Biomimetic Total Synthesis of Santalin Y

Article abstract of DOI:10.1002/anie.201411350

A biomimetic total synthesis of santalin Y, a structurally complex but racemic natural product, is described. The key step is proposed to be a (3+2) cycloaddition of a benzylstyrene to a "vinylogous oxidopyrylium", which is followed by an intramolecular F

Full text of DOI:10.1002/anie.201411350

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International Edition: DOI: 10.1002/anie.201411350
German Edition: DOI: 10.1002/ange.201411350
Biomimetic Synthesis Very Important Paper
Biomimetic Total Synthesis of Santalin Y**
Sebastian Strych, Guillaume Journot, Ryan P. Pemberton, Selina C. Wang, Dean J. Tantillo,* and
Dirk Trauner*
Abstract: A biomimetic total synthesis of santalin Y, a structur-
ally complex but racemic natural product, is described. The key
step is proposed to be a (3 + 2) cycloaddition of a benzylstyrene
to a “vinylogous oxidopyrylium”, which is followed by an
intramolecular Friedel–Crafts reaction. This cascade generates
the unique oxafenestrane framework of the target molecule and
sets its five stereocenters in one operation. Our work provides
rapid access to santalin Y and clarifies its biosynthetic relation-
ship with other colorants isolated from red sandalwood.
T
he structural diversity and sophistication of natural prod-
ucts contributes much to the fascination they have always
exerted on chemists. Metabolites that bear a multitude of
stereocenters usually occur in enantiomerically pure, or at
least scalemic, form. Complex natural products that are true
racemates are comparatively rare. There are, however,
notable exceptions, a small collection of which is shown in
Figure 1. The formation of these natural products is often
associated with pericyclic reactions, such as Diels–Alder
reactions, which can set up to four stereocenters in a single
step from achiral precursors. Electrocyclization cascades or
cyclizations via ionic intermediates can lead to similar or even
higher levels of complexity. The occurrence of these reactions
in biosynthetic pathways has been strongly suggested by
a multitude of biomimetic syntheses. Classics, such as the ones
of carpanone[1] and endiandric acid A,[2] have been recently
complemented by the synthesis of rubioncolin B,[3] exiguami-
ne B,[4] and kingianin A.[5]
Figure 1. Complex racemic natural products that have succumbed to
biomimetic synthesis.
Another complex, yet racemic, natural product, santa-
lin Y, occurs in “red sandalwood”, the hardwood of Ptero-
carpus santalinus (Figure 2A). The deep-red color of the
[*] Dr. S. Strych,[+] Dr. G. Journot,[+] Prof. Dr. D. Trauner
Department of Chemistry and Centre for Integrated Protein Science
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, 81377 Mꢁnchen (Germany)
E-mail: dirk.trauner@lmu.de
Homepage: http://www.cup.uni-muenchen.de/oc/trauner/
R. P. Pemberton, Dr. S. C. Wang, Prof. Dr. D. J. Tantillo
Department of Chemistry, University of California-Davis
1 Shields Avenue, Davis, CA 95616 (USA)
E-mail: djtantillo@ucdavis.edu
Figure 2. A) The santalins and santarubins. B) X-ray structure of santa-
lin Y (crystallized from acetonitrile) seen from the top and the side.
Some hydrogen atoms in the side view are omitted for clarity.
Homepage: http://blueline.ucdavis.edu
Dr. S. C. Wang
Current address: UC Davis Olive Center (USA)
[+] These authors contributed equally to this work.
highly valued material is mostly due to a series of benzox-
anthenones, namely santalins A, B and santarubins A, B.[6]
The yellow pigment santalin Y, was isolated by Nohara
and co-workers in 1995 as a minor component.[7] Apart from
its lack of optical activity, this molecule has several structural
features that makes it an attractive target for chemical
[**] We are grateful to SFB 749 (Dynamics and Intermediates of
Molecular Transformations) and the US National Science Founda-
tion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411350.
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synthesis. It exhibits a unique [6,6,6,5]-oxafenestrane frame-
work that bears a catechol moiety as well as partially
methylated pyrogallol and resorcinol substituents. As seen
in Figure 2B, a bicyclic and a tricyclic ring system come
together in an almost orthogonal fashion to form a “ridge”
that contains three of the five stereocenters of santalin Y.
In addition to the isolation and structural elucidation of
santalin Y by NMR analysis and X-ray crystallography,
Nohara and co-workers provided a biosynthetic rationale
for its formation.[7] According to their hypothesis, the natural
product stems from an isoflavylium ion (1) and a benzylstyr-
ene (2; Scheme 1A). Nucleophilic attack of 2 on 1 would form
a benzyl cation, shown here as diastereomer 3, which would
then undergo ring closure with concomitant dearomatization
to afford a tetrahydrofuran intermediate 4. A subsequent
intramolecular Friedel–Crafts cyclization would form the
tertiary alcohol and complete the biosynthesis of santalin Y.
Although this ionic cascade involves reasonable biosyn-
thetic starting materials and reactivity patterns, the diaste-
reoselectivities of its individual steps, as shown in Scheme 1,
are not readily explained, at least in the absence of enzymatic
catalysis. We, therefore, considered an alternative pathway
that involves a concerted cycloaddition (Scheme 1B). Depro-
tonation of isoflavylium ion 1 at position 7 would afford the
anhydrobase 5 in a process that is well-precedented amongst
flavonoid and isoflavonoid plant pigments.[8] Alternatively,
the deprotonation of 1 at position 6 would yield a “vinylogous
oxidopyrylium” 6. At the outset of our studies it was not clear
whether this deprotonation would be energetically viable
under thermal conditions. We hypothesized that the forma-
tion of 6 would require a photochemically triggered excited-
state intramolecular proton transfer (ESIPT) of 5. The
analogous formation of oxidopyrylium species by ESIPT,
followed by cycloadditions, has been studied in detail by
Porco and co-workers, and has been recently used in a total
synthesis of rocaglamides.[9] Once the vinylogous oxidopyri-
lium 6 is formed, it would undergo a stereospecific 1,3-dipolar
cycloaddition that would again afford 4 and, after Friedel–
Crafts closure of the final ring, santalin Y (1).
In previous studies on the biomimetic synthesis of
santalins A, B and santarubins A, B, we described an efficient
synthesis of both isoflavylium salt 8 and anhydrobase 5.[8d]
This synthesis, summarized in Scheme 2A, started from malic
acid and 1,2,4-triacetoxybenzene (7) and afforded isoflavy-
Scheme 1. A) Proposed biosynthetic pathway leading to santalin Y.
B) A modification of the proposal involving excited-state intramolecu-
lar proton transfer and a concerted cycloaddition.
Scheme 2. A) Synthesis of isoflavylium salt 8 and anhydrobase 5.
B) Synthesis of benzylstyrene 2. TBDPS=tert-butyldiphenylsilyl,
TBAF=tetrabutylammonium fluoride, TBS=tert-butyldimethylsilyl.
2
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lium perchlorate 8 and anhydrobase 5 in 7 and 8 steps,
respectively.
formation of 16 presumably involves a nucleophilic attack of 2
on anhydrobase 5. The resulting adduct, shown here without
considering the stereochemistry, could then undergo proton
transfer to afford 14. Deprotonation of this intermediate and
cyclization along pathway b (whereas pathway a would have
led to santalin Y), followed by oxidation of the labile product
15 by ambient air then yields compound 16. Benzoxanthe-
none 16 has not been described as a genuine natural product,
but closely resembles santarubin A and B.[6a] If it were to be
isolated from natural materials we propose to call this brightly
colored compound “santarubin S”.
Contemplating the mechanism shown in Scheme 3, we
realized that we had to find a way to bias the cyclization of
intermediate 14 toward path a. We reasoned that this could be
achieved with a bifunctional organocatalyst[12] that could
activate the anhydrobase 5 toward nucleophilic attack by
hydrogen bonding to the carbonyl function at C7 and
subsequently deprotonate the phenolic hydroxy group at
C6. Indeed, when the racemic Takemoto catalyst 17[12k,13] was
employed in THF solution, we were able to detect the
formation of santalin Y for the first time (Table 1, entry 1).
This reaction, however, proved to be difficult to reproduce
and the solubility of our starting materials in THF was low.
We, therefore, screened for better solvents that could also
serve as hydrogen-bond donors, mediate proton transfers, and
stabilize ionic intermediates. Amongst these, trifluoroethanol
(TFE) turned out to be the most suitable. When an equimolar
mixture of 2 and 5 in TFE solution was exposed to 20 mol%
of 17 at À208C, santalin Y was formed in 45% yield, as
determined by NMR spectroscopy (entry 2). The use of
a stoichiometric amount of catalyst 17 did not significantly
The requisite benzylstyrene 2 was prepared by olefin
cross-metathesis, as shown in Scheme 2B. Monoallylation of
resorcinol, followed by protection of the remaining phenolic
hydroxy group as a silyl ether gave 9, which underwent
a Lewis acid catalyzed Claisen rearrangement,[10] methyla-
tion, and deprotection to yield allyl resorcinol 10. Conversely,
protection of the catechol 11, followed by Wittig olefination,
afforded styrene 12 as an inseparable mixture of the E and Z
isomers (1.7:1). Cross-metathesis of 10 and 12, followed by
global deprotection, then gave E-configured benzylstyrene 2
as a single diastereomer.
With building blocks 5, 8, and 2 in hand, we first
investigated the possibility of synthesizing santalin Y by
photochemically triggered ESIPT,[11] followed by 1,3-dipolar
cycloaddition, as outlined in Scheme 1B. However, despite an
extensive screening of solvents, light sources, and additives,
santalin Y could never be isolated and this approach was
abandoned (see the Supporting Information).
Since our photochemical strategy proved unsuccessful, we
began to investigate thermal conditions. When benzylstyrene
2 was exposed to isoflavylium perchlorate 8, which corre-
sponds to 1 in Nohara’s proposal,[7] rapid decomposition of 2
was observed. This decomposition was attributed to the
acidity of 8, which might initiate polymerization of the
styrene. Consequently, the moderately basic anhydrobase 5,
obtained by deprotonation of 8, was heated in the presence of
benzylstyrene 2 in a variety of solvents. Although santalin Y
was never found under these conditions, we often detected the
benzoxanthenone 16 as a product (Scheme 3, see the Sup-
porting Information). The addition of Lewis and Brønsted
acids gave various amounts of 16, but no santalin Y. The
Table 1: Optimization of the reaction conditions.
Entry[a] Additives (equiv) Solvent Conc. [m] T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
17 (0.2)
17 (0.2)
18 (0.2)
17 (1)
17 (0.2)
17 (0.2)/Et3N (1) TFE
17 (0.2)/Et3N (1) TFE
Et3N (1)
Et3N (0.2)
Et3N (1)
THF
TFE
TFE
TFE
TFE
0.015
0.015
0.015
0.015
0.03
0.015
0.015
0.015
0.015
0.06
À208C 0–20
À208C 45
À208C
0
À208C 43
À208C 51
À208C 64
RT
RT
39
40
TFE
TFE
TFE
À208C 52
10
À208C 81(67)[c]
[a] Conditions: compound 5 (1 equiv), compound 2 (1 equiv), 48 h,
under Ar. [b] Yield calculated by NMR spectroscopy. [c] Yield of isolated
product.
Scheme 3. Formation of the benzoxanthenone 16 (“santarubin S”) by
an unintended cyclization.
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change the outcome of the reaction (entry 4), while increasing
the concentration was beneficial (entry 5). Schreiner’s orga-
nocatalyst 18[12l,14] was ineffective, thus highlighting the
importance of the basic functionality of 17 (entry 3). The
addition of an external base, such as Et3N, further increased
the yield (entry 6). However, when the reagents were added
at room temperature instead of À208C, we observed a drop in
the yield (entry 7).
We next omitted the organocatalyst 17 and ran the
reaction in TFE solution and in the presence of various
amounts of Et3N. Surprisingly, these conditions also provided
santalin Y in decent yields (entries 8 and 9). Apparently, the
solvent TFE and the base Et3N can substitute for the
bifunctional catalyst. Finally, after considerable experimenta-
tion (see the Supporting Information), we arrived at the
optimal conditions for the synthesis of santalin Y. Exposure of
2 and 5 in TFE at their solubility limit (c = 0.06m) to Et3N at
À208C, followed by warming to room temperature and
stirring for 12 h, gave the racemic natural product in 81%
yield, as determined by NMR spectroscopy, and 67% yield of
the isolated product (Table 1, entry 10). Compound 16 was
not observed under these optimized conditions.
Figure 3. Computed transition-state structures (M06-2X/6-31G(d);
selected distances in [ꢂ]). Top: Transition-state structure TS-1 for the
formation of 4. Bottom: Transition-state structure TS-2 for the
formation of the unobserved diastereomer 19. At this level of theory,
TS-1 is predicted to be 1.4 kcalmolÀ1 lower in energy than TS-2.
The spectroscopic data of our synthetic santalin Y fully
matched those reported for the natural product. This was
further confirmed by an independent X-ray structure analysis
of synthetic santalin Y as its acetonitrile solvate (Figure 1 and
see the Supporting Information).
7 steps (longest linear sequence) and in 8% overall yield from
readily available starting materials. Our results indicate that
an isoflavylium (1) and a benzylstyrene (2), which have not
yet been isolated as genuine natural products, are biosynthetic
progenitors of santalin Y. We also provide evidence that
a concerted cycloaddition is involved, although a stepwise
mechanism cannot be entirely ruled out. Santalin S (16) is
proposed as a natural product. Our results demonstrate, once
again, that enzymes are not always necessary to promote
reactions that lead to complex natural products.[17] It would be
difficult to conceive of a non-biomimetic synthetic strategy
that could deliver santalin Y in such an expedient way.
Insight into the mechanism of our key reaction was
obtained through quantum chemical computations.[15] First,
we established that the 1,3-dipole 6 is only 7–10 kcalmolÀ1
higher in energy than anhydrobase 5. The energy barrier for
conversion of 5 into 6 by thermal intramolecular proton
transfer was predicted to be 10–12 kcalmolÀ1 (see the
Supporting Information). It is, therefore, conceivable that 6
is formed in sufficient concentrations under thermal con-
ditions. Second, once it is formed, we found a favorable
pathway for the cycloaddition of 6 to benzylstyrene 2
(Figure 3). The energy barrier of this reaction was estimated
to be approximately 20 kcalmolÀ1 (free energies with M06-
2X/6-31G(d), although the absolute barrier height varied with
the level of theory used; see the Supporting Information).
This is compatible with our optimized reaction conditions
(À208C to RT). The energy of the transition-state structure
TS-1, which leads to 4, was found to be lower than that of TS-
2, which would afford 19, a diastereomer of 4, by 0.3–
3.0 kcalmolÀ1, depending on the level of theory employed
(see the Supporting Information). Note that the dipole and
dipolarophile portions of this transition-state structure inter-
act through p-stacking and hydrogen-bonding interactions.[16]
Although bond formation in all of the transition-state
structures examined occurs asynchronously, no intermediates
expected for stepwise pathways were found. We therefore
favor a concerted cycloaddition mechanism.[17a] The role of
the polar and comparatively acidic solvent TFE in combina-
tion with the base Et3N in our optimal conditions could lie in
facilitating the proton transfers that equilibrate 5 with 6.
In conclusion, we have developed a concise, diastereose-
lective and highly convergent synthesis of santalin Y. This
complex, yet racemic, natural product was synthesized in
Experimental Section
Triethylamine (5 mL, 0.0356 mmol, 1 equiv) was added to a stirred
solution of anhydrobase 5 (14 mg, 0.0445 mmol, 1.2 equiv) and
benzylstyrene 2 (9.7 mg, 0.0356 mmol, 1 equiv) in TFE (0.6 mL) at
À208C. The reaction mixture was allowed to reach room temperature
and was stirred for 12 h. Then, the reaction mixture was concentrated
in vacuo. The crude product was purified twice by preparative TLC
(CH2Cl2/MeOH 10:1) and afforded santalin Y (15.5 mg, 67%) as
a yellow powder. Santalin Y could be recrystallized in acetonitrile to
give yellow crystals. Rf = 0.38 (CH2Cl2/MeOH 9:1). UV (MeCN):
lmax = 357 nm. IR (ATR): n˜ = 3271 (m), 2925 (s), 2854 (s), 1733 (w),
1666 (m), 1596 (m), 1508 (m), 1462 (m), 1381 (w), 1278 (s), 1243 (m),
1176 (s), 1131 (s), 1024 (s), 1005 cmÀ1 (m). HRMS (ESI): calcd for
C33H31O10+ [M + H]+: 587.1912, found: 587.1918. 1H NMR (600 MHz,
[D6]DMSO): d = 9.21 (s, 1H), 8.88 (s,1H), 8.78 (s, 1H), 8.66 (s, 1H),
6.91 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.42 (d, J = 8.9 Hz, 1H), 6.50 (d,
J = 0.8 Hz, 1H), 6.36 (s, 1H), 6.27 (d, J = 2.3 Hz, 1H), 6.18 (dd, J = 8.0,
2.3 Hz, 1H), 6.07 (d, J = 8.8 Hz), 5.82 (s, 1H), 5.62 (d, J = 0.6 Hz, 1H),
4.84 (s, 1H), 3.77 (s, 3H), 3.66 (s, 3H), 3.56 (s, 3H), 3.30 (m, 1H), 3.00
(dd, J = 13.8, 4.0 Hz, 1H), 2.67 (dd, J = 13.8, 10.3 Hz, 1H), 2.62–2.47
(ABq, J = 10.7 Hz, 2H), 2.46 ppm (m, 1H). 13C NMR (150 MHz,
[D6]DMSO): d = 198.4, 157.9, 157.4, 154.9, 152.9, 149.6, 146.2, 145.5,
143.7, 139.5, 130.6, 128.8, 124.5, 121.5, 120.8, 119.8, 118.0, 117.9, 113.8,
4
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112.3, 107.0, 106.6, 98.9, 83.2, 80.9, 78.0, 59.8, 55.8, 55.0, 54.9, 50.6,
46.3, 36.4 ppm.
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Keywords: biomimetic synthesis · dipolar cycloaddition ·
polyphenols · racemic natural products · total synthesis
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Received: November 23, 2014
Revised: March 6, 2015
Published online: && &&, &&&&
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Communications
Biomimetic Synthesis
S. Strych, G. Journot, R. P. Pemberton,
S. C. Wang, D. J. Tantillo,*
D. Trauner*
&&&& — &&&&
Biomimetic Total Synthesis of Santalin Y
High five! The five stereocenters of
point to a concerted 1,3-dipolar cyclo-
addition that involves a “vinylogous oxi-
dopyrylium species” as the key step.
santalin Y, a complex yet racemic natural
product, were installed in a single oper-
ation. Quantum chemical computations
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!