Highly trans-Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ-Deoxygenation and Heck-Matsuda Reaction: Asymmetric Total Synthesis of (-)-Musellarins A-C and Their Analogues

Article abstract of DOI:10.1002/chem.201501713

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji-Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads. O leaves, Ar comes: A highly regio- and diastereoselective trans-arylation of Achmatowicz rearrangement products by an unprecedented Zn-mediated reductive γ-deoxygenation and Heck-Matsuda reaction was developed for the efficient synthesis of trans-2-aryl-6-alkyl dihydropyranones (see scheme: L.A.=Lewis acid). The synthetic utility of this new method was further demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps.

Full text of DOI:10.1002/chem.201501713

DOI: 10.1002/chem.201501713
Full Paper
&
Synthetic Methods
Highly trans-Selective Arylation of Achmatowicz Rearrangement
Products by Reductive g-Deoxygenation and Heck–Matsuda
Reaction: Asymmetric Total Synthesis of (À)-Musellarins A–C and
Their Analogues
Zhilong Li,[a] Fanny C. F. Ip,[b] Nancy Y. Ip,[b] and Rongbiao Tong*[a]
Abstract: Fully functionalized pyranuloses derived from Ach-
matowicz rearrangement (AR) are versatile building blocks in
organic synthesis. However, access to trans-2,6-dihydropyr-
ans from pyranuloses remains underexplored. Herein, we
report a new two-step trans arylation of AR products to
access 2,6-trans-dihydropyranones. This new trans-arylation
method built on numerous plausible, but unsuccessful,
direct arylation reactions, including Ferrier-type and Tsuji–
Trost-type reactions, was finally enabled by an unprecedent-
ed, highly regioselective g-deoxygenation of AR products by
using Zn/HOAc and a diastereoselective Heck–Matsuda cou-
pling. The synthetic utility of the reaction was demonstrated
in the first asymmetric total synthesis of (À)-musellarins A–C
and 12 analogues in 11–12 steps. The brevity and efficiency
of our synthetic route permitted preparation of enantiomeri-
cally pure musellarins and analogues (>20 mg) for prelimi-
nary cytotoxicity evaluation, which led us to identify two an-
alogues with three-to-six times greater potency than the
musellarins as promising new leads.
Introduction
Achmatowicz rearrangement (AR) is a powerful transformation
that can convert furfuryl alcohols (I) into, otherwise poorly ac-
cessible, fully functionalized dihydropyranone acetals (also
known as pyranuloses; I!II, Figure 1) through an oxidative re-
arrangement process.[1] The synthetic utility[2] of AR products
has been considerably expanded in recent decades by identifi-
cation of new oxidants[3] (e.g., meta-chloroperbenzoic acid and
N-bromosuccinimide) and the development of highly efficient
transformations of dihydropyranone acetals (II), such as Kishi
reduction[4] (II!III; Figure 1), Feringa-O’Doherty O-glycosyla-
tion[5] (II!IV; Figure 1), [5+2] cycloaddition[6] (II!V; Figure 1),
and bicycloketalization[7] (II!VI; Figure 1). Exploiting these re-
actions as the key step provided efficient routes for the synthe-
sis of complex natural products[2] and a library of skeletally di-
verse compounds for biological activity studies.[8] In particular,
Kishi reduction has been widely recognized as the method of
choice for the synthesis of functionalized cis-2,6-dihydropyra-
Figure 1. Selected key transformations of AR products and structures of the
diarylheptanoids musellarin A–C. Ac=CH3CO, Boc=tert-butoxycarbonyl,
AR=Achmatowicz rearrangement, CSA=camphor sulfonic acid.
[a] Z. Li, Prof. Dr. R. Tong
Department of Chemistry
nones (cis-DHPOs; III) due to the reproducibly high yield and
predictable excellent cis diastereoselectivity (diastereomeric
ratio (d.r.)>20:1).[9] However, access to the corresponding
trans-DHPOs from AR products has been rarely explored and,
to the best of our knowledge, only two examples employing
Ferrier-type alkynylation (SnCl4, RCꢀCSiMe3) or allylation
(BF3·Et2O, allylsilane) were reported by Srihari and Sridhar[10]
The closely related trans arylation leading to trans-DHPOs (II!
VII; Figure 1) remains unknown. Herein, we disclose an effi-
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong (P. R. China)
Fax: (+852)2358-1594
E-mail: rtong@ust.hk
[b] Dr. F. C. F. Ip, Prof. Dr. N. Y. Ip
Division of Life Science & State Key Laboratory of Molecular Neuroscience
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501713.
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cient method that led to the first arylation of AR rearrange-
ment products (II) with excellent 2,6-trans diastereoselectivity
by an unprecedented regioselective reductive g-deoxygenation
and Heck–Matsuda coupling. The efficiency and utility of this
new trans arylation were demonstrated in the first asymmetric
total synthesis of the cytotoxic (À)-musellarins A–C[11] (Figure 1)
and twelve analogues in only seven steps from furfuryl alcohol
derivatives of type I.
Initially, we attempted direct arylation of pyranuloses 1a
and 1b by a Ferrier-type reaction[12] (e.g., via cyclic oxonium
ion 2a) or Tsuji–Trost-type allyl–aryl coupling[13] (e.g., via allyl-
palladium 2b)[14] (Scheme 1a). After extensive examination of
stable but undesired conjugate enone 4b and 2) unprecedent-
ed Heck–Matsuda reaction of d-keto cyclic enol ethers of type
4a.
Results and Discussion
After preliminary studies of Pd-catalyzed reductive deoxygena-
tion[17] of AR products that gave inseparable mixtures of 4a
and 4b, among other compounds, presumably via intermedi-
ate 2e (Scheme 1b), we concentrated our efforts on deoxyge-
nation by single-electron transfer (SET) by taking advantage of
the adjacent enone functionality (1a/1b!4a). As shown in
Table 1, SmI2 was first evaluated as the reducing agent because
Table 1. Selected conditions for regioselective g-deoxygenation of AR
products to 4a.[a]
Entry
R
M (SET)
Solvent
Time
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H (1a)
Ac (1b)
Piv
SmI2
SmI2
SmI2
SmI2
SmI2
SmI2
Mg
Mg
Fe
Zn
Zn
Zn
Zn
THF/H2O (60:1)
THF/H2O (60:1)
THF/H2O (60:1)
THF/H2O (60:1)
THF/MeOH (10:1)
THF/iPrOH (20:1)
MeOH
HOAc
HOAc
HOAc
HOAc
10 min
10 min
10 min
10 min
10 min
10 min
1.5 h
48 h
<5
82
42
0
35
26
0
10
49
81
23
72
68
60
0
Boc
Ac (1b)
Ac (1b)
Ac (1b)
Ac (1b)
Ac (1b)
Ac (1b)
H (1a)
Piv
48 h
1.5 h
1.5 h
3 h
3 h
11 h
HOAc
HOAc
CH2Cl2
MeOH
Boc
Ac (1b)
Ac(1b)
H (1a)
Zn
Zn
Zn
9 h
8 h
CH2Cl2
48
Scheme 1. a) Attempted direct arylation of AR products and b) postulated
indirect trans arylation. NBS=N-bromosuccinimide.
[a] The reaction was performed with AR products 1a, 1b, or derivatives
(20 mg). [b] Isolated yield of 4a. Piv=pivaloyl.
the various Lewis acids and palladium precatalysts along with
different arylmetal nucleophiles (see the Supporting Informa-
tion for the screening conditions), we were disappointed to
find that only PhB(OH)2/BF3·Et2O or TiCl4/ArZnCl promoted the
reaction and only gave 7–11% yield of 3. We speculated that
the unsuccessful arylation might be attributed to facile forma-
tion of the reactive oxidopyrylium ion 2c through loss of
water or acetic acid.[2a–c] The capricious reactivity of AR prod-
ucts under both acidic and basic conditions prompted us to
explore an indirect arylation approach based on a reduction–
oxidation process (Scheme 1b). Inspired by Schmidt’s seminal
work[15] on Heck–Matsuda[16] arylation of simple 6-substituted
dihydropyran enol ethers with aryl diazonium salts for trans-se-
lective synthesis of 2,6-disubstituted dihydropyrans, we envi-
sioned that g-deoxygenation of AR products with migration of
the double bond coupled with Heck–Matsuda arylation might
provide a viable solution for the synthesis of trans-2-aryl-6-
alkyl DHPOs VII (e.g., 3). Challenges in implementing this strat-
egy from a mechanistic point of view include 1) chemo- and
regioselective g-deoxygenation versus possible a- and g’-deox-
ygenation, and subsequent a-protonation versus potential g-
protonation that could produce the thermodynamically more-
it has been used in a number of efficient reductive deoxygena-
tion reactions.[18] Pleasingly, we found that SmI2 (2.4 equiv)
could efficiently reduce 1b at 08C within 10 min to provide
the deoxygenation product 4a in 82% yield as the exclusive
regioisomer (Table 1, entry 2) presumably through chemoselec-
tive g-deoxygenation followed by regioselective a-protonation
of 2d, whereas under identical conditions 1a gave a complex
mixture (Table 1, entry 1). Notably, g-protonation of 2d leading
to 4b did not occur, which could not be rationalized at this
stage without further experimentation. In addition, it was sur-
prising that 4a was stable to routine aqueous workup and
column chromatography on silica gel and did not isomerize to
the conjugate enone 4b, which permitted full spectroscopic
characterization of the product. Further screening of the reac-
tion conditions revealed that the efficiency of the g-deoxyge-
nation was highly dependent on the leaving group (Table 1,
entries 3 and 4), solvent (Table 1, entries 5 and 6), and the SET
reagent (Table 1, entries 7–9). Unexpectedly, during these
screenings we identified Zn (activated powder) in acetic acid
as a new, cheap, and competent system for the regioselective
g-deoxygenation (Table 1, entry 10).[19] In particular, the strict
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exclusion of oxygen from the reaction vessel required for the
SmI2 reaction was not necessary, which made the Zn reagent
an attractive and practical alternative. It was noted that the de-
oxygenation efficiency was solvent dependent (Table 1, en-
tries 10 and 11 versus 14–16) and that the SET metal (Table 1,
entries 8–10) had more influence on the yield than the leaving
group (Table 1, entries 10–13).
To further evaluate the efficiency and reproducibility of
these two systems (SmI2 versus Zn/HOAc) on a synthetically
useful scale (200 mg to 1.0 g) and to determine whether race-
mization occurs, we carried out AR of optically active substrate
6c (98% enantiomeric excess (ee); see Scheme 3 below for
preparation of 6c), then acetylation, and g-deoxygenation
(Scheme 2). The g-deoxygenation yield after reaction with SmI2
Scheme 2. Comparison of g-deoxygenation with Zn/HOAc and SmI2 on
a 200 mg scale with enantiomerically pure substrate. TIPS=triisopropylsilyl,
Tf=triflyl, Ms=mesityl, TBAF=tetrabutylammonium fluoride.
on a 200 mg scale dropped significantly to 25–45% (repeated
three times), even though no racemization was observed. In
contrast, Zn/HOAc gave a consistently high yield (77–81%) of
8c on a 200 mg, 500 mg, and 1.0 g scale without epimerization
(98% ee, repeated three times, the ee value of each run was
determined by chiral HPLC). These findings clearly suggested
that Zn/HOAc was the method of choice for large-scale g-deox-
ygenation of AR products, especially with the additional advan-
tages, which included easy operation (rt, no exclusion of
oxygen), low cost, and readily available reagents.
Scheme 3. Asymmetric total syntheses of (À)-musellarins A–C.
asymmetric total synthesis of musellarins A–C (Scheme 3)[21] by
exploiting Zn-mediated g-deoxygenation and Heck–Matsuda
coupling.
Our synthesis (Scheme 3) began with the preparation of
enantiomerically pure furfuryl alcohol 6a, which was obtained
in 89% yield from aldehyde 10a through a straightforward
five-step sequence: Horner–Wadsworth–Emmons (HWE) olefi-
nation, Pd-catalyzed hydrogenation, Weinreb amide formation,
lithiated furan addition, and Noyori asymmetric transfer hydro-
genation (ATH).[22] AR of 6a followed by acetylation provided
substrate 7a for the key g-deoxygenation step, which proceed-
ed smoothly under our optimized conditions (Zn/HOAc) to
afford 8a in 86% yield. Heck–Matsuda coupling of 8a with
one of three different aryl diazonium salts, corresponding to
musellarins A–C, was catalyzed by Pd(OAc)2 in acetonitrile at rt
to give 9a–c in excellent yield. Protection of the phenol group
of 9a as the acetate derivative (9a’) was required to minimize
destructive interference in the subsequent intramolecular Frie-
del–Crafts reaction, one of the key steps in this new synthetic
strategy. Chemoselective carbonyl reduction of 9a’ and 9b–
c with NaBH4 (or CeCl3-NaBH4, diisobutylaluminum hydride, or
LiBEt3H) gave a 1:1 to 1:4 diastereomeric mixture of secondary
alcohols that was subjected to triflic anhydride-promoted intra-
molecular Friedel–Crafts[23] cyclization at À788C for 4 h to pro-
vide the tetracyclic compounds 13a–c as single diastereomers
in excellent overall yield over two steps. Careful monitoring of
the reaction progress by TLC suggested that one diastereomer
With the optimal g-deoxygenation conditions in hand, we
explored the Heck–Matsuda coupling of 4a with aryl diazoni-
um salts postulated in Scheme 1b. Gratifyingly, after prelimina-
ry investigation of the palladium catalyst and solvent palladi-
um tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) was
found to rapidly catalyze the coupling of 4a with PhN2BF4 in
acetonitrile at rt to give trans-2,6-DHPO 3 in 88% yield as
1
a single diastereomer (d.r.ꢁ20:1, based on H NMR spectrosco-
py of the crude reaction mixture). Subsequently, we found that
Pd(OAc)2 was a more-effective and general precatalyst for elec-
tron-rich aryl diazonium salts such as (4-MeO)PhN2BF4. The 2,6-
trans-diastereoselectivity was further confirmed by NOE experi-
ments (see the Supporting Information). Notably, the d-carbon-
yl group of the dihydropyran 4a did not provoke any prob-
lems for the Heck–Matsuda coupling but facilitated b-hydride
elimination (5!3, Scheme 1b) to form the corresponding
thermodynamically favorable conjugate enone, which would
not undergo Pd-catalyzed migratory olefin isomerization
through the well-known hydridopalladium addition/elimination
sequence.[20] This exciting result prompted us to initiate the
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underwent rapid Friedel–Crafts cyclization (<0.5 h), whereas
the other was slowly consumed (3–4 h at À788C). Interestingly,
individual subjection of these two diastereomeric alcohols to
mesylation for the Friedel–Crafts cyclization revealed that the
trans isomer (13I) gave 88% yield after 3 h at 808C, whereas
the cis isomer (13II) afforded only 46% yield after 7 h under
identical conditions, along with significant decomposition (Ar
was 4-acetoxyphenyl, 3-methoxy-4-acetoxyphenyl, or 3-acetox-
yl-4-methoxyphenyl. These findings implied that reaction of
the cis isomer (13II) might involve a SN1-type mechanism (via
a carbocation such as 13III) and an SN2-type pathway might
operate for the trans isomer (13I). Although more work is nec-
essary to fully elucidate a detailed mechanism, we chose to
move forward. Global deprotection of 13a–c furnished (À)-mu-
sellarins A–C in 83–95% yield. All spectroscopic data for our
synthetic samples were in good agreement with those report-
ed for the natural musellarins A–C.[24] The identical sign of the
optical rotations of the synthetic and natural musellarins con-
firmed their absolute configurations.[24] This represents the first
asymmetric total synthesis of cytotoxic diarylheptanoids (À)-
musellarins A–C with 38–42% overall yield in 11–12 steps (lon-
gest linear sequence), which is much-more efficient than our
previous synthesis (7.8–9.8% yield, 15–16 steps).
The remarkable brevity and efficiency of our synthetic route,
enabled by the newly established reductive g-deoxygenation
and Heck–Matsuda reaction, was further demonstrated in the
Table 2. Examples of trans-2-aryl-6-alkyl DHPOs and their conversions to musellarins A–C and 12 analogues.
[a] Isolated yield from 6a–c over four steps. [b] Isolated yield from 9a–o over three/four steps. [c] IC50 [mM] was obtained in 48 h against HL60 by using ox-
aliplatin as the positive control (IC50 =1.6 mm).
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enantioselective synthesis of trans-2-aryl-6-alkyl DHPOs 9d–o
and 12 musellarin analogues 14d–o (Table 2). Three different
aromatic aldehydes (10a–c) and five readily available aryl di-
azonium salts (i–v)[21,24] were employed in our studies to show-
case the efficiency and utility of the two-step trans-arylation
method to access trans-DHPOs of type VII. A three/four step
elaboration of trans-DHPOs 9a–o produced 12 enantiomeri-
cally pure analogues 14d–o with comparable overall yields
(19–48% yield, 20–56 mg) to the above-described musellarins.
Because naturally occurring musellarin B (14b) was reported
to be cytotoxic to several cancer cell lines with IC50 values
ranging from 21.3 mm (HL-60) to >40 mm (MCF7)[11b] and mu-
sellarin A was shown to significantly induce quinone reductase
(QR) activity (9.3 mm),[11a,25] we performed a preliminary evalua-
tion of the cytotoxicity of 14a–o against cancer cell lines HL60
(blood), HepG2 (liver), and MCF7 (breast) by using normal cells
of primary cortical neurons (PCN) as a selectivity reference. As
shown in Table 3, our synthetic musellarins were moderately
logues 14d and 14k as promising antitumor lead compounds
selective against HL60.
Experimental Section
Deoxygenation
Method a: Compound 1b (0.11 g, 0.51 mmol) dissolved in THF/
H2O (6.0:0.1 mL) was added to a stirred solution of SmI2 (0.1m in
THF, 11.6 mL, 1.16 mmol) in a round-bottomed flask at 08C. The re-
action mixture was stirred for 10 min, then the reaction was
quenched by addition of a saturated aqueous solution of NaHCO3
(10 mL) and extracted with EtOAc (3”5 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/
EtOAc=10:1) to afford 4a (133 mg, 0.95 mmol, 82%) as a colorless
oil.
Method b: Activated Zn powder (0.16 g, 2.53 mmol) was added to
a stirred solution of 1b (0.11 g, 0.51 mmol) in acetic acid (5 mL) at
rt. The reaction mixture was stirred for 1.5 h. The reaction was
quenched by addition of a saturated aqueous solution of K2CO3
(10 mL) and extracted with CH2Cl2 (3”5 mL). Workup and purifica-
tion as described for method a gave 4a (132 mg, 0.94 mmol, 81%).
Table 3. Cytotoxicity of musellarins A–C and selected analogues.[a]
Compound
PCN[b] IC50
[mM]
HL60 IC50
[mM]
HepG2 IC50
[mM]
MCF7 IC50
[M]
Heck–Matsuda Coupling
14a (musellarin A)
14b (musellarin B)
14c (musellarin C)
14d
23.8
65.3
>50
23.6
33.1
29.6
>50
17.7
N/A[d]
9.7
25.9
22.0
7.4
11.9
10.8
23.1
3.9
44.1
>50
>50
>50
>50
>50
46.1
>50
>50
>50
>50
>50
>50
>50
>50
12.99
Phenyldiazonium tetrafluoroborate (53.1 mg, 0.27 mmol), NaOAc
(56 mg, 0.69 mmol), and Pd2(dba)3 (16.8 mg, 18.1 mmol) were
added to a stirred solution of 4a (32.1 mg, 0.23 mmol) in CH3CN
(3 mL) at rt. The reaction mixture was stirred for 3 h. The reaction
was quenched by addition of a saturated aqueous solution of
NH4Cl (5 mL) and extracted with EtOAc (3”5 mL). The combined
organic fractions were washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The resulting res-
idue was purified by flash column chromatography on silica gel
(hexane/EtOAc=8:1) to afford 3 (43.8 mg, 0.20 mmol, 88%) as
a reddish oil.
14e
14i
14j
14k
40.4
5.28
oxaliplatin[c]
1.56
[a] IC50 [mM] was obtained in 48 h. [b] PCN=primary cortical neurons.
[c] Oxaliplatin was used as the positive control [mM]. [d] Not applicable.
active to HL60 but inactive to HepG2 and MCF7, consistent
with the corresponding reported cytotoxicity of the natural
musellarins. Notably, analogues 14d and 14k have a more-
potent and selective in vitro antitumor activity against HL60
with IC50 values of 7.4 (selectivity index: 3.19) and 3.9 mm (se-
lectivity index: 4.54), respectively,[24] whereas they are inactive
(IC50 >40 mm) to HepG2 and MCF7.
Acknowledgements
This research was financially supported by the Hong Kong Uni-
versity of Science and Technology (HKUST) (R9309), the Re-
search Grant Council of Hong Kong (ECS 605912, GRF 605113,
and GRF 16305314), and the National Natural Science Founda-
tion of China (NSFC 21472160). The authors are also grateful to
Prof. Dr. Ian Williams (HKUST) and Dr. Herman Sung (HKUST)
for the single-crystal X-Ray diffraction analyses.
Conclusion
We have developed a highly regio- and diastereoselective
trans arylation of AR products by an unprecedented Zn-medi-
ated reductive g-deoxygenation and Heck–Matsuda reaction,
leading to a novel, efficient, and stereoselective synthesis of
trans-2-aryl-6-alkyl DHPOs. The synthetic utility of this new
trans-arylation method was demonstrated in the first asymmet-
ric total synthesis of (À)-musellarins A–C and 12 analogues. Im-
portantly, this protocol can greatly expand the utility of AR in
the synthesis of tetrahydropyran-containing natural products
and might be exploited for stereoselective C-aryl glycosyla-
tion.[26] Finally, preliminary cytotoxicity evaluation of the tetra-
cyclic diarylheptanoids synthesized allowed us to identify ana-
Keywords: Achmatowicz rearrangement
musellarins · total synthesis · zinc
·
arylation
·
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Received: May 1, 2015
Published online on June 24, 2015
Chem. Eur. J. 2015, 21, 11152 – 11157
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