
O
HO
H
H
O
O
H
O
O
O
OTBS
MeO
Ph
Ph
5
6
7
O
HO
O
OMe
OMe
Scheme 1 Retrosynthetic analysis of 4-epi-methoxy-gonioheptolide
A (3)
4
3
4-epi-methoxy-goniofupyron
4-epi-methoxy-gonioheptolide A
Figure 1 (–)-Gonioheptolide A (1), (–)-goniofupyron (2), and the
epimeric methoxy compounds 3 and 4
The envisaged route to 4-epi-methoxy-gonioheptolide A
(3) consisted of an organocatalytic aldol reaction followed
by diastereoselective RAMP-hydrazone alkylation. Sub-
sequent reduction of the keto group and anionic ring clo-
sure should form the furan moiety.
SYNTHESIS 2012, 44, 3483–3488
Advanced online publication: 09.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316803; Art ID: SS-2012-Z0740-OP
© Georg Thieme Verlag Stuttgart · New York

3484
D. Enders et al.
PAPER
In the first stereogenic step, we employed an (S)-proline-
catalyzed aldol reaction of dioxanone (6) with the TBS-
protected aldehyde 7, which could be easily synthesized
from (R)-mandelic acid13 (Scheme 2). The aldol product 8
was obtained with very good diastereoselectivity
(de = 90%) and the minor diastereomer could be separat-
ed by column chromatography giving access to the diaste-
O
OMe
1. t-BuLi, MeO2CCH2Br
THF, –100 °C →r.t., 15 h
2. O3, CH2Cl2, –78 °C, 0.5 h
MeO
Ph
10
O
O
O
OTBS
66%
Me Me
11
de ≥ 95%, ee ≥ 99%
(after separation of the
minor diastereomer)
reo- and enantiomerically pure aldol product
8
(de ≥95%, ee ≥99%) in very good yield (86%). Subse-
quent reaction of the free alcohol group with Meerwein’s
reagent in the presence of proton sponge [1,8-bis(dimeth-
ylamino)naphthalene] gave the methyl ether 9 in 83%
yield and condensation of the ketone with RAMP resulted
in 74% the desired hydrazone 10 in good yield.
Scheme 3 α-Alkylation of 10 with methyl bromoacetate (5) as elec-
trophile
OH OMe
MeO
Ph
Zn(BH4)2, Et2O
–78 °C → r.t., 10 h
11
O
O
O
OTBS
97%
O
O
OH
O
(S)-proline, H2O
Ph
12
DMSO, 3 d, r.t.
Ph
+
de ≥ 95%, ee ≥ 99%
H
86%
O
O
O
O
OTBS
OTBS
OMs OMe
MsCl, 4-DMAP
Et3N, CH2Cl2
0 °C → r.t., 2.5 h
8
6
7
MeO
Ph
de ≥ 95%, ee ≥ 99%
(after separation of the minor
diastereomer)
O
O
O
OTBS
93%
Me3OBF4
13
proton sponge
83%
CH2Cl2, 4 h, 40 °C
Scheme 4 Anti-diastereoselective reduction with Zn(BH)4 and mesyl-
OMe
ation
N
O
OMe
N
OMe
RAMP, 3 Å MS
We initially thought that the acidic removal of the protec-
tion groups and subsequent treatment with CaCO3 could
provide the target compound 3 directly. However, only
lactone 14 was obtained in 70% yield. By refluxing 14 in
pyridine the cyclization to the bicyclic goniofupyron de-
rivative could be achieved in 82% yield. Finally, in anal-
ogy to McLaughlin’s synthesis the 4-epi-methoxy-
goniofupyron (4) was opened under acidic conditions to
the target compound 3 (Scheme 5).
benzene
15 h, 80 °C
Ph
Ph
O
O
OTBS
74%
O
O
OTBS
10
9
proton sponge = 1,8-bis(dimethylamino)naphthalene
Scheme 2 Organocatalytic anti-aldol reaction as a key step
The RAMP-hydrazone α-alkylation methodology14 was
used to give the alkylated product 11 in a two-step se-
quence consisting of the alkylation of hydrazone 10 with
tert-butyllithium and methyl bromoacetate (5) in THF at
–100 °C and a subsequent ozonolysis to remove the chiral
auxiliary. The alkylation proceeded with a diastereomeric
excess of 94%. Column chromatography yielded the dia-
stereo- and enantiomerically pure alkylation product in a
one-pot fashion from 10 to 11 with 66% yield over 2 steps
(Scheme 3).
OMs OMe
H2SO4, THF
HO
Ph
r.t., 12 h, aq CaCO3
13
O
OH
70%
14
O
pyridine
reflux, 5 h
82%
O
OH
Anti-diastereoselective reduction of ketone 11 with zinc
borohydride gave the alcohol 12 in 97% yield (de ≥95%,
ee ≥99%). In accordance with previous findings it should
be noted that other reducing reagents, such as boron hy-
drides were not selective enough or led to the wrong dia-
stereomer.15 The cyclization precursor 13 was finally
obtained by mesylation of the secondary alcohol under ba-
sic conditions (Scheme 4).
OH
O
Amberlyst 15
MeOH
H
H
O
O
MeO
Ph
Ph
85%
HO
O
OMe
OMe
3
4
de ≥ 95%, ee ≥ 99%
4-epi-methoxy-(–)-goniofupyron
de ≥ 95%, ee ≥ 99%
Scheme 5 Final steps in the synthesis of the epimeric goniheptolide
analogues 3 and 4
Synlett 2012, 44, 3483–3488
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Gonioheptolide A Analogues
3485
Attempts to convert the methoxy group into the corre- All commercially available compounds were used without further
purification. (R)-2-[(tert-Butyldimethylsilyl)oxy]-2-phenylacetal-
sponding free secondary alcohol turned out to be difficult.
Protocols with different Lewis acids and on different stag-
es were tried without success. Thus, the epimeric natural
product 2 could not be obtained via this route. To support
dehyde (7) was synthesized following a procedure published by
Kobayashi et al.13 For preparative column chromatography silica
gel 60 (particle size 0.040–0.063 mm, 230–240 mesh, flash) was
used. Yields are reported based on pure, separated diastereomers.
our expectations for the stereochemical outcome of the
synthesis the absolute configuration of the acyclic ester 15
was determined by X-ray crystal structure analysis. This
compound was obtained by deprotection of 13 under
methanolic acidic conditions. Additional NOE measure-
ments of 3 confirmed the expected inversion of the stereo-
center at C-2 during the cyclization step (Figure 2).
Melting points were determined with a Büchi Melting Point B-540
and optical rotation values with a Perkin-Elmer P241 polarimeter.
TLC was carried out with silica gel 60 F254 plates from Merck and
visualization was achieved by staining with vanillin solution in
EtOH with 1% concd H2SO4. IR spectra were acquired with a
1
PerkinElmer Spectrum 100 spectrophotometer. H and 13C NMR
spectra were recorded on Varian Mercury 300 or Inova 400 spec-
trometers with TMS as internal standard. Mass spectra were mea-
sured with a Finnigan SSQ7000 spectrometer (CI 100 eV; EI 70
eV). HRMS data were recorded with a ThermoFinnigan LCQ Deca
XP plus (ESI) or a ThermoFisher Scientific LTQ-Orbitrap XL (ESI)
instrument.
(S)-4-{(1R,2R)-2-[(tert-Butyldimethylsilyl)oxy]-1-hydroxy-2-
phenylethyl}-2,2-dimethyl-1,3-dioxan-5-one (8)
To a solution of 2,2-dimethyl-1,3-dioxan-5-one (6; 781 mg,
6.0 mmol) and (R)-2-[(tert-butyldimethylsilyl)oxy]-2-phenylacet-
aldehyde (7; 500 mg, 2 mmol) in DMSO (8 mL) were added (S)-
proline (69 mg, 0.3 mmol) and H2O (180 mg, 10 mmol). The mix-
ture was stirred at r.t. for 3 d, quenched with brine (5 mL), and ex-
tracted with Et2O (3 × 10 mL). Drying of the combined Et2O
extracts (MgSO4), evaporation of the solvent, and column chroma-
tography (n-pentane–Et2O, 15:1 to 6:1) of the crude product afford-
ed 8 as a colorless oil; yield: 655 mg (86%); [α]D26 –121.3 (c = 1.02,
CHCl3); Rf = 0.3 (n-pentane–EtOAc, 15:1).
IR (capillary): 3517, 3064, 3033, 2987, 2929, 2856, 1748, 1578,
1542, 1466, 1381, 1253, 1225, 1159, 1083, 1007, 938, 860, 838,
778, 702, 673, 635, 562, 537 cm–1.
1H NMR (300 MHz, CDCl3): δ = –0.24 (s, 3 H, CH3Si), 0.06 (s,
3 H, CH3Si), 0.88 (s, 9 H, t-C4H9Si), 1.35 (s, 3 H, CH3), 1.47 (s, 3 H,
CH3), 3.07 (d, J = 2.3 Hz, 1 H, OH), 3.80 (d, J = 16.6 Hz, 1 H,
a
b
CH2 ), 3.96 (dd, J = 16.6, 1.2 Hz, 1 H, CH2 ), 4.07–4.10 (m, 1 H, H-
4), 4.17–4.18 (m, 1 H, H-3), 4.99 (d, J = 7.2 Hz, 1 H, H-5), 7.26–
7.38 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = –5.0, –4.4, 18.1, 23.0, 24.8, 25.8
(3 C), 67.0, 74.8, 75.6, 76.4, 100.4, 127.7 (2 C), 128.1 (2 C), 128.2,
140.4, 207.2.
Figure 2 X-ray crystal structure of 1516 and NOE measurement of 3
MS (EI, 70 eV): m/z (%) = 59 (20), 72 (11), 73 (73), 75 (68),
91 (21), 105 (13), 115 (12), 117 (16), 129 (62), 131 (12), 159 (22),
193 (62), 194 (10), 221 (100), 222 (20).
HRMS-ESI: m/z [2 M + Na]+ calcd for C40H64O10Si2 + Na:
In summary, we have developed an asymmetric synthesis
of new epimeric (–)-gonioheptolide A analogues using an
organocatalytic aldol reaction with (S)-proline as the ste-
reogenic key step. 4-epi-Methoxy-gonioheptolide A was
obtained in ten steps in a good overall yield of 15% in dia-
stereo- and enantiopure form starting from the dioxanone
(6), aldehyde 7, and methyl bromoacetate (5). Besides this
key step an α-alkylation employing the RAMP-hydrazone
methodology and an SN2 ring closure gave us access to the
epimeric methoxy-gonioheptolide A (3) and the epimeric
methoxy-goniofupyron (4). This synthetic strategy could
also lead to different stereoisomers and derivatives of (–)-
gonioheptolide A (1). Compared to conventional strate-
gies stereoisomers can be accessed by using (S)- or (R)-
proline in the key step and/or the RAMP- or SAMP-hy-
drazone for the alkylation, respectively. Furthermore, the
reduction of the ketone can be directed to the opposite
diastereomer by using L-Selectride as the reducing agent.
783.3930; found: 783.3931.
(S)-4-{(1R,2R)-2-[(tert-Butyldimethylsilyl)oxy]-1-methoxy-2-
phenylethyl}-2,2-dimethyl-1,3-dioxan-5-one (9)
To a solution of 8 (3.61 g, 9.49 mmol) in anhyd CH2Cl2 (94 mL)
were added Me3OBF4 (2.10 g, 14.23 mmol) and proton sponge
(5.08 g, 23.72 mmol). The mixture was refluxed under argon for
4 h. After cooling to r.t., the mixture was washed with HCl (1.5 N,
50 mL). The aqueous layer was extracted with Et2O (2 × 30 mL).
The combined organic layers were dried (MgSO4) and the solvent
was evaporated. The resulting solid was suspended in Et2O
(200 mL) and filtered over a short plug of silica gel. The filtrate was
evaporated and purified by column chromatography (n-pentane–
26
Et2O, 8:1) to afford 9 as a colorless oil; yield: 3.11 g (83%); [α]D
–129.9 (c = 1.02, CHCl3); Rf = 0.5 (n-pentane–Et2O, 8:1).
IR (capillary): 3065, 3034, 2988, 2931, 2893, 2857, 1779, 1751,
1726, 1673, 1467, 1424, 1380, 1315, 1223, 1125, 1089, 1056, 986,
890, 863, 837, 779, 670, 626, 573, 541, 481 cm–1.
1H NMR (300 MHz, CDCl3): δ = –0.18 (s, 3 H, CH3Si), 0.06 (s,
3 H, CH3Si), 0.92 (s, 9 H, t-C4H9Si), 1.28 (s, 3 H, CH3), 1.43 (s, 3 H,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 44, 3483–3488

3486
D. Enders et al.
PAPER
CH3), 3.59 (s, 3 H, OCH3), 3.61–3.63 (m, 2 H, CH2), 3.73 (dd,
J = 8.3, 1.8 Hz, 1 H, H-4), 4.09 (m, 1 H, H-3), 4.97 (d, J = 8.3 Hz,
1 H, H-5), 7.24–7.37 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = –4.9, –4.8, 18.1, 22.7, 25.0, 25.8
(3 C), 60.9, 66.9, 76.0, 76.7, 87.2, 100.1, 127.9 (2 C), 127.9, 128.4
(2 C), 140.9, 206.8.
IR (capillary): 2938, 2857, 1743, 1444, 1380, 1258, 1202, 1170,
1122, 1087, 920, 851, 776, 702 cm–1.
1H NMR (300 MHz, CDCl3): δ = –0.19 (s, 3 H, CH3Si), 0.03 (s,
3 H, CH3Si), 0.81 (s, 9 H, t-C4H9Si), 1.42 (s, 3 H, CH3), 1.50 (s, 3 H,
a
CH3), 2.32 (dd, J = 16.3, 8.9 Hz, 1 H, CH2 ), 2.58 (dd, J = 16.3,
b
3.7 Hz, 1 H, CH2 ), 3.59 (s, 3 H, OCH3), 3.65–3.68 (m, 1 H, H-4),
3.70 (s, 3 H, CO2CH3), 4.15–4.16 (m, 1 H, H-3), 4.59–4.62 (m, 1 H,
CHOH), 5.89 (d, J = 8.2 Hz, 1 H, H-5), 7.24–7.41 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = –4.9, –4.8, 18.1, 20.7, 25.7 (3 C),
28.9, 35.7, 52.0, 61.5, 74.5, 75.4, 78.3, 87.7, 98.7, 127.7 (4 C),
128.1, 141.3, 171.1, 205.8.
MS (EI, 70 eV): m/z (%) = 59 (27), 73 (71), 75 (15), 89 (38),
91 (18), 115 (20), 129 (98), 130 (15), 131 (11), 147 (12), 173 (47),
195 (10), 203 (11), 205 (10), 219 (16), 221 (100), 222 (55),
223 (15), 231 (30), 247 (27), 263 (24), 265 (29), 279 (16), 337 (12),
395 (3, [M + H]+).
HRMS-ESI: m/z [M + Na]+ calcd for C21H34O5Si + Na: 417.2068;
found: 417.2068.
MS (EI, 70 eV): m/z (%) = 55 (11), 57 (15), 59 (29), 73 (83),
75 (19), 85 (24), 89 (54), 91 (25), 105 (11), 115 (27), 131 (10),
143 (19), 183 (20), 201 (15), 221 (100), 222 (19), 245 (19).
(2R)-N-((R)-4-{(1R,2R)-2-[(tert-Butyldimethylsilyl)oxy]-1-
methoxy-2-phenylethyl}-2,2-dimethyl-1,3-dioxan-5-ylidene)-2-
(methoxymethyl)cyclopentanamine (RAMP Hydrazone 10)
To a solution of 9 (1.66 g, 4.20 mmol) and RAMP (2.18 g,
16.79 mmol) in benzene (21 mL) were added 3 Å molecular sieves.
The mixture was heated at reflux for 15 h. After filtration of the mo-
lecular sieves, the solvent was removed under reduced pressure. Pu-
rification of the crude product by column chromatography (n-
pentane–Et2O, 4:1) afforded 10 as a yellow oil; yield: 1.58 g (74%);
[α]D23 –41.5 (c = 1.01, CHCl3); Rf = 0.2 (n-pentane–Et2O, 5:1).
HRMS-ESI: m/z [M + H]+ calcd for C24H39O7Si: 467.2460; found:
467.2460.
Methyl 2-((4R,5R,6R)-6-{(1R,2R)-2-[(tert-Butyldimethylsi-
lyl)oxy]-1-methoxy-2-phenylethyl}-5-hydroxy-2,2-dimethyl-
1,3-dioxan-4-yl)acetate (12)
A solution of Zn(BH4)2 in dry Et2O (0.14 M, 50.5 mL, 7.06 mmol)
was added dropwise under argon to a solution of 11 (589 mg,
1.26 mmol) in anhyd Et2O (9.0 mL) at –78 °C. The mixture was
slowly warmed to r.t. and stirred for 10 h. After cooling to 0 °C,
MeOH (10 mL) was added and the mixture was stirred for addition-
al 30 min. The reaction was quenched with sat. aq NH4Cl (30 mL)
and extracted with CH2Cl2 (3 × 30 mL). Drying of the combined
CH2Cl2 layers (MgSO4), evaporation of the solvent, and column
chromatography (n-pentane–Et2O, 2:1) of the crude product afford-
ed 12 as a colorless oil; yield: 574 mg (97%); [α]D25 –10.1 (c = 1.00,
CHCl3); Rf = 0.5 (n-pentane–Et2O 2:1).
IR (capillary): 3469, 2935, 1460, 1377, 1222, 1086, 933, 841, 760,
701, 669, 625, 572, 517 cm–1.
1H NMR (300 MHz, CDCl3): δ = –0.16 (s, 3 H, CH3Si), 0.05 (s,
3 H, CH3Si), 0.84 (s, 9 H, t-C4H9Si), 1.28 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 1.59–1.74 (m, 1 H, RMP-H), 1.78–1.88 (m, 2 H, RMP-H),
a
1.92–2.03 (m, 1 H, RMP-H), 2.68–2.76 (m, 1 H, NCH2 ), 2.85–2.92
b
(m, 1 H, NCH2 ), 3.07–3.16 (m, 1 H, NCH), 3.23 (dd, J = 7.2,
a
9.3 Hz, 1 H, MeOCH2 ), 3.36 (s, 3 H, OCH3), 3.43 (s, 3 H, OCH3),
IR (capillary): 3502, 2994, 2935, 2858, 1742, 1454, 1381, 1321,
1257, 1201, 1169, 1068, 933, 845, 760, 702 cm–1.
b
3.48 (dd, J = 4.5, 9.3 Hz, 1 H, MeOCH2 ), 3.60 (dd, J = 3.5, 6.9 Hz,
a
1 H, H-4), 4.12 (dd, J = 1.5, 15.8 Hz, 1 H, CH2 ), 4.25 (dd, J = 1.5,
1H NMR (300 MHz, CDCl3): δ = –0.19 (s, 3 H, CH3Si), 0.05 (s,
3 H, CH3Si), 0.90 (s, 9 H, t-C4H9Si), 1.28 (s, 3 H, CH3), 1.36 (s, 3 H,
b
3.5 Hz, 1 H, H-3), 4.48 (d, J = 15.8 Hz 1 H, CH2 ), 5.10 (d,
J = 6.7 Hz, 1 H, H-5), 7.21–7.25 (m, 3 H, ArH), 7.41–7.45 (m, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): δ = –4.7 (2 C), 18.2, 22.7, 23.3, 25.8
(3 C), 26.6, 26.8, 55.4, 59.1, 60.7, 60.9, 66.8, 72.5, 74.6, 75.1, 88.1,
99.2, 127.1, 127.7 (2 C), 127.9 (2 C), 142.6, 159.0.
a
CH3), 2.40 (dd, J = 3.2, 15.6 Hz, 1 H, CH2 ), 2.85 (dd, J = 8.9,
b
15.6 Hz, 1 H, CH2 ), 3.20 (s, 3 H, OCH3), 3.24–3.33 (m, 2 H, H-2,
H-4), 3.58 (d, J = 1.0 Hz, 1 H, OH), 3.68 (s, 3 H, CO2CH3), 3.73
(dd, J = 7.2, 9.2 Hz, 1 H, H-3), 4.10 (dt, J = 3.2, 9.2 Hz, 1 H,
CHOH), 4.81 (d, J = 3.5 Hz, 1 H, H-5), 7.24–7.39 (m, 5 H, ArH).
MS (EI, 70 eV): m/z (%) = 70 (13), 73 (21), 82 (6), 89 (20), 91 (6),
98 (16), 112 (5), 114 (7), 139 (8), 183 (100), 184 (27), 195 (14), 221
(9), 241 (6), 242 (12), 461 (6), 506 (1, [M + H]+).
13C NMR (75 MHz, CDCl3): δ = –4.9, –4.4, 18.2, 19.4, 25.9 (3 C),
29.3, 37.7, 51.6, 61.7, 69.3, 70.0, 71.3, 74.5, 90.8, 98.7, 127.2 (2 C),
127.4, 127.9 (2 C), 141.8, 171.8.
HRMS-ESI: m/z [M + H]+ calcd for C27H47O5N2Si: 507.3249;
MS (EI, 70 eV): m/z (%) = 59 (19), 73 (31), 89 (15), 113 (10),
found: 507.3247.
115 (11), 145 (16), 185 (27), 221 (100), 222 (20).
HRMS-ESI: m/z [2 M + Na]+ calcd for C48H80O14Si2 + Na:
959.4979; found: 959.4959.
Methyl 2-((4R,6S)-6-{(1R,2R)-2-[(tert-Butyldimethylsilyl)oxy]-
1-methoxy-2-phenylethyl}-2,2-dimethyl-5-oxo-1,3-dioxan-4-
yl)acetate (11)
Methyl 2-((4R,5R,6S)-6-{(1R,2R)-2-[(tert-butyldimethylsi-
lyl)oxy]-1-methoxy-2-phenylethyl}-2,2-dimethyl-5-[(methylsul-
fonyl)oxy]-1,3-dioxan-4-yl)acetate (13)
Under argon 10 (411 mg, 0.81 mmol) was dissolved in anhyd THF
(3.2 mL) and cooled to –78 °C. t-BuLi (1.47 M in n-pentane,
0.61 mL, 0.89 mmol) was added dropwise and the mixture was
stirred at –78 °C for 2 h. After cooling to –100 °C, methyl bromo-
acetate (5; 0.13 mL, 0.89 mmol) dissolved in anhyd THF (0.9 mL)
was added subsequently. The mixture was stirred for 2 h and
warmed to r.t. over 15 h. The reaction was quenched with pH 7 buf-
fer solution (5.0 mL) and extracted with Et2O (3 × 5 mL). The com-
bined organic layers were dried (MgSO4) and the solvent was
evaporated. The crude product was dissolved in anhyd CH2Cl2 (50.0
mL) under argon and cooled to –78 °C. Ozone was bubbled through
the solution for 15 min. Excess of ozone was removed by flushing
the solution with argon while warming to r.t. The mixture was dried
(MgSO4) and the solvent was removed under vacuum. Purification
of the crude product by column chromatography (n-pentane–Et2O,
4:1) afforded 11 as a yellow oil; yield: 251 mg (66%); [α]D23 –11.0
(c = 1.03, CHCl3); Rf = 0.4 (n-pentane–Et2O, 6:1).
Et3N (0.43 mL, 3.06 mmol) and a catalytic amount of 4-DMAP
were added to a solution of 12 (552 mg, 1.18 mmol) in CH2Cl2
(12.0 mL). After cooling to 0 °C, a solution of MsCl (0.13 mL,
1.65 mmol) in CH2Cl2 (1.0 mL) was added dropwise. The mixture
was stirred for 30 min at 0 °C and for 2 h at r.t., then quenched with
sat. aq NH4Cl (10 mL), and extracted with CH2Cl2 (3 × 10 mL).
Drying of the combined CH2Cl2 layers (MgSO4), evaporation of the
solvent, and column chromatography (n-pentane–Et2O, 2:1) of the
crude product afforded 13 as a colorless solid, yield: 598 mg (93%);
24
mp 89–91 °C [α]D –12.0 (c = 0.75, CHCl3); Rf = 0.3 (n-pentane–
Et2O, 2:1).
IR (capillary): 3469, 2934, 2856, 1742, 1448, 1360, 1255, 1177,
1069, 956, 846, 763, 701, 629, 573, 531 cm–1.
1H NMR (300 MHz, CDCl3): δ = –0.20 (s, 3 H, CH3Si), 0.04 (s, 3
H, CH3Si), 0.88 (s, 9 H, t-C4H9Si), 1.21 (s, 3 H, CH3), 1.34 (s, 3 H,
Synlett 2012, 44, 3483–3488
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Gonioheptolide A Analogues
3487
a
CH3), 2.44 (dd, J = 6.2, 16.1 Hz, 1 H, CH2 ), 2.89 (dd, J = 2.5,
HRMS-ESI: m/z [M + H]+ calcd for C16H25O9S: 393.1214; found:
393.1219.
b
16.1 Hz, 1 H, CH2 ), 3.13 (s, 3 H, SO2CH3), 3.41–3.45 (m, 1 H, H-
4), 3.45 (s, 3 H, OCH3), 3.68 (s, 3 H, CO2CH3), 3.85 (dd, J = 3.5,
8.2 Hz, 1 H, H-3), 4.16–4.29 (m, 2 H, H-2, CHOMs), 4.73 (d,
J = 6.7 Hz, 1 H, H-5), 7.26–7.39 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = –4.9, –4.5, 18.1, 19.1, 25.7 (3 C),
29.1, 37.5, 39.3, 51.7, 61.4, 69.0, 71.6, 75.3, 75.9, 88.2, 99.1, 127.7
(2 C), 127.8, 128.2 (2 C), 141.3, 171.1.
(2R,3S,3aS,7R,7aS)-7-Hydroxy-3-methoxy-2-phenyltetra-
hydro-2H-furo[3,2-b]pyran-5(6H)-one (4)
Lactone 14 (150 mg, 0.4 mmol) was dissolved in pyridine (0.8 mL)
and the mixture was heated at reflux for 5 h. After adding H2O (20
mL), the aqueous phase was extracted with EtOAc (3 × 15 mL).
The combined organic phases were washed with HCl (1.5 M, 5 mL)
and brine (10 mL), dried (MgSO4), and evaporated. Chromato-
graphic purification on silica gel (eluent: CH2Cl2–MeOH, 20:1) af-
forded the title compound 4 as a colorless glassy solid; yield: 89 mg
MS (EI, 70 eV): m/z (%) = 59 (14), 73 (31), 89 (16), 153 (10),
221 (100), 222 (20), 223 (36).
HRMS-ESI: m/z [M + Na]+ calcd for C25H42O9SSi + Na: 569.2211;
found: 569.2201.
25
(82%); [α]D –21.2 (c = 0.52, CHCl3); Rf = 0.3 (CH2Cl2–MeOH,
20:1).
(2S,3R,4R)-4-Hydroxy-2-[(1S,2R)-2-hydroxy-1-methoxy-2-
phenylethyl]-6-oxotetrahydro-2H-pyran-3-yl Methanesulfo-
nate (14)
IR (ATR): 3404, 2923, 2853, 2322, 2190, 2098, 1728, 1496, 1454,
1397, 1354, 1256, 1225, 1192, 1130, 1059, 1009, 920, 841, 791,
763, 725, 702 cm–1.
To a solution of 13 (583 mg, 1.07 mmol) in THF (10 mL) was added
concd H2SO4 (0.46 mL, 8.53 mmol). The mixture was stirred at r.t.
overnight and quenched with sat. aq CaCO3 (1 mL). After extrac-
tion with EtOAc (3 × 10 mL), the combined organic layers were
dried (MgSO4). Evaporation of the solvent and column chromatog-
raphy (n-pentane–EtOAc, 1:3) of the crude product mixture afford-
ed 14 as a colorless solid; yield: 270 mg (70%); mp 26–27 °C;
[α]D24 –34.6 (c = 0.75, CHCl3); Rf = 0.4 (n-pentane–EtOAc, 1:3).
a
1H NMR (300 MHz, CDCl3): δ = 2.66–2.76 (m, 1 H, CH2 ), 2.79–
b
2.89 (br s, 1 H, OH), 3.03–2.89 (m, 4 H, CH3, CH2 ), 3.87 (dd,
J = 2.9, 5.7 Hz, 1 H, H-4), 4.18–4.28 (m, 1 H, H-2), 4.36–4.43 (m,
1 H, CH), 4.78 (d, J = 2.9 Hz, 1 H, H-5), 5.36 (dd, J = 5.7, 8.4 Hz,
1 H, H-3), 7.04–7.77 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 35.6, 60.6, 66.6, 74.6, 80.1, 81.5,
82.0, 126.9 (2 C), 127.0, 128.1 (2 C), 135.0, 170.2.
IR (ATR): 3440, 3026, 2937, 1729, 1453, 1344, 1222, 1171, 1090,
936, 850, 816, 762, 705 cm–1.
MS (EI, 70 eV): m/z (%) = 58 (100), 65 (11), 77 (21), 79 (12), 87
(61), 91 (51), 103 (12), 107 (26), 115 (11), 131 (13), 134 (48), 135
(11), 144 (29), 264 (22, [M+]).
1H NMR (300 MHz, CDCl3): δ = 2.69 (dd, J = 9.6, 17.5 Hz, 1 H,
a
b
CH2 ), 2.86 (dd, J = 5.9, 17.5 Hz 1 H, CH2 ), 3.12 (s, 3 H, OCH3),
3.28 (s, 3 H, SO2CH3), 3.67–3.73 (m, 1 H, H-4), 4.54–4.61 (m, 1 H,
CH), 4.65–4.69 (m, 1 H, H-3), 4.80 (d, J = 4.7 Hz, 1 H, H-5), 5.34–
5.39 (m, 1 H, CHOMs), 7.32–7.44 (m, 5 H, ArH).
Anal. Calcd for C14H16O5 (264.01): C, 63.63; H, 6.10. Found:
C, 63.26; H, 5.96.
(R)-Methyl 3-Hydroxy-3-[(2S,3S,4R,5R)-3-hydroxy-4-methoxy-
5-phenyltetrahydrofuran-2-yl]propanoate (3)
The integrals at 2.86 ppm and 3.28 ppm were slightly larger than ex-
pected and it was assumed that the two missing alcohol protons
overlap.
13C NMR (75 MHz, CDCl3): δ = 34.7, 38.8, 62.2, 63.7, 72.6, 76.1,
4-epi-Methoxy-(–)-goniofupyron (4; 45 mg, 0.17 mmol) was dis-
solved in MeOH (1 mL) and Amberlyst 15 (17 mg) was added. The
mixture was stirred overnight. Direct chromatographic purification
on silica gel (eluent: CH2Cl2–MeOH, 20:1) afforded 4-epi-me-
thoxy-(–)-gonioheptolide (3) as a colorless solid; yield: 43 mg
80.8, 85.9, 126.2 (2 C), 128.6 (2 C), 128.9, 140.0, 167.9.
25
(85%); mp 92–93 °C, [α]D –58.7 (c = 0.53, CHCl3), Rf = 0.4
MS (EI, 70 eV): m/z (%) = 107 (13), 127 (10), 135 (91), 145 (10),
155 (17), 159 (12), 161 (12), 215 (65), 229 (32), 233 (41), 247
(100), 248 (16), 265 (17), 343 (41, [M – OH]+).
(CH2Cl2–MeOH, 20:1).
IR (ATR): 3447, 3037, 2927, 2861, 1894, 1727, 1605, 1542, 1495,
1437, 1367, 1262, 1148, 1101, 1068, 999, 957, 913, 873, 850, 757,
698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.74–2.77 (m, 2 H, CH2), 3.02 (s,
3 H, OCH3), 3.29 (d, J = 9.2 Hz, 1 H, OH), 3.51 (d, J = 6.2 Hz, 1 H,
OH), 3.71 (s, 3 H, CO2CH3), 3.84 (dd, J = 3.9, 5.1 Hz, 1 H, H-4),
4.04 (dd, J = 3.3, 7.0 Hz, 1 H, H-2), 4.37–4.46 (m, 1 H, CH), 4.55–
4.65 (m, 1 H, H-3), 4.84 (d, J = 3.9 Hz, 1 H, H-5), 7.25–7.47 (m, 5
H, ArH).
Anal. Calcd for C15H20O8S (360.09): C, 49.99; H, 5.59. Found: C,
50.13; H, 5.48.
Methyl (3R,4R,5S,6S,7R)-3,5,7-Trihydroxy-6-methoxy-4-
[(methylsulfonyl)oxy]-7-phenylheptanoate (15)
Compound 13 (583 mg, 1.07 mmol) was deprotected with concd
H2SO4 (0.46 mL) in MeOH–THF (1:1, 22 mL). The workup proce-
dure was done as described above. Crystallization from EtOAc in
the refrigerator resulted in suitable single crystals; yield: 192 mg
(46%); mp 109–111 °C; [α]D25 +5.6 (c = 0.75, MeOH); Rf = 0.5 (n-
pentane–EtOAc, 1:3).
13C NMR (75 MHz, CDCl3): δ = 38.8, 51.7, 60.0, 67.3, 73.4, 80.5,
80.8, 82.8, 127.0 (2 C), 127.9, 128.1 (2 C), 136.1, 172.1.
MS (EI, 70 eV): m/z (%) = 103 (22), 135 (36), 145 (45), 163 (100),
229 (73), 230 (11), 233 (13), 247 (16), 265 (21, [M + H]).
IR (ATR): 3491, 3188, 3027, 2914, 2828, 2076, 1720, 1498, 1443,
1386, 1337, 1291, 1236, 1172, 1063, 1014, 979, 914, 856, 823, 763,
731, 700, 675 cm–1.
Anal. Calcd for C15H20O6 (264.01): C, 60.80; H, 6.80. Found:
C, 60.83; H, 6.92.
1H NMR (300 MHz, CDCl3): δ = 2.63 (dd, J = 9.4, 16.8 Hz, 1 H,
a
b
CH2 ), 2.86 (dd, J = 3.0, 16.8 Hz, 1 H, CH2 ), 3.08 (s, 3 H,
CHOCH3), 3.18 (s, 3 H, SO2CH3), 3.58 (dd, J = 1.7, 6.7 Hz, 1 H, H-
4), 3.72 (m, 4 H, CO2CH3, OH), 3.97 (d, J = 4.3 Hz, 1 H, OH), 4.14–
4.23 (m, 2 H, OH, H-3), 4.46–4.53 (m, 1 H, CHCH2), 4.88 (dd,
J = 4.2, 5.7 Hz, 1 H, CHOMs), 5.17 (d, J = 6.2 Hz, 1 H, H-4), 7.25–
7.41 (m, 5 H, ArH).
Acknowledgment
We thank the former Degussa AG and BASF SE for the donation of
chemicals.
13C NMR (75 MHz, CDCl3): δ = 36.9, 38.8, 52.1, 60.1, 67.1, 70.7,
72.0, 83.5, 85.4, 125.9 (2 C), 127.5, 128.4 (2 C), 141.2, 173.2.
References
MS (EI, 70 eV): m/z (%) = 113 (7), 115 (13), 119 (9), 121 (17), 125
(10), 134 (29), 135 (15), 140 (18), 144 (10), 157 (26), 165 (29), 172
(11), 249 (17), 393 (1, [M + H]).
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 44, 3483–3488

3488
D. Enders et al.
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(16) Crystallographic data for 15 reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 818574. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
Synlett 2012, 44, 3483–3488
© Georg Thieme Verlag Stuttgart · New York