Total synthesis of (+)-lactiflorin by an intramolecular [2+2] photocycloaddition

Article abstract of DOI:10.1002/anie.201106889

Enlightning synthesis: A light-induced intramolecular [2+2] photocycloaddition reaction (1→2) was the key step in the stereoselective synthesis of (+)-lactiflorin (3) and its triacetate. By comparison with reported analytical data, it was possible to unambiguously elucidate the structure of this natural product, to which three different structures had been previously assigned. Copyright

Full text of DOI:10.1002/anie.201106889

Angewandte
Chemie
DOI: 10.1002/anie.201106889
Natural Product Synthesis
Total Synthesis of (+)-Lactiflorin by an Intramolecular [2+2]
Photocycloaddition**
Ping Lu and Thorsten Bach*
The final confirmation of a structure assignment has remained
one of the preeminent tasks of natural product synthesis.
Despite the advancement in analytical techniques, there are
several cases in which the synthesis of a compound with the
proposed structure of a natural product has led to a correction
of the original assignment.[1,2] Along these lines, we were
intrigued by (+)-lactiflorin, a natural product first isolated
from the roots of Paeonia lactiflora Pall.[3] The same
compound was also isolated from the related species Paeonia
anomala var. intermedia (C. A. Mey.) O. & B. Fedtsch.[4] Three
structures 1–3 have been suggested for (+)-lactiflorin.[3–5] The
numbering of compounds 2 and 3 in Figure 1 has been taken
from the original papers. A total synthesis of (+)-lactiflorin
has not yet been achieved.
Figure 2. Structures of (ꢀ)-paeoniflorin (4) and of a putative common
intermediate 5 of compounds 2 and 4.
It was envisioned that a retrosynthetic disconnection at
the glycosidic bond would lead to a subunit of compound 2,
which could be derived from d-glucose, and to a tricyclic
aglycon with general structure A (Scheme 1), which could be
Figure 1. Previously proposed structures 1–3 of (+)-lactiflorin.
Scheme 1. Possible ways of obtaining tertiary alcohol A by intramolec-
ular [2+2] photocycloaddition of precursors B or C.
Although the fact that natural (+)-lactiflorin can be
converted in low yield into paeoniflorin (4)[6,7] and although a
biogenetic congener compound, which can be tentatively
described by structure 5 (Figure 2), makes structure 2 the
most likely structure for (+)-lactiflorin, it was desirable to
provide synthetic evidence for this assumption. We therefore
embarked on a total synthesis of compound 2 with the aim to
use a [2+2] photocycloaddition reaction[8] as one of the key
steps in the reaction sequence.[9,10] In this manuscript we
present preliminary results of this research, which culminated
in the total synthesis of (+)-lactiflorin and its unambiguous
structure proof.
accessible by intramolecular [2+2] photocycloaddition reac-
tions.[8] Conceivable precursors were the b,g-substituted
cyclopentenone B and the a,b,g-trisubstituted a,b-unsatu-
rated lactone C. Preliminary studies with model compounds
revealed that the intramolecular [2+2] photocycloaddition of
substrates B was not feasible. When we employed readily
available, pyruvate-derived silyl enol ethers (R = trimethyl-
silyl), which had been shown in intermolecular [2+2] photo-
cycloaddition reactions to be competent alkene substrates,[11]
we were not able to detect the desired products upon
irradiation at l = 300 nm or l = 350 nm in various solvents.
With model compounds related to lactone C, the initial
screening was more successful. Clean photocycloaddition
products were obtained, the constitution (straight or crossed)
of which turned out to be dependent on the relative
configuration of the protected (PG = protecting group)
secondary alcohol. Since the corresponding alcohol will
eventually be oxidized to a ketone (C4 in structure 2), this
stereogenic center, which is in a 1,3-diol relationship to the
stereogenic center at the lactone, can be freely chosen. Based
on preliminary studies an anti-1,3-diol configuration[12] deliv-
[*] Dr. P. Lu, Prof. Dr. T. Bach
Lehrstuhl fꢀr Organische Chemie I
Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
[**] P.L. wishes to acknowledge support by the Alexander von Humboldt
foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106889.
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ered the best results in the intramolecular [2+2] photo-
cycloaddition reaction.
regioisomers. Chromatographic separation delivered aglycon
10 as a single diastereomer in 53% yield over two steps
starting from substrate 9. The relative configuration of
compound 10 was confirmed by extensive two-dimensional
NMR experiments.
The synthesis of a suitable [2+2] photocycloaddition
precursor commenced with enantiomerically pure (2’R)-2,2-
dimethyl-6-(2’-hydroxybut-3’-enyl)-1,3-dioxin-4-one
(6)[13]
(Scheme 2). Refluxing of dioxinone 6 and methanol in
Glucosyl acceptor 10 turned out to be unstable under
basic conditions. Glucosylation attempts were therefore
limited to reactions in which the glycosidic linkage was
formed under neutral or acidic conditions. Various leaving
groups (at C1’) and neighboring groups (at C2’) were tested[20]
on the tribenzylated glucosyl donor derived from d-glu-
cose.[21] The best results have so far been obtained with
glucosyl donor 11, which bears N-phenyltrifluoroacetimidate
(PTFAI)[22] as the leaving group at C1’ and the 2-chloro-2-
methylpropanoyl group[23] as the protecting group for the
alcohol at C2’ (Scheme 3). The fact that the glucosyl acceptor
is a tertiary alcohol renders the glycoside formation difficult
and may also be responsible for the limited diastereoselec-
tivity.[24] Despite the expected neighboring-group participa-
Scheme 2. Synthesis of aglycon 10; exact conditions and yields:
a) Methanol (2.8 equiv), toluene, reflux, 3 h, 78%; b) NMe4BH(OAc)3
(5 equiv), CH3CN/HOAc, ꢀ358C, 44 h, 88%; c) TBSOTf (1.05 equiv),
2,6-lutidine (3 equiv), CH2Cl2, ꢀ788C, 4 h, 90%; d) LDA (2.2 equiv),
TMSCl (2.5 equiv), THF, ꢀ788C!RT, 19 h; then (COCl)2 (1 equiv),
CH2Cl2, ꢀ788C!RT, 21 h, 61%; e) NaH (2 equiv), BnBr (2 equiv),
DMF, RT, 21 h, 67%; f) Ba(OH)2·8H2O (5 equiv), THF/H2O, 60 h,
71%; g) NMM (1 equiv), ClCO2Me (1 equiv), THF, ꢀ108C, 0.5 h; then
NaBH4 (3 equiv), MeOH, 08C, 0.5 h, 63%; h) BzCl (1.5 equiv), DMAP
(0.2 equiv), NEt3 (2 equiv), CH2Cl2, 08C!RT, 1 h, 91%; i) hn
(l=300 nm), CH3CN/acetone, RT, 2 h; (j) H2, Pd/C (0.5 equiv), EtOH,
RT, 16 h, 53% over 2 steps. Bn=benzyl, Bz=benzoyl, DMAP=4-
dimethylaminopyridine, NMM=N-methylmorpholine, TBSOTf=tert-
butyldimethylsilyl trifluoromethanesulfonate.
toluene, anti reduction[14] of the resulting b-keto ester, and
selective TBS protection[15] of the 1,3-diol led to b-hydroxy
ester 7. Cyclization of a 1,3-bis(silyloxy)alk-1-ene, which was
generated from 7 in situ, with oxalyl chloride[16] allowed for
the formation of the butenolide chromophore. Subsequent O-
benzylation and selective saponification provided compound
8. Two-step reduction of the carboxylic acid[17] and benzoy-
lation of the resulting primary alcohol furnished the [2+2]
photocycloaddition precursor 9.
Irradiation of substrate 9 at l = 300 nm gave the intra-
molecular photocycloaddition products with similar regiose-
lectivity (straight/crossed ffi 75:25)[18] irrespective of the other
reaction conditions (i.e. variation of solvent, glassware,
reaction time). The reaction went to full conversion in two
hours when acetone (ET = 332 kJmolꢀ1)[19] was chosen as a
sensitizing co-solvent (Duran filter). Since the regioisomers
were not separable at this stage, the hydrogenolysis of the
intermediate benzyl ether was performed with the mixture of
Scheme 3. Completion of the synthesis of (+)-lactiflorin (2); exact
conditions and yields: a) 11 (3 equiv), TBSOTf (0.4 equiv), 4 ꢂ MS,
hexane/CH2Cl2, 08C, 12 h, 26% for 12, and 44% for a anomer;
b) MeLi (13 equiv), THF, ꢀ788C, 5 h; then PPTS, CH2Cl2, RT, 3 h,
70%; c) K2CO3 (3 equiv), MeOH/THF, then PPTS, CH2Cl2, RT, 3 h,
quant.; d) NEt3 (5 equiv), DMAP (1 equiv), BzCl (5 equiv), CH2Cl2,
18 h, 88%; e) TBAF (3.4 equiv), THF, RT, 2 h; f) DMP (3 equiv),
NaHCO3 (8 equiv), CH2Cl2, RT, 4 h, 81% over 2 steps; g) Pd(OH)2/C,
H2, EtOH, RT, 4 h, 99%. TBAF=tetra-n-butylammonium fluoride,
DMP=Dess–Martin periodinane, PPTS=pyridinium para-toluenesulfo-
nate.
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Chemie
tion of the 2-chloro-2-methylpropanoyl group, the desired b-
glycoside 12 was isolated in only 26% yield, along with the
readily separable a anomer as the other product (44% yield).
The missing methyl group was introduced by methyl
addition to glycoside 12. It turned out that the reaction was—
under a variety of conditions—not selective towards reaction
at the lactone unit. Consequently, an excess of methyllithium
was employed, delivering a ketone intermediate, which could
be cyclized to ketal 13 under acidic conditions. In some cases
the C2’-protected alcohol 14 was obtained as a side product in
the methyl-addition step. Separation from the ketone was
feasible and after deprotection, the latter compound was
quantitatively converted into the former. As expected, the
primary hydroxy group (at C8) did not participate in ketal
formation because of the geometric constraints exerted by the
rigid cyclobutane ring. Benzoylation of primary alcohol 13,
cleavage of the TBS ether at C4, and oxidation with Dess–
Martin periodinane (DMP) smoothly furnished the triply
benzylated intermediate 15. Global debenzylation with Pearl-
manꢀs catalyst gave compound 2, the 13C NMR spectrum of
which perfectly matched the reported spectrum of lactiflorin[4]
(see the Supporting Information). The specific rotation was
also in agreement with the reported value.
However, there was some ambiguity regarding the
1H NMR data provided by Iskander et al.[4] Most significantly,
for a spectrum recorded at a field strength of 300 MHz they
reported a doublet of triplets at d = 2.79 ppm with coupling
constants of J = 13.2, 4.5, 4.5 Hz (assigned to H4 in structure
3) and at d = 2.80 ppm a doublet with J = 18.0 Hz (assigned to
H2b), while our data at a field strength of 500 MHz suggested
two doublets of doublets with J = 17.5, 4.6 Hz at d = 2.80 ppm
and J = 13.0 Hz, 4.9 Hz at d = 2.81 ppm. Further clarification
was expected from lactiflorin triacetate (16, Figure 3), the
synthesis of which was readily achieved upon treatment of
triol 2 with acetic anhydride in pyridine (59% yield).
proton at C9. The other suggested structure 1 of lactiflorin
had been previously corrected because of a wrong interpre-
tation of the ketone carbonyl signal.[5]
In conclusion, we have achieved the first total synthesis of
(+)-lactiflorin (2) starting from the known dioxinone 6 in 16
steps (0.7% overall yield). The synthesis proves unambigu-
ously one of the previously suggested structures (structure 2,
Figure 1) of this natural product. Further studies regarding a
potential common synthetic precursor to lactiflorin and
paeoniflorin continue in our laboratory.
Received: September 28, 2011
Revised: October 24, 2011
Published online: December 21, 2011
Keywords: cycloaddition · glycosylation · photochemistry ·
.
structure elucidation · total synthesis
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