Synthetic approaches to the bottom half fragment for bryostatin 11

Article abstract of DOI:10.1055/s-0030-1260784

An approach towards the stereoselective synthesis of the bottom half fragment of bryostatin 11 is described. Key steps -include asymmetric aldol and Saksena-Evans reduction reactions -to construct multiple stereogenic centers and thioketalization-lactoniz

Full text of DOI:10.1055/s-0030-1260784

LETTER
1555
Synthetic Approaches to the Bottom Half Fragment for Bryostatin 11
Synthesis of the
Bo
ttom
Half
F
o
ragment
f
or
Br
yostatin 11o Nakagawa-Goto,*1 Michael T. Crimmins
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Fax +1(919)9663893; E-mail: goto@email.unc.edu
Received 31 January 2011
strategies for our proposed C-ring intermediate 3 are
shown in Scheme 1. In both strategies 1 and 2 (Scheme 2),
the C21 exocyclic olefin is incorporated at the final stage
of the synthesis. The cyclic intermediate 4 in strategy 1 is
provided from linear unit 5, derived from (R)-isobutyl lac-
tate (6) using combinations of asymmetric allylations. In
alternative strategy 2, the C19 five-carbon side chain of 7
is added to C-ring intermediate 8, which is protected at the
C21 position with a thioketal, constructed through
Nakata’s thioketalization–lactonization14 of 9. Compound
9 is obtained by cyclization of the linear C21–C27 unit 10,
synthesized from the same starting material 6 as men-
tioned above using asymmetric aldol condensation and
Saksena–Evans reduction.15
Abstract: An approach towards the stereoselective synthesis of the
bottom half fragment of bryostatin 11 is described. Key steps
include asymmetric aldol and Saksena–Evans reduction reactions
to construct multiple stereogenic centers and thioketalization–
lactonization reactions to form the thioketal-protected C-ring.
Key words: bryostatin 11, bottom half fragment, asymmetric aldol,
Saksena–Evans reduction, thioketalization–lactonization
The bryostatins,2 isolated from marine bryozoan Bugula
neritina Linnaeus and Amathia convoluta, are interesting
synthetic targets, because of their unique structure as well
as biological activities resulting from their mechanism of
action, binding to protein kinase C (PKC). Currently, bryo-
statin 1 (1) is under investigation as a potent antineoplas-
tic agent in numerous human clinical trials.3 In addition, 1
has expectations as a possible anti-Alzheimer’s disease
modifying drug.4 Twenty kinds of bryostatins have been
reported to date.5 Their common skeleton contains a bryo-
pyran ring system, which consists of a 26-membered ring
containing three individual pyran rings. The main differ-
ences among the bryostatins occur at the C7 and C20
functional groups. Numerous synthetic studies directed
toward the byrostatins have been reported to date.2
Among them, the first total synthesis of bryostatin 7 was
completed by Masamune in 1990.6 Subsequently, bryo-
statins 2, 3, 16, and 1 were prepared by various groups, in-
cluding Evans in 1998,7 Nishiyama–Yamamura in 2000,8
Hale in 2006,9 Trost in 2008,10 and Keck in 2011.11 Since
Wender and his group initiated the development of simpli-
fied analogues with potent PKC binding properties and se-
lectivity, some potent simplified analogues have also been
discovered.12 However, bryostatins without an oxygen
functionality at C20, such as bryostatin 11 (2, Figure 1),
have not yet been synthesized. Herein, we describe our
approach to the bottom half fragment for construction of
2.
HO
11
OAc
MeO2C
9
7
A
13
B
top half fragment
(C1–C16)
O
O
1
O
16
OH
H
OH
25
O
O
C
R
OH
21
CO2Me
bottom half fragment
(C17–C27)
bryostatin 1 (1) R = OC(O)CH=CHCH=CHC3H7
bryostatin 11 (2) R = H
Figure 1
Lactate 6 was protected as the benzyl ether and subse-
quently reduced with DIBAL to supply the corresponding
aldehyde 11 in good yield. SnCl4-promoted allylation16 of
11 provided 12 in 77% yield with 17:1 diastereoselectivi-
ty. Sequential protection of the hydroxy group as the PMB
ether and oxidative cleavage of the terminal olefin afford-
ed aldehyde 13.17 anti-Selective allylation of 13 with allyl
trimethylsilane in the presence of BF3·OEt2 generated the
allylic alcohol 1417a in 78% yield based on recovered
starting material with good diastereoselectivity (anti/
syn = 7.5:1). Other attempts to produce the C23 stereo-
genic center using Brown’s method,17b Lewis acid pro-
moted Mukaiyama aldol condensation, and asymmetric
aldol reactions with thiazolidinethiones as chiral auxiliary
showed less selectivity or no reaction (Scheme 3). The hy-
droxy group of 14 was silylated with TESCl, and then the
terminal olefin was oxidatively cleaved to produce alde-
hyde 15. Aldol condensation between 15 and ketones 16a
and 16b furnished the C16–C27 linear fragments 17a and
The popular and classical approach to the byrostatins has
involved a disconnection between the C16–C17 double
bond and lactone to divide the molecule into top (C1–
C16) and bottom (C17–C25) half fragments. Our synthet-
ic strategy also involves the coupling of the top and bot-
tom half fragments through a Yamaguchi lactonization
and a ring-closing olefin metathesis (RCM)13 or Julia cou-
pling to form the C16–17 double bond. The synthetic
SYNLETT 2011, No. 11, pp 1555–1558
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260784; Art ID: S01111ST
© Georg Thieme Verlag Stuttgart · New York

1556
K. Nakagawa-Goto, M. T. Crimmins
LETTER
17b, respectively. The ketone 16a was prepared from pre-
nyl bromide in two steps (1: MeCHO, Zn, sat. aq NH4Cl,
THF, 2: Swern oxidation, 60% overall yield), and 16b was
derived from 2,2-dimethyl-1,3-propanediol in four steps
(1: TsCl, pyridine, 67%, 2: PhSH, NaH, 87%, 3: MCPBA,
93%, 4: Swern oxidation, 95%).7 Unfortunately, the acid-
catalyzed cyclization of 17a and 17b provided <30% yield
of the desired compound 18a and 18b, respectively, under
various conditions. Presumably, the presence of the C21
hydroxy group and steric hindrance around C19 impeded
the formation of 18 to produce 18c–e by dehydration. Al-
though the resulting double bond is necessary in the syn-
thesis of bryostatins with an alkoxy group at C206 as well
as bryostains 16 and 17 with a double bond at C19–C20,
it is not wanted in the synthesis of our target bryostatin 11
without an alkoxy group at C20. Therefore, we switched
to an alternative approach for the synthesis of the bottom
half fragment.
OH
O
OPMB
OHC
a, b
i-BuO2C
d, e
c
OBn
11
OH
6
13
12 OBn
OBn
O
OR OPMB
OH OPMB
i
g, h
f
O
X
15 R = TES
OBn
14
OBn
16
X
OR
OMe
O
O
OH
OPMB
H
j
OPMB
OBn
X
21
a X = CH2=CH2
b X = CH2SO2Ph
OBn
17
18
OH
X
X
H
OMe
O
H
O
OPMB
OBn
OPMB
OBn
18c R = H
18d R = Me
OR
18e
X
X
OH
H
OMe
O
H
Scheme 2 Synthetic route (strategy 1) Reagents and conditions: (a)
BnOC(NH)CCl3, TMSOTf, CH2Cl2, 0 °C to r.t., 5 h (89%); (b)
DIBAL, Et2O, –78 °C, 1.5 h (90%); (c) AllylTMS, SnCl4, CH2Cl2,
–78 °C, 15 min (77%, anti/syn = 17:1); (d) PMBCl, KH, THF, r.t.,
overnight (99%); (e) 1% OsO4 in H2O, NMO, NaIO4, THF, H2O, r.t.,
2 h (87%) (f) AllylTMS, BF3·OEt2, toluene, –78 °C, 30 min (62%,
brsm 78%, 7.5:1); (g) TESCl, imidazole, DMF, r.t., overnight (91%);
(h) 1% OsO4 in H2O, NMO, NaIO4, THF, H2O, r.t., 2 h (72%); (i)
LDA, 16, THF, –78 °C, 1.5 h then 15, –78 °C, 15 min (89% for 17a,
81% for 17b); (j) H+ (PPTS, PTSA, CSA, or Ph3PHBr), solvents
(THF, CH2Cl2, or MeCN); brsm: based on recovered starting materi-
al.
25
26
O
C
OH
OH
OP
OP
strategy 1
23
21
X = CH2=CH2 for RCM
or CH2SO2Ph for Julia
4
OH
3
CO2Me
strategy 2
X
OH
H
25
O
OP
OP
O
OH
OP
X
OP
S
S
OP
5
7
OH OPMB
1) (2-ICr)2B-allyl
2) H2O2, NaOH
26
i-BuO2C
23
83% (anti/syn = 6:1)
6
H
S
OH
14
OH OH
OBn
O
O
OP
OP
R = PMB
OH OPMB
OTBS
X
Lewis acid
23
O
OR
RO2C
OP
S
O
10
8
OBn
OBn
13
Ac
N
R'
OP
H
S
O
OH OTBS
MeO
O
P: protecting group
S
26
R = TBS
t-BuO2C
21
Xc
TiCl4, DIEA
R' = Bn (69%, anti/syn = ca. 1:1)
R' = i-Pr (84%, anti/syn = ca. 2.4:1)
23
OBn
9
OH
Scheme 1 Retrosynthetic plan for bottom fragment of bryostatin 11
Scheme 3 Other trials for the construction of C23 stereogenic center
Thioester 22 was converted to 20 by aldol reaction with or
without silyl protection. Reduction of 20 under Saksena–
Evans conditions15 supplied anti-1,3-diol 23, which was
cyclized to lactone 2421 with trifluoroacetic acid. Methyl
acetal 2522 was obtained via protection of the hydroxy
group as the TES ether, insertion of tert-butyl acetate into
the ketone with LDA, followed by treatment with methyl-
orthoformate under acidic conditions. Lactonization–
thioketalization14 of 25 with 1,3-propanedithiol in the
presence of BF3·OEt2 in CH2Cl2–MeNO2 (1:2, v/v) solu-
tion gave 2623 in 91% yield, while the use of CH2Cl2 as
solvent gave an unsatisfactory yield. After protecting 26
Because a hydroxy group on C21 might prohibit the de-
sired C-ring formation, we focused on the preparation of
28, with a thioketal protecting group at C21, as shown in
Scheme 4. TiCl4-promoted asymmetric Mukaiyama aldol
reaction of 11 with bis(trimethylsilyl)dienol ether (19,
R = t-Bu) led to hydroxyketone 20 with 11:1 diastereo-
selectivity, while the use of Chan’s diene18 (19, R = Me)
gave less diastereoselectivity (ca. 4:1).19 Alternatively,
treatment of 11 with tert-butyldimethylenolsilane 21,20
derived from tert-butylthioacetate, in the presence of
SnCl4 provided b-hydroxyketoester 22 in good yield and
diastereoselectivity (syn/anti = 13.5:1).
Synlett 2011, No. 11, 1555–1558 © Thieme Stuttgart · New York

LETTER
Synthesis of the Bottom Half Fragment for Bryostatin 11
1557
as the TBS ether, Grignard reaction of the resulting 2724
with prenyl magnesium bromide in the presence of
CeCl325 provided the desired compound 28 in good yield
with moderate selectivity (b/a = 4:1).
Products I, In Recent Progress in Medical Plants, Vol. 15;
Govil, J. N.; Singh, V. K.; Ahmad, K.; Sharma, R. K., Eds.;
Studium Press: New Delhi, 2006, 363. (e) Hale, K. J.;
Manaviazar, S. Chem. Asian J. 2010, 5, 704. (f) Green, A.
P.; Hardy, S.; Lee, A. T. L.; Thomas, E. J. Phytochem. Rev.
2010, 9, 501. (g) Szpilman, A. M.; Carreira, E. M. Angew.
Chem. Int. Ed. 2010, 49, 9592.
Because the RCM method has been tried unsuccessfully
to form the C16–C17 double bond,13 we also considered
the preparation of a phenyl sulfone from a vinyl group in
four steps [1: OsO4, NMO, 2: Pd(OAc)4, 3: NaBH4, 4:
Bu3P, (PhS)2]2e for the Julia coupling procedure. Subse-
quent completion of the bottom half fragment is in
progress for the ultimate synthesis of bryostatin 11.
(3) For current information, see: http://clinicaltrials.gov.
(4) (a) Etcheberrigaray, R.; Tan, M.; Dewachter, I.; Kuip_eri,
C.; Van der Auwera, I.; Wera, S.; Qiao, L.; Bank, B.; Nelson,
T. J.; Kozikowski, A. P.; Van Leuven, F.; Alkon, D. L. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 11141. (b) Alkon, D. L.;
Sun, M.-K.; Nelson, T. J. Trends Pharmacol. Sci. 2007, 28,
51.
(5) (a) Pettit, G. R. J. Nat. Prod. 1996, 59, 812; and references
cited therein. (b) Lopanik, N.; Gustafson, K. R.; Lindquist,
N. J. Nat. Prod. 2004, 67, 1412.
(6) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem.
Soc. 1990, 11, 27407.
OTBS
21
O
OH
O
OH
b or c
St-Bu
RO2C
11
t-BuS
a
20
22
OBn
OBn
syn/anti
TMSO
OTMS
OR
R = Me 4 :1
R = t-Bu 11:1
19
d
(7) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M. Angew.
Chem. Int. Ed. 1998, 37, 2354. (b) Evans, D. A.; Carter, P.
H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540.
OBn
OBn
t-BuO2C
OMe
O
OH OH
H
H
O
O
e
g–i
f
(8) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.;
Nishiyama, S.; Yamamura, S. Angew. Chem. Int. Ed. 2000,
39, 2290.
OBn
t-BuO2C
23
24
25
OH
OH
(9) Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone,
M. G.; Aliev, A. E.; Hale, K. J. Org. Lett. 2006, 8, 4477.
(10) (a) Trost, B. M.; Dong, G. Nature (London) 2008, 456, 485.
(b) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2010, 132,
16403.
H
O
OH
O
H
S
O
OR
OTBS
OBn
j
l
OBn
S
S
S
(11) Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.;
26 R = H
27 R = TBS
k
28
Covel, J. A. J. Am. Chem. Soc. 2011, 133, 744.
(12) (a) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.;
Brenner, S. E.; Clarke, M. O.; Horan, J. C.; Kan, C.; Lacote,
E.; Lippa, B.; Nell, P. G.; Turner, T. M. J. Am. Chem. Soc.
2002, 124, 13648. (b) Hale, K. J.; Frigerio, M.; Manaviazar,
S.; Hummersone, M. G.; Fillingham, I. J.; Barsukov, I. G.;
Damblon, C. F.; Gescher, A.; Roberts, G. C. K. Org. Lett.
2003, 5, 499. (c) Trost, B. M.; Yang, H.; Thiel, O. R.;
Frontier, A. J.; Brindle, C. S. J. Am. Chem. Soc. 2007, 129,
2206. (d) Keck, G. E.; Li, W.; Kraft, M. B.; Kedei, N.;
Lewin, N. E.; Blumberg, P. M. Org. Lett. 2009, 11, 2277.
(e) See also ref. 2e–g.
(13) Thomas and Trost reported an unsuccessful trial of the RCM
method for C16–C17 double-bond construction: (a) Ball,
M.; Bradshaw, B. J.; Dumeunier, R.; Gregson, T. J.;
MacCormick, S.; Omori, H.; Thomas, E. J. Tetrahedron
Lett. 2006, 2223. (b) Trost, B. M.; Yang, H.; Thiel, O. R.;
Frontier, A. J.; Brindle, C. S. J. Am. Chem. Soc. 2007, 129,
2206.
Scheme 4 Reagents and conditions: (a) 21, SnCl4, CH2Cl2, –78 °C,
1 h (82%, syn/anti = 13.5:1); (b) LDA, MeCO2t-Bu, THF, –78 °C, 1
h, then 22, –78 °C to 0 °C, 1 h (55%); (c) i)TESCl, imidazole, DMF,
r.t., 2.5 h (93%); ii) LDA, MeCO2t-Bu, THF, –78 °C, 1 h then TES
ether, –78 °C to 0 °C, 2 h (92%); iii) TBAF, THF (84%); (d) Chan’s
diene (19), TiCl4, CH2Cl2, –78 °C, 30 min (50%); (e)
Me4NHB(OAc)3, AcOH–MeCN, –35 °C, 20 h (88%); (f) TFA,
CH2Cl2, r.t., 3 h (95%); (g) TESOTf, 2,6-lutidine, –78 °C, 30 min
(82%); (h) LDA, MeCO2t-Bu, THF –78 °C, 1 h, then 24 (97%); (i)
CH(OMe)3, PPTS, PhH–MeOH, r.t., 2 h (91%); (j) HS(CH2)3SH,
BF3·OEt2, CH2Cl2–MeNO2 (2:1), –45 °C, 1 h (91%); (k) TBSCl,
im-idazole, DMF, r.t., overnight (87%); (l) PrenylMgBr, CeCl3, THF,
–45 °C to –10 °C (88%, brsm 24%, a/b = 1:4)
Acknowledgment
K.N-Goto acknowledges support from a research fellowship from
Uehara Memorial Foundation in Japan.
(14) Nakata, T.; Takao, S.; Fukui, M.; Tanaka, T.; Oishi, T.
Tetrahedron Lett. 1983, 24, 3873.
(15) (a) Saksena, A. K.; Mangiaraeina, P. Tetrahedron Lett. 1983,
24, 273. (b) Evans, D. A.; Dimare, M. J. Am. Chem. Soc.
1986, 108, 2476.
References and Notes
(1) Current address: K. Nakagawa-Goto, School of Pharmacy,
University of North Carolina at Chapel Hill, Chapel Hill,
NC 27599, USA.
(16) (a) Heathcock, C. H.; Kiyooka, S.; Blumenkopf, T. A.
J. Org. Chem. 1984, 49, 4214. (b) Gerlach, K.; Quitschalle,
M.; Kalesse, M. Tetrahedron Lett. 1999, 40, 3533.
(17) The constructions of similar aldehydes via anti-selective
allylation have been reported by other groups. See: (a) De
Brabander, J.; Vandewalle, M. Synthesis 1994, 855.
(b) Wender, P. A.; Brabander, J. D.; Harran, P. G.; Jimenez,
J. M.; Koehler, M. F. T.; Lippa, B.; Park, C. M.; Shiozaki,
M. J. Am. Chem. Soc. 1998, 120, 4534. (c) Keck, G. E.;
Truong, A. P. Org. Lett. 2005, 7, 2149.
(2) For recent reviews on bryostatin chemistry and biology, see:
(a) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841.
(b) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.;
Frigerio, M. Nat. Prod. Rep. 2002, 413. (c) Sun, M. K.;
Alkon, D. L. CNS Drug Rev. 2006, 12, 1. (d) Abadi, G.;
Palen, W.; Geddings, J.; Irwin, T.; Kasali, N.; Colyer, J.;
Goodson, F.; Sith, J.; Jone, K.; Hester, J.; Noble, L.;
Groundwater, P. W.; Phillips, D.; Manning, T. J. Natural
Synlett 2011, No. 11, 1555–1558 © Thieme Stuttgart · New York

1558
K. Nakagawa-Goto, M. T. Crimmins
LETTER
extracted with EtOAc (3×). The combined organic layers
(18) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J.
Can. J. Chem. 1983, 61, 688.
(19) (a) Baxter, J.; Mata, E. G.; Thomas, E. J. Tetrahedron Lett.
1998, 54, 14359. (b) Voight reported that the use of TiCl2
(Oi-Pr)2 as a Lewis acid provided a 5:1 selectivity ratio. See:
Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org. Chem.
2004, 69, 4534.
were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Purification by flash chromatography gave
methyl acetal 25 (153 mg, 91%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): d = 7.40–7.25 (m, 5 H), 4.66 (d, J = 12.0
Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.16–4.04 (m, 1 H),
3.64–3.50 (m, 2 H), 3.23 (s, 3 H), 2.71 (d, J = 13.7 Hz, 1 H),
2.51 (d, J = 13.7 Hz, 1 H), 2.32 (ddd, J = 12.5, 4.7, 1.8 Hz, 1
H), 1.94–1.87 (m, 1 H), 1.60–1.52 (m, 1 H), 1.46 (s, 9 H),
1.35–1.24 (m, 1 H), 1.19 (d, J = 6.4 Hz, 3 H). HRMS:
m/z calcd for C27H46O6SiNa [M + Na]+: 517.2961; found:
517.2974.
(20) Gennari, C.; Cozzi, P. G. Tetrahedron 1988, 44, 5965.
(21) Lactone 24
To an ice-cold solution of anti-diol 23 (260 mg, 0.8 mmol)
in CH2Cl2 (5.0 mL), TFA (0.6 mL, 7.8 mmol) was added.
The mixture was stirred at r.t. for 2.5 h, and then quenched
with sat. NaHCO3 at 0 °C. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo.
Purification by flash chromatography gave lactone 24 (189
mg, 95%) as a colorless oil. 1H NMR (400 MHz, CDCl3):
d = 7.40–7.25 (m, 5 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.54 (d,
J = 11.7 Hz, 1 H), 4.32–4.18 (m, 2 H), 3.76–3.68 (m, 1 H),
2.87 (ddd, J = 17.2, 5.7, 1.2 Hz, 1 H), 2.48 (dd, J = 17.2, 7.8
Hz, 1 H), 2.26–2.18 (m, 2 H), 1.82–1.71 (m, 1 H), 1.27 (d,
J = 6.4 Hz, 3 H). HRMS: m/z calcd for C14H18O4Na [M +
Na]+: 273.1103; found: 273.1100.
(23) Thioketal 26
A solution of methyl acetal 25 (175 mg, 0.46 mmol) in
MeNO2 (2.0 mL) and CH2Cl2 (1.0 mL) was cooled to –45
°C. 1,3-Propanedithiol (0.15 mL, 1.5 mmol) and BF3·OEt2
(0.3 mL, 2.4 mmol) were added in succession. The mixture
was gradually warmed to 0 °C over 1 h and purified directly
by column chromatography to obtain thioketal 26 (160 mg,
91%).
(24) TBS ether 27
To a solution of thioketal 26 (226 mg, 0.59 mmol) in DMF
(2.0 mL), imidazole (320 mg, 4.7 mmol) and TBSCl (304
mg, 2.0 mmol) were added, and the mixture was stirred at r.t.
overnight. After quenching with sat. NaHCO3, the mixture
was extracted with EtOAc (3×). The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
gave TBS ether 25 (254 mg, 87%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): d = 7.36–7.33 (m, 3 H), 7.31–7.25 (m, 2
H), 4.87–4.78 (m, 1 H), 4.55 (s, 2 H), 4.21 (ddd, J = 10.5,
4.5, 2.0 Hz, 1 H), 3.20 (dd, J = 17.2, 2.2 Hz, 1 H), 3.02–2.78
(m, 5 H), 2.45 (ddd, J = 14.1, 2.6, 2.2 Hz, 1 H), 2.17 (s, 2 H),
2.10–1.91 (m, 1 H), 2.34–2.21 (m, 4 H), 1.64–1.55 (m, 1 H),
1.13 (d, J = 6.5 Hz, 3 H), 0.86 (s, 9 H), 0.07 (s, 3 H), 0.01 (s,
3 H). 13C NMR (400 MHz, CDCl3): d = 167.9, 138.7, 128.5,
127.8, 127.7, 76.6, 73.3, 71.2, 68.0, 45.3, 43.8, 42.0, 36.5,
31.1, 26.9, 26.7, 26.2, 26.0, 24.8, 18.1, 13.4, –4.3, –4.7. MS
(ESI+): m/z = 519 [M+ + Na]. IR (film): nmax = 2951.1,
2927.9, 2851.7, 1737.9, 1249.9, 1240.2, 1222.9, 1101.4,
1076.3, 835.2, 775.4 cm–1. HRMS: m/z calcd for
(22) Methyl Acetal 25
To a solution of lactone 24 (171 mg, 0.7 mmol) in CH2Cl2
(2.0 mL), 2,6-lutidine (0.2 mL, 1.7 mmol), and TESOTf (0.2
mL, 0.9 mmol) were added at –78 °C. After 0.5 h, the
mixture was quenched with sat. NaHCO3 and then extracted
with CH2Cl2 (3×). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. Purification by flash chromatography gave TES ether
(205 mg, 92%) as a colorless oil. To a solution of (i-Pr)2NH
(0.25 mL, 1.8 mmol) in THF (1.5 mL), n-BuLi (1.5 M in
hexane, 1.2 mL, 1.8 mmol) was added dropwise at –30 °C
and stirred 10 min. After addition of tert-butyl acetate (0.25
mL, 1.9 mmol) at –78 °C, the mixture was stirred for 1 h, and
the TES ether (205 mg, 0.6 mmol) in THF (2.0 mL) was
added slowly. The mixture was stirred for 10 min, quenched
with H2O, and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated in
vacuo. Purification by flash chromatography gave tert-butyl
ester (253 mg, 0.5 mmol, 97%) as a colorless oil, which was
dissolved in benzene (2.0 mL) and MeOH (0.5 mL).
Methylorthoformate (0.6 mL, 5.5 mmol) and PPTS (14 mg,
0.055 mmol) were added. After stirring at r.t. for 2 h, the
mixture was quenched with sat. NaHCO3. The whole was
C25H40O4S2SiNa [M + Na]+: 519.2030; found: 519.1979.
[a]D23 +31.2 (c 3.31, CH2Cl2).
(25) Yoda, H.; Mizutani, M.; Takabe, K. Heterocycles 1998, 48,
679.
Synlett 2011, No. 11, 1555–1558 © Thieme Stuttgart · New York