Total Synthesis of (À)-Lemonomycin
COMMUNICATION
yield. After protection of the tertiary alcohol of 30 with
a TBS group, removal of the Cbz group of the resulting
compound 31 and the subsequent in situ formation of the di-
methyl amino group of 32 were achieved by a hydrogenolysis
reaction performed in the presence of formaldehyde. As de-
scribed later, the glycosyl fluoride 34[22] was found to be suit-
able for the glycosidation reaction with 25. Thus, lactone 32
was subjected to reduction with DIBAL, followed by fluori-
nation with DAST.[23]
Scheme 3. Equilibrium between compounds 24 and 26.
The next challenge in the synthesis was glycosidation of
the aglycon 25 with the fluoride 34 (Scheme 5). Considering
the strong acid-sensitivity of the tertiary amine, we initially
selected a soft Lewis acid for the activation of the glycosyl
Scheme 3, the equilibrium presumably occurs during an
acid-induced, ring-opening reaction to form the para-qui-
ACHTUNGTRENNUNGnoneACHTUNGTRENNUNGmethide intermediate 27 that is stabilized by conjuga-
tion of the p-system with the styryl group. Thus, the thermo-
dynamically more stable b isomer 24 was obtained exclu-
sively at a high reaction temperature.
One-pot conversion from 24 to the aglycon alkaloid 25
was accomplished by acetylation of the phenol group, ozon-
ACHTUNGTRENNUNGolACHTUNGTRENNUNGyACHTUNGTRENNUNGsis, and a subsequent reduction reaction. Notably, the
nature of the amino nitrile group on the C ring allowed us
to construct the B ring directly, without any change to the C
ring. This is in contrast to related reports[7,8] in which the re-
ductive conversion of the C-ring lactam to the correspond-
ing amino alcohol has generally been required to achieve
a successful Pictet–Spengler reaction, and therefore subse-
quent oxidative re-cyclization of the C ring was required.
Having successfully obtained the key intermediate 25, we
then turned our attention to the preparation of the glycosyl
donor 34 (Scheme 4). By using a slight modification of the
reported protocol for the conversion of related sugar deriva-
Scheme 5. Completion of the total synthesis of 1. Reagents and condi-
tions: a) TMSOTf, Drierite, CH2Cl2, À408C, 86%, a/b =5:1; b) K2CO3,
MeOH; then MOMCl, iPr2NEt, CH2Cl2, 99%; c) H2, Pd/C, EtOH, 73%;
d) TBAF, THF, 758C; e) Swern oxidation; then HCl (2m), 69% (2 steps);
f) AgNO3, MeCN/H2O, 70%; g) CAN, H2O, 0 8C, 67%. CAN=ceric am-
monium nitrate, MOM=methoxymethyl, TBAF=tetrabutylammonium
fluoride.
fluoride. When Sn, Hf, and Ag salts, which have convention-
ally been used in similar cases,[24] were used, the formation
of the undesired oxazolidine 37 occurred.[25] Next, we exam-
ined the reaction with the use of hard Lewis acids, such as
BF3·OEt2 or trimethylsilyl trifluoromethanesulfonate
(TMSOTf). Upon treatment of 25 and 34 with TMSOTf and
Drierite at À408C,[15] the desired glycosidation reaction pro-
ceeded smoothly to give 35 in 86% yield with good stereo-
selectivity (a/b=5:1). After a one-pot conversion of the ace-
tate of 35 to the corresponding MOM ether,[26] stepwise
cleavage of the Cbz and TBS groups gave the amino alcohol
36. In accordance with the protocol reported by Stoltz et al.,
conversion to the geminal diol was performed by Swern oxi-
dation. In this reaction, an acidic workup was particularly
effective, enabling the simultaneous cleavage of the MOM
ether and the methylthiomethyl (MTM) ether.[27] After gen-
eration of the labile hemiaminal from the amino nitrile by
treatment with AgNO3 in CH3CN/H2O, CAN-mediated oxi-
Scheme 4. Preparation of the glycosyl subunit 34. Reagents and condi-
tions: a) CbzCl, THF/NaHCO3 aqueous; b) MeNHOMe·HCl, EDCI,
NMM, THF, À108C; c) Me2C
ACHTUNGNERTN(NUG OMe)2, BF3·OEt2, CH2Cl2, 92% (3 steps);
d) MeMgBr, THF, À788C to RT, 85%; e) LDA, AcOEt, THF, À788C;
then HCl (3m), 85%; f) TBSOTf, 2,6-lutidine, CH2Cl2, À788C, 93%;
g) H2, HCHO, Pd(OH)2, EtOH, 92%; h) DIBAL, CH2Cl2 À788C, 100%;
i) DAST, THF, À458C, 84%. DAST=N,N-diethylaminosulfur trifluoride,
LDA=lithium diisopropylamide, NMM=N-methylmorpholine, TBS=
tert-butyldimethylsilyl, TfO=trifluoromethanesulfonate.
tives, conversion of d-threonine (28) to the lemonose deriva-
tive 34 was accomplished. The methyl ketone 29 was synthe-
sized by a four-step sequence involving Cbz-protection of
the amino group, formation of the Weinreb amide, aceto-
nide protection, and treatment with excess MeMgBr. Upon
treatment of 29 with the lithium enolate of ethyl acetate, the
chelation-controlled aldol reaction[7,21] proceeded in a highly
diastereoselective manner to afford compound 30 in 85%
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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