Toward a total synthesis of divergolide A; Synthesis of the amido hydro- Quinone core and the C10-C15 fragment

Article abstract of DOI:10.1055/s-0032-1317491

A ring-closing metathesis (RCM) approach was envisioned for installing the E double bond at the C9 and C10 positions of divergolide A, isolated from a mangrove endophyte. Accordingly, the C10-C15 diene diol fragment and the amido hydroquinone core with the requisite functionalities and stereochemistry have been synthesized by using the norephedrine-based syn-selective glycolate aldol and the anti-selective aldol reactions, respectively. CuI-catalyzed amidation was employed to access the anilide intermediate, which was further transformed into the amido hydroquinone core. Copyright

Full text of DOI:10.1055/s-0032-1317491

LETTER
▌2845
letter
Toward a Total Synthesis of Divergolide A; Synthesis of the Amido Hydro-
quinone Core and the C10–C15 Fragment
Toward the Total Synthesis of Divergolide A
Guanglian Zhao,a Jinlong Wu,a Wei-Min Dai*a,b
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear
Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax +852(2)3581594; E-mail: chdai@ust.hk
Received: 20.08.2012; Accepted after revision: 26.09.2012
shown in Scheme 1, divergolide A (1) can be derived ret-
Abstract: A ring-closing metathesis (RCM) approach was envi-
rosynthetically from the larger macrocycle 2. The latter
sioned for installing the E double bond at the C9 and C10 positions
can be further divided into five small fragments 3–7 ac-
of divergolide A, isolated from a mangrove endophyte. According-
ly, the C10–C15 diene diol fragment and the amido hydroquinone
cording to RCM at C9–C10, ester cleavage, methyl ketone
core with the requisite functionalities and stereochemistry have aldol–oxidation at C3–C4, anti-selective aldol at C1–C2,8
and CuI-catalyzed amidation.9 Because divergolide A–D
been synthesized by using the norephedrine-based syn-selective
glycolate aldol and the anti-selective aldol reactions, respectively.
share the same C6–C15 polyketide bridge appended on
CuI-catalyzed amidation was employed to access the anilide inter-
different heteroaromatic motifs, this RCM approach
mediate, which was further transformed into the amido hydroqui-
should enable use of the same C10–C15 fragment 5 in the
none core.
total synthesis of all these ansa macrolides. We report here
Key words, aldol reactions, selectivity, natural products, hydroqui-
on the synthesis of the C10–C15 fragment 5 through a
none, total synthesis
syn-selective norephedrine glycolate aldol reaction,10 and
on the amido hydroquinone core from the starting materi-
als 6 and 7 (Scheme 1).
Divergolide A–D were reported recently as the novel ansa
macrolides isolated from an endophyte strain (Streptomy-
ces sp. HKI0576) of the dominant mangrove tree Brugui-
The norephedrine glycolate aldol reaction reported by An-
drus and co-workers is sensitive to the oxygen protecting
era gymnorrhiza found on the Chinese coast.1 The
structures of these four ansa macrolides were elucidated
by conventional spectroscopic methods, and the identity
of divergolide A (1; Scheme 1) was further confirmed by
X-ray crystallographic analysis. It was suggested that
these ansa macrolides share a macrocyclic intermediate
possessing a hydroxy anilide core and a polyketide chain.
This intriguing finding suggested a highly divergent bio-
synthetic pathway, which was an observation that led to
the naming of these new compounds. Preliminary antibac-
terial and cytotoxic activities were undertaken.
Divergolide A (1) and D (not shown) exhibited the stron-
gest activity against Mycobacterium vaccae (Mv), and
Bacillius subtilis (Bs) and methicillin-resistant Staphylo-
coccus aureus (MRSA), respectively, whereas
divergolide D gave IC50 values of 1.0–2.0 μM for lung
cancer (LXFA 629L), pancreatic cancer (PANC-1), renal
cancer (RXF 486L), and sarcoma (Saos-2).1,2 As a contin-
uation of our work on diverted total synthesis3 of marine
macrolides, such as amphidinolide T1–T5,4 X,5b and Y,5a
and iriomoteolide-1a stereoisomers,6 we initiated a re-
search program for the total synthesis of divergolide A–D
based on a ring-closing metathesis (RCM)7 approach. As
group, which might influence chelation of the oxygen
atom with boron. Good to excellent diastereomeric ratios
(dr > 9:1) were obtained with methyl and benzyl glyco-
lates but not for the silyl analogue.10 For our purpose, a
readily removable protecting group was necessary be-
cause the diols at C11 and C12 in 13 (Scheme 2) should
be orthogonally protected for synthesis of divergolide A–
D. Therefore, we used the PMB-protected chiral glycolate
10 in the synthesis of 13. Carboxylic acid 9, prepared from
4-methoxybenzyl alcohol 8, was condensed with the
known
(1R,2S)-norephedrine
derivative
168b
(DCC/DMAP) to give 10 in 88% yield. Treatment of the
latter with c-Hex2BOTf–Et3N in CH2Cl2 at –78 °C formed
the Z-boron enolate,10a which reacted with aldehyde 17a
to furnish the syn-aldol product 11a in 89% isolated yield.
Unfortunately, the diastereomeric ratio of 11a was only
63:37, which was consistent with the result reported for
the aldol reaction of the same aldehyde using the methyl
glycolate.10a In contrast, the reaction of 10 with acrolein
17b gave the syn-aldol product 11b in 97% yield and with
a diastereomeric ratio of 89:11. Attempted reductive re-
moval of the norephedrine auxiliary in the silyl ether de-
rived from 11b using DIBAL-H resulted in the formation
of a complex mixture. Thus, the norephedrine-derived es-
ter 11b was hydrolyzed using LiOH in THF–H2O and the
resultant acid was treated with trimethylsilyldiazometh-
ane (TMSCHN2) to form the corresponding methyl ester
SYNLETT 2012, 23, 2845–2849
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317491; Art ID: ST-2012-W0701-L
© Georg Thieme Verlag Stuttgart · New York

2846
G. Zhao et al.
LETTER
15
Me
The amido hydroquinone core is the main structural unit
unique to divergolide A. We envisioned the 3,5-disubsti-
tuted benzaldehyde 19 (Scheme 3) as the precursor,
which could be derived from 1,3,5-tribromobenzene 18.
Nucleophilic aromatic substitution of 18 with 4-me-
thoxybenzyl alcohol in the presence of NaH in DMF at
120 °C produced the 3,5-dibromophenyl ether in 74%
yield.15 The latter, upon treatment with n-BuLi at
–95 °C, was selectively converted into the mono-bromo
aryllithium followed by quenching with DMF to furnish
the bromobenzaldehyde 19 in 85% yield. An anti-selec-
tive aldol reaction of the norephedrine propionate 7 with
19 in the presence of c-Hex2BOTf and Et3N8 afforded the
anti-aldol product 20 in 88% yield with a diastereomeric
ratio of 91:9. Protection of the hydroxyl group in 20 as
the silyl ether, DIBAL-H reduction of the ester moiety,
and silylation of the primary alcohol, afforded aryl bro-
Me
Me
10
11
12
8
HO
O
9
5
3
O
O
O
2
O
H
N
1
Me
Me
H
O
OH
divergolide A (1)
acetal cleavage
anti-aldol
HO HO
1
CuI-catalyzed
amidation
aldol and oxidation
O
O
Me
H
O
N
2
8
3
5
RCM
Me
9
10
12
15
Me
HO
MeO
MeO
NaH
BrCH2CO2H
Me
O
11
O
O
OH
Me
O
OH
ester cleavage
THF, reflux, 4 h
(92%)
OH
2
8
9
syn-glycolate
aldol
HO
11
Me
O
Ph
1R
MeO2C
10, c-Hex2BOTf
Et3N, CH2Cl2, –78 °C;
O
16, DCC, DMAP
15
Me
Me
2S
9
O
4
Me
8
5
CH2Cl2, r.t.
(88%)
17a or 17b
12
10
+
N
+
PMBO
Bn
10
SO2Mes
PMBO
Me
NH2
O
Me
3
4
5
Ph
R
HO
O
Ph
1R
O
Ph
1S
Br
CHO
Me
HO
2S
Me
Me
Me
2R
R
O
+
+
O
N
Bn
R
SO2Mes
PMBO
N
N
Bn
SO2Mes
16
MesO2S
Bn
OPMB
11a: R = Me (dr = 63:37; 89%)
11b: R = H (dr = 89:11; 97%)
6
7
CHO
R
Scheme 1 Retrosynthetic analysis of divergolide A (1) based on ring-
1. LiOH, THF–H2O (4:1);
then 1 M HCl, 0 °C (87%)
2. TMSCHN2, PhH–MeOH (98%)
3. TBSOTf, 2,6-lutidine
17a: R = Me
17b: R = H
closing metathesis (RCM) at C9 and C10
for 11b
in excellent overall yield. The latter was further silylated
to furnish the fully protected methyl ester 12. Partial re-
duction of 12 using DIBAL-H at –78 °C formed the alde-
hyde which, without isolation, was transformed into 1,1-
dibromoalkene 14 under the Corey–Fuchs conditions11 in
86% overall yield for the two steps. We attempted to per-
form double B-alkyl Suzuki–Miyaura cross-coupling of
14 with MeB(OH)2 using our Pd(OAc)2–Aphos catalyst,12
but, instead of 13, the unexpected product 15b was isolat-
ed in 33% yield (not optimized). Formation of the cyclo-
pentene derivative 15b is interesting and might involve an
intramolecular Heck reaction to produce the bromo cyclo-
pentene intermediate 15a, followed by an intermolecular
B-alkyl Suzuki–Miyaura cross-coupling of 15a with
MeB(OH)2. We have demonstrated that both types of re-
actions can be catalyzed by our Pd(OAc)2–Aphos cata-
lyst.12,13 The target C10–C15 diene diol 13 was finally
CH2Cl2, –78 °C (98%)
TBSO
11
TBSO
O
1. DIBAL-H, CH2Cl2
–78 °C
Me
OMe
12
10
2. Ph3P+CH(Me)2I–
n-BuLi, 0 °C
PMBO
13
Me
PMBO
12
(88% for 2 steps)
i-Pr2N
Aphos =
O
1. DIBAL-H, CH2Cl2, –78 °C
2. CBr4, Ph3P, 2,6-lutidine
CH2Cl2, 0 °C
PCy2
(86% for 2 steps)
TBSO
X
Pd(OAc)2–Aphos
Br
MeB(OH)2, K3PO4
OTBS
OPMB
THF–H2O (10:1)
60 °C, 20 h
(15b, 33%)
PMBO
14
Br
15a: X = Br
15b: X = Me
synthesized by
a Wittig reaction of the ylide,
Ph3P=CH(Me)2, in 88% overall yield from ester 12
(Scheme 2).14
Scheme 2 Synthesis of the C10–C15 fragment 13
Synlett 2012, 23, 2845–2849
© Georg Thieme Verlag Stuttgart · New York

LETTER
Toward the Total Synthesis of Divergolide A
2847
ylethylenediamine (catalyst C) was found to be efficient
for promoting the amidation, however, substrate conver-
sion demonstrated a remarkable solvent dependence (Ta-
ble 1, entries 3–5). Upon reacting at 110 °C for 24 hours
in 1,4-dioxane, the product 22a was isolated in 91% yield.
Similarly, the reaction of 21 with trifluoroacetamide fur-
nished the product 22b in 94% yield (Table 1, entry 6).
Br
Br
Br
CHO
1. NaH, 4-MeOC6H4CH2OH
DMF, 120 °C, 4 h (74%)
2. n-BuLi (1.1 equiv), THF
–95 °C; then DMF (85%)
Br
OPMB
18
19
OH
O
Ph
1S
Br
Me
2R
O
7, c-Hex2BOTf, Et3N
Table 1 Pd- or Cu-Catalyzed Amidation of 21a
Me
N
CH2Cl2, –78 °C; then 19
Bn
SO2Mes
(dr = 91:9, 88%)
Entry Cat.b Base
Solvent
Time
(h)
Product Yield
(%)c
OPMB
20
O
Ph
1S
1. TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C (98%)
2. DIBAL-H, CH2Cl2
–78 °C (96%)
3. TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C (99%)
Me
O
2R
1
2
3
4
5
6
A
B
C
C
C
C
K2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
toluene
1.5
20e
24
22a
22a
22a
22a
22a
22b
17d
trace
22f
71g
91
Me
N
Bn
SO2Mes
DMF
7
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
17
OTBS
Me
O
Br
24
OTBS
R
NH ,
NHMe
NHMe
2
24
94
CuI, K2CO3
1,4-dioxane, 100 °C, 24 h
OPMB
a The reaction was carried out at 110 °C in the given base (3 equiv),
solvent, and catalyst.
21
OTBS
OTBS
b Catalyst A: Pd(OAc)2 (3 mol%) and BINAP (5 mol%); Catalyst B:
CuI (5 mol%) and 1,10-phenanthroline (10 mol%); Catalyst C: CuI (5
mol%) and N,N′-dimethylethylenediamine (10 mol%).
c Isolated yield.
H
R
N
for 22a:
DDQ, MeCN, pH 7
O
Me
(93%)
d Many spots were observed by TLC analysis of the reaction.
e Reaction performed at 120 °C.
OPMB
22a: R = Me (91%)
22b: R = CF3 (94%)
f With recovery of 21 in 65% yield.
OTBS
Me
H
g With recovery of 21 in 24% yield.
Me
N
OTBS
O
Cleavage of the PMB ether in 22a by treatment with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave
amido phenol 23 in 93% yield. Oxidation of 23 to quinone
24 was examined using a variety of oxidants16 and the re-
sults are summarized in Table 2. All oxidants failed in the
oxidation except for 2,6-dicarboxypyridinium fluorochro-
mate (2,6-DCPFC), which was prepared from 2,6-dicar-
boxypyridine, 40% aqueous HF, and CrO3.17 Treatment of
the amido phenol 23 with 2,6-DCPFC for 1 min at room
temperature afforded the amido quinone 24 in 79% isolat-
ed yield (Scheme 3 and Table 2, entry 9).18 Finally, reduc-
tion of 24 using Na2S2O4 furnished the model amido
hydroquinone core 25 in 99% yield.19
OH
23
OH OTBS
H
N
Me
OTBS
2,6-DCPFC
MeCN (79%)
O
Me
OH
O
OTBS
25
H
N
Me
OTBS
Na2S2O4
(99%)
O
Me
O
24
Scheme 3 Synthesis of the amido hydroquinone core 25
In summary, we have synthesized the C10–C15 diene syn-
diol fragment and the amido hydroquinone core appended
with the C1–C3 anti-aldol subunit. The norephedrine-
based syn-selective glycolate aldol10 and the anti-selective
aldol8 reactions were used to secure four among the five
stereogenic centers in divergolide A (1). Moreover, the
CuI-catalyzed amidation reaction was utilized for installa-
tion of the anilide intermediate. The latter was then trans-
formed into the amido hydroquinone core through 2,6-
DCPFC-mediated oxidation of the meta-amidophenol.
The results described above should lay down a firm foun-
dation for advancement of our total synthesis of
divergolide A based on the proposed ring-closing metath-
esis strategy.
mide 21 in excellent overall yield. With 21 in hand, we
investigated the metal-catalyzed model amidation reac-
tions; the results are summarized in Table 1. The reac-
tion of acetamide with 21 in the presence of Pd(OAc)2
and BINAP (catalyst A) in toluene at 110 °C for
1.5 hours formed many new components, from which
the desired amidation product 22a was isolated in only
17% yield (Table 1, entry 1).
The same amidation catalyzed by CuI and 1,10-phenanth-
roline (catalyst B) did not form the product, although the
aryl bromide 21 underwent decomposition (Table 1, entry
2). Fortunately, the combination of CuI with N,N′-dimeth-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2845–2849

2848
G. Zhao et al.
LETTER
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock, R.
R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592.
(e) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
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K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005,
44, 4490. (h) Gradillas, A.; Pérez-Castells, J. Angew. Chem.
Int. Ed. 2006, 45, 6086. (i) Schrodi, Y.; Pederson, R. L.
Aldrichimica Acta 2007, 40, 45. (j) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243. (k) Handbook of
Metathesis; Vol. 1–3; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003. (l) Kotha, S.; Dipak, M. K. Tetrahedron
2012, 68, 397.
Table 2 Selected Results for the Oxidation of 23 to Amido Quinone
24
Entry [O]a
Solvent
Temp Time
Yield
(%)b
(°C)
(h)
1
2
3
4
5
6
7
8
9
CAN
MeCN–H2O
CH2Cl2–H2O
CH2Cl2
20
20
20
0
3
3
3
NR
NR
NR
DDQ
IBX
K2S2O8
CrO3
THF–H2O
CH2Cl2–H2O
THF–H2O
MeCN–H2O
DMF
10 (min) NR
5 (min) NR
(8) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (b) Inoue, T.; Liu, J.-F.; Buske, D.; Abiko,
A. J. Org. Chem. 2002, 67, 5250. (c) Abiko, A. Acc. Chem.
Res. 2004, 37, 387.
(9) For a review, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (b) See also: Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421.
(10) (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.;
Meredith, E. L. Tetrahedron Lett. 2001, 42, 7197.
(b) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Soma
Sekhar, B. B. V.; Hicken, E. J. Org. Lett. 2002, 4, 3549.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(12) (a) Dai, W.-M.; Li, Y.; Zhang, Y.; Lai, K. W.; Wu, J.
Tetrahedron Lett. 2004, 45, 1999. (b) Dai, W.-M.; Zhang, Y.
Tetrahedron Lett. 2005, 46, 1377. (c) Dai, W.-M.; Li, Y.;
Zhang, Y.; Yue, C.; Wu, J. Chem.–Eur. J. 2008, 14, 5538.
(d) Sun, L.; Dai, W.-M. Tetrahedron 2011, 67, 9072. (e) See
also ref. 5b.
0
KMnO4
BTI
20
0
1
3
5
NR
NR
NR
PbO2
20
20
2,6-DCPFC
MeCN
1 (min) 79
a Oxidants [O]: CAN = cerium(IV) ammonium nitrate; IBX = 2-io-
doxybenzoic acid; BTI = [bis(trifluoroacetato)iodo]benzene; 2,6-
DCPFC = 2,6-dicarboxypyridinium fluorochromate.
b Isolated yield. NR = no reaction.
Acknowledgment
The Laboratory of Asymmetric Catalysis and Synthesis was esta-
blished under the Cheung Kong Scholars Program of The Ministry
of Education of China.
(13) For asymmetric Heck reaction using atropisomeric Aphos,
see: Dai, W.-M.; Yeung, K. K. Y.; Wang, Y. Tetrahedron
2004, 60, 4425.
(14) Synthesis of Diene 13 from Ester 12: To a solution of 12
(285.4 mg, 0.75 mmol) in anhydrous CH2Cl2 (8 mL) cooled
in a dry ice–acetone bath (–78 °C) under an N2 atmosphere
was added slowly a solution of DIBAL-H (1 M in toluene,
1.1 mL, 1.1 mmol). The resultant mixture was stirred for
1.5 h at the same temperature, then MeOH (2 mL) was added
to quench the reaction. The reaction mixture was allowed to
warm to –40 °C, then a saturated aqueous solution of
potassium sodium tartrate was added followed by stirring at
r.t. until the mixture became clear. The mixture was
extracted with CH2Cl2 (5 × 3 mL) and the combined organic
layer was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give the crude
aldehyde. The latter was dissolved in anhydrous THF (2 mL)
for use in the next step without further purification.
To a solution of Ph3P+CH(Me)2I– (486.3 mg, 1.13 mmol) in
anhydrous THF (10 mL) cooled in an ice–water bath (0 °C)
under an N2 atmosphere was added n-BuLi (1.5 M in hexane,
0.74 mL, 1.1 mmol) followed by stirring at the same
temperature for 30 min. After cooling the resultant solution
of the ylide to –78 °C, the above THF solution of the
aldehyde was added and the resultant mixture was stirred for
2 h at –78 °C. The reaction was quenched by the addition of
saturated aqueous NH4Cl at –78 °C and the reaction mixture
was allowed to warm to r.t. and extracted with EtOAc (8 × 3
mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO2;
EtOAc–petroleum ether, 1:120) to give diene 13 (248.6 mg,
88% yield for 2 steps from 12).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) For isolation and structures of divergolide A–D, see: Ding,
L.; Maier, A.; Fiebig, H.-H.; Görls, H.; Lin, W.-H.; Peschel,
G.; Hertweck, C. Angew. Chem. Int. Ed. 2011, 50, 1630.
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(4) (a) Li, H.; Wu, J.; Luo, J.; Dai, W.-M. Chem.–Eur. J. 2010,
16, 11530. (b) Wu, D.; Li, H.; Jin, J.; Wu, J.; Dai, W.-M.
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Synlett 2011, 3036.
(5) (a) Dai, W.-M.; Chen, Y.; Jin, J.; Wu, J.; Lou, J.; He, Q.
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(6) (a) Liu, Y.; Wang, J.; Li, H.; Wu, J.; Feng, G.; Dai, W.-M.
Synlett 2010, 2184. (b) Liu, Y.; Feng, G.; Wang, J.; Wu, J.;
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(7) For selected reviews on RCM, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012. (c) Trnka, T. M.;
Compound 13: Colorless oil; [α]D20 +3.78 (c 1.20, CHCl3);
Rf = 0.40 (EtOAc–petroleum ether, 1%); IR (film): 2954,
2925, 2854, 1614, 1514, 1249, 1064, 1039 cm–1. 1H NMR
Synlett 2012, 23, 2845–2849
© Georg Thieme Verlag Stuttgart · New York

LETTER
(400 MHz, CDCl3): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.85 (d, J
Toward the Total Synthesis of Divergolide A
2849
80–81 °C (CH2Cl2–pentane); [α]D20 +53.60 (c 1.10, CHCl3);
Rf = 0.40 (EtOAc–petroleum ether, 2.4%). IR (film): 3380,
3296, 2957, 2925, 2854, 1714, 1650, 1606, 1502, 1255,
1099 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.06 (br s, 1 H,
NH), 7.50 (d, J = 2.8 Hz, 1 H), 6.70 (dd, J = 2.0, 1.2 Hz,
1 H), 4.73 (d, J = 4.8 Hz, 1 H), 3.57 (dd, J = 10.0, 5.6 Hz,
1 H), 3.44 (dd, J = 10.0, 5.2 Hz, 1 H), 2.22 (s, 3 H), 1.94–
1.91 (m, 1 H), 0.90 (s, 9 H), 0.89 (d, J = 6.0 Hz, 3 H), 0.81
(s, 9 H), 0.06 (s, 3 H), –0.05 (s, 3 H), –0.07 (s, 3 H), –0.09 (s,
3 H). 13C NMR (100 MHz, CDCl3): δ = 188.2, 182.6, 169.1,
148.2, 138.1, 133.3, 114.5, 69.1, 63.5, 42.4, 25.8 (3×), 25.8
(3×), 24.8, 18.3, 18.0, 14.2, –4.6, –5.2, –5.5, –5.6. HRMS
(EI+): m/z [M+] calcd for C24H43NO5Si2: 481.2680; found:
481.2682.
= 8.8 Hz, 2 H), 5.87 (ddd, J = 16.8, 10.4, 5.2 Hz, 1 H), 5.24
(d, J = 17.2 Hz, 1 H), 5.09 (d, J = 10.0 Hz, 1 H), 5.07 (d, J =
7.6 Hz, 1 H), 4.52 and 4.31 (ABq, J = 11.6 Hz, 2 H), 4.17
(dd, J = 5.6, 5.2 Hz, 1 H), 3.95 (dd, J = 9.6, 6.4 Hz, 1 H),
3.80 (s, 3 H), 1.76 (s, 3 H), 1.59 (s, 3 H), 0.88 (s, 9 H), 0.03
(s, 3 H), 0.02 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
158.8, 137.9, 137.4, 131.2, 129.2 (2×), 122.5, 114.9, 113.5
(2×), 78.4, 75.8, 69.4, 55.2, 26.0, 25.9 (3×), 18.7, 18.3, –4.7,
–4.8. HRMS (EI+): m/z [M+] calcd for C22H36O3Si:
376.2434; found: 376.2433.
(15) Jeges, G.; Nagy, T.; Meszaros, T.; Kovacs, J.; Dorman, G.;
Kowalczyk, A.; Goodnow, R. A. J. Comb. Chem. 2009, 11,
327.
(16) Fremy’s salt (potassium nitrosodisulfonate) was not
available to us and it was not tested in the oxidation of 23.
For recent examples, see: (a) Bouaziz, Z.; Ghérardi, A.;
Régnier, F.; Sarciron, M.-E.; Bertheau, X.; Fenet, B.;
Walchshofer, N.; Fillion, H. Eur. J. Org. Chem. 2002, 1834.
(b) Jana, C. K.; Scopelliti, R.; Gademann, K. Chem.–Eur. J.
2010, 16, 7692. (c) Jadhav, V. D.; Duerfeldt, A. S.; Blagg, B.
S. J. Bioorg. Med. Chem. Lett. 2009, 19, 6845.
(17) (a) Tajbakhsh, M.; Hosseinzadeh, R.; Sadatshahabi, M.
Synth. Commun. 2005, 35, 1547. (b) Urimi, A. G.;
Alinezhad, H.; Tajbakhsh, M. Acta Chim. Slov. 2008, 55,
481.
(18) Synthesis of Quinone 24 via Oxidation of Phenol 23: To a
solution of phenol 23 (257.0 mg, 0.55 mmol) in MeCN (4
mL) at r.t. was quickly added an aqueous solution of 2,6-
DCPFC (334 mg in 1.1 mL H2O, 1.1 mmol), prepared
according to the literature procedure.17a After stirring for
1 min, the reaction was quenched by addition of saturated
aqueous NaHCO3. The reaction mixture was extracted with
EtOAc (10 × 3 mL) and the combined organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (SiO2; EtOAc–petroleum ether, 1:40) to
give quinone 24 (209.3 mg, 79% yield) as a yellow solid. Mp
(19) Synthesis of Hydroquinone 25 via Reduction of 24: To a
yellow solution of quinone 24 (144.5 mg, 0.30 mmol) in a
mixed solvent of THF–Et2O–H2O (6 mL; v/v/v = 1:1:1) at
r.t., was added Na2S2O4 (525 mg, 3 mmol) in portions with
vigorous stirring until the yellow color of the mixture
disappeared. The reaction mixture was diluted with H2O (5
mL) and extracted with EtOAc (5 × 3 mL). The combined
organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO2; EtOAc–
petroleum ether, 1:3) to give hydroquinone 25 (145.2 mg,
99% yield) as a colorless oil. Rf = 0.50 (EtOAc–PE, 33%).
[Note: Hydroquinone 25 was oxidized to quinone in air
during acquisition of 13C NMR data. No optical rotation data
was taken for this sample]. 1H NMR (400 MHz, CDCl3): δ =
8.19 (s, 1 H, NH), 8.10 (s, 1 H, OH), 7.91 (s, 1 H, OH), 7.55
(s, 1 H), 6.32 (s, 1 H), 4.84 (d, J = 6.0 Hz, 1 H), 3.61 (dd, J
= 9.6, 4.4 Hz, 1 H), 3.43 (dd, J = 9.2, 7.2 Hz), 2.34 (s, 3 H),
2.15–2.07 (m, 1 H), 0.94 (s, 9 H), 0.89 (s, 9 H), 0.74 (d, J =
6.8 Hz, 3 H), 0.11 (s, 3 H), 0.9 (s, 6 H), –0.05 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 169.3, 149.7, 137.0, 126.9,
126.0, 109.8, 106.2, 64.7, 60.4, 42.4, 25.9 (4×), 25.7 (3×),
24.8, 18.3, 18.1, –5.1, –5.3 (2×), –5.5. HRMS (EI+): m/z
[M+] calcd for C24H45NO5Si2: 483.2836; found: 483.2834.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2845–2849

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