C.G. Webster, H. Park, A.F. Ennis et al.
Tetrahedron Letters 71 (2021) 153055
TMS
TMS
O
O
b
c
a
R
R
rac-6
H
H
rac-11
(R = CH2CH2OPMB)
rac-12
OH
O
OH
R
R
R
R
d
H
rac-3
H
rac-13
H
rac-14
OH
no reaction
or
decomposition
e
Scheme 3. Mn(OAc)3-mediated free radical cyclization of alkynyl b-keto ester 17
and reduction of bicyclo[3.2.1]octane 19. Reagents and conditions: (a) vinylmag-
nesium bromide, CuBrÁSMe2, THF, –78 °C, 1 h, 54%; (b) KOt-Bu, t-BuOH, reflux,
30 min, then, TMSCCCH2Br, reflux, 1 h, 73%, d.r.>10:1; (c) Mn(OAc)3 (12.5 equiv),
EtOH/HOAc, 90 °C, 48 h, 43%; (d) p-TsOH, MeCN, 0 to 25 °C, 2 h, 69%; (e) SmI2, PhSH,
HMPA, THF, 0 °C, 5 h, rac-20a:rac-20b = 1:3; (f) ClCH2SO2Cl, 2,6-lutidine, CH2Cl2,
0 °C, 1 h, quantitative; (g) KO2, 18-crown-6, DMSO, 25 °C, 2 h, 5% (rac-20a), 14%
(rac-20b).
H
rac-14
Scheme 2. Mn(OAc)3-mediated radical cyclization of alkynyl ketone 11. Reagents
and conditions: (a) MeLiÁLiBr, THF, 0 °C, 1 h, then, TMSCCCH2Br, HMPA, –78 to 25 °C,
16 h, 34%, d.r. = 1:1; (b) Mn(OAc)3 (20 equiv), EtOH/HOAc, 100 °C, 72 h, 50%; (c) p-
TsOH, MeCN, 0 °C, 2 h, 73%; (d) NaBH4, MeOH, 0 °C, 2 h, 65%; (e) DIAD or DEAD, 4-
nitrobenzoic acid, PPh3, THF, –20 to 40 °C.
stereoisomer. Careful analysis of the 1H NMR spectral data indi-
cated that the NaBH4 reduction afforded the undesired axial alco-
hol 14 (see the ESI for details). Reduction of 13 under various
reduction conditions such as DIBAL-H and L-Selectride did not
afford the desired alcohol 3. These results were consistent with
observations made by Newhouse and co-workers during the syn-
thesis of principinol D [11]. To obtain the desired alcohol 3, we also
attempted the Mitsunobu inversion (PPh3, DIAD or DEAD, 4-
nitrobenzoic acid) of 14, but the reaction resulted in either recov-
ery of 14 or decomposition.
Scheme 4. SmI2-mediated reduction of b-hydroxy ketone 23. Reagents and
conditions: (a) LiAlH4, THF, 0 °C, 1 h, 81%; (b) TBSCl, imidazole, CH2Cl2, 25 °C,
24 h, 84%; (c) PCC, CH2Cl2, 25 °C, 1 h, 79%; (d) 6 N HCl, THF, 0 to 25 °C, 4 h, 67%; (e)
PhSH, HMPA, SmI2, THF, 0 °C, 5 h, 78%.
Since no attempts with the PMB protected c-hydroxyl ketone
84% (Scheme 4). PCC oxidation and TBS deprotection set the stage
for the SmI2 reduction. Following Newhouse’s conditions, when 23
was subjected to the SmI2 reduction (SmI2, PhSH, and HMPA), the
reaction proceeded smoothly to give the desired equatorial alcohol
24 in 78% yield, as a single stereoisomer [11].
Having established the stereoselective route to the bicyclo
[3.2.1]octane fragment of rhodojaponin III (1), we prepared the
enantiopure b-vinyl cyclic ketone 16 by exploiting Helmchen’s
auxiliary (see the ESI for details) [27,28]. Enantiopure 16 can be
converted to the enantiopure bicyclo[3.2.1]octane fragment 24 of
rhodojaponin III (1) by following the procedure established for
racemic b-vinyl cyclic ketone 16.
13 afforded the desired equatorial alcohol, we explored b-keto
esters or b-hydroxy ketones for the stereoselective reduction to
give the desired alcohol. Starting from known cyclic enone 15
[26], the Cu(I)-mediated addition of vinylmagnesium bromide
(54%) followed by TMS-propargylation provided TMS-alkynyl
ketone 17 (73%) (Scheme 3). As expected, subjecting 17 to the
Mn(III)-mediated radical cyclization reaction afforded the desired
bicyclo[3.2.1]octane 18 in 43% yield as an (E)/(Z) mixture. TMS
deprotection of 18 was accomplished by treatment with p-TsOH
to give 19 (69%). We explored a wide range of reducing agents
(e.g., NaBH4, MnCl2ÁNaBH4, Zn(BH4)2, Me4NBH(OAc)3, NH3ÁBH3) to
stereoselectively reduce the b-keto ester to the desired b-hydroxy
ester, but none of these conditions gave the desired equatorial
alcohol 20a. Instead, the undesired axial alcohol 20b was obtained,
as was the case with 14 (see Scheme 2 for details). We also
attempted the SN2 inversion of 20b to 20a, but the SN2 inversion
reaction resulted in a limited success. When the chloromethane-
sulfonate 21, prepared from 20b and ClCH2SO2Cl, was treated with
KO2 and 18-crown-6, the SN2 inversion reaction afforded the
desired alcohol 20a (5%) and the recovered undesired alcohol
20b (14%).
Conclusion
Rhodojaponin III (1) shows great potential as a non-opioid anal-
gesic agent for pain management. Our synthetic efforts were
focused on the stereoselective synthesis of the bicyclo[3.2.1]octane
fragment of rhodojaponin III (1). The Cu-catalyzed conjugate addi-
tion of a vinyl Grignard reagent to
a,b-unsaturated cyclic enones
followed by subsequent TMS-propargylation set the stage for the
key cyclization reaction of alkynyl ketones. After an extensive
search for cyclization conditions, Mn(III)-initiated radical cycliza-
tion of alkynyl ketones (11 and 17) provided the desired bicyclo
[3.2.1]octanes (13 and 19, respectively). We expect that our stere-
Then, we decided to adopt Newhouse’s b-hydroxy ketone sub-
strate for the formation of the desired alcohol. LiAlH4 reduction
of keto ester 19 (81%) followed by mono TBS protection of the
resulting diol gave the corresponding TBS protected alcohol 22 in
3