Organic Letters
Letter
provided 11, followed by a subsequent oxidation of the crude
allylic alcohol with MnO2, which produced the α,β-unsaturated
ketone 9 in a yield of 86%. Convergently, Wittig methylenation
of 2,3:5,6-di-O-isopropylidene-D-mannofuranose (8) on the
anomeric carbon in the presence of lithium hexamethyldisila-
zide (LHMDS) afforded the terminal alkene 12 in 87% yield.
However, the Grubbs-II-catalyzed16 CM reaction of 12 with 9
generated the undesired furanosyl C-glycoside 14 as a major
product alone with the desired product 13 in only 15% yield.17
It is noteworthy that 1,2-trans furanosyl C-glycoside was
obtained as a single diastereomer, and the other isomer was
not observed. This stereoselectivity might have originated from
the steric interaction of two adjacent bulky cyclic acetonides.
Attempts to improve the reaction outcome by decreasing the
reaction temperature and using other Grubbs catalysts18 were
fruitless. We believe that the enhanced oxa-conjugate
reactivity19 in hydroxy-enone 13 would facilitate the formation
of tetrahydrofuran 14 under these reaction conditions.
Therefore, the free hydroxyl group of 12 was temporarily
blocked with a benzyl group using BnBr and NaH in dry THF
to give the intermediate 15 in excellent yield. The following
CM of 15 and 9 in the presence of Hoveyda−Grubbs-II
catalyst proceeded smoothly to give the desired α,β-
unsaturated ketone 7 in 77% yield with excellent E/Z
selectivity (>20:1).
TFA/CH2Cl2 system gave a messy thin layer chromatography
(TLC) result. The stereochemistry of 16 was confirmed by the
nuclear Overhauser effect (NOE) between Ha and Hb and the
structure assignments from the following derivatives. More-
over, when we reinvestigated the thermodynamic stability on
all potential products of 7, as described in Figure 2, the 6,8-
DOBCO structure 16 displayed the lowest energy with
consideration of the solvation effect, matching our exper-
imental results in methanol.
Oxidative cleavage of the adjacent hydroxyls in 16 with
sodium periodate, followed by Wittig olefination with ylide 6
(Z)-olefin 4 in 67% yield with Z/E > 10:1. The free hydroxyl
group of 4 was protected with TBDMS, then subjected to
Williamson etherification with serinol derivative 322 to give the
DOBCO−serinol moiety 17 in 83% isolated yield. The
hydrogenation of 17 with Pd(OH)2/C under a hydrogen
atmosphere simultaneously saturated the double bond and
removed the benzyl protecting group. The formation of
terminal alkene 19 from alcohol 17 was carried out smoothly
under the modified Grieco−Nishizawa procedure,23 involving
the introduction of 2-nitrophenyl selenide and the subsequent
oxidative elimination with H2O2 in a one-pot procedure, to
give 19 in 87% yield. Desilylation of 19 with TBAF followed by
acetylation with acetic anhydride in one pot24 provided the
advanced intermediate 20 in 91% yield.
After the access to the key fragment 7, we next focused our
attention on the synthesis of the 6,8-dioxabicyclo[3.2.1]octane
skeleton (Scheme 3). The hydrogenation of 7 over 20%
With the key intermediate 20 in hand, we were ready to
complete the total synthesis of siladenoserinol A (1), as
summarized in Scheme 4. The functionalized α,β-unsaturated
Scheme 3. Synthesis of Fragment 20
Scheme 4. Total Synthesis of Siladenoserinol A (1)
ester 5 was prepared in two steps and in 51% overall yield from
the commercially available glycerophosphocholine 21. CM
between 20 and the α,β-unsaturated ester 5 in the presence of
the second-generation Hoveyda−Grubbs catalyst afforded 22
in 66% yield without our worrying about the sensitive choline
moiety. Next, a two-step, one-pot sequence reaction was used
to convert TBDPS silyl ether 22 into diacetate 23, involving
the selective removal of the TBDPS protecting group with HF·
Py followed by acetylation with acetic anhydride in pyridine.
Finally, removal of the acid-labile 2,2-dimethyloxazolidine ring
from 23 with 4 M HCl in dioxane followed by a regioselective
sulfamation on the serinol moiety with SO3·Py in THF/H2O
(v/v 1:1) provided siladenoserinol A (1) in 56% yield.
Pd(OH)2/C in methanol removed both the benzyl group and
the conjugate double bond, affording the saturated ketone
intermediate in excellent yield. This ketone intermediate,
without further purification, was subjected to acid hydrolysis at
ambient temperature for 4 h to deliver the intramolecular
bicyclized compound 16. We found that hydrochloric acid (1
M, a few drops) in methanol was the best reaction conditions
for triggering the deacetalization and ketalization in one pot,
leading to the desired 6,8-DOBCO structure 16 in 87% yield
as a single diastereoisomer,20 whereas the same reaction in the
With the complete synthesis of siladenoserinol A, we
thought it would be straightforward to finish the first total
synthesis of siladenoserinol D (2) (Scheme 5). Thus global
deprotection was routinely performed on 22 with TFA in THF
at room temperature to afford the precursor 24,25 which was
3266
Org. Lett. 2021, 23, 3264−3268