Total synthesis of linoxepin through a palladium-catalyzed domino reaction

Article abstract of DOI:10.1002/anie.201209868

Convergent and elegant: Linoxepin (see picture), a new lignan with an unusual oxepin moiety, has been synthesized in only 10 steps. The protecting-group-free total synthesis includes a palladium- catalyzed Sonogashira reaction and a domino carbopalladation/Heck reaction of an allylsilane.

Full text of DOI:10.1002/anie.201209868

Angewandte
Chemie
DOI: 10.1002/anie.201209868
Total Synthesis
Total Synthesis of Linoxepin through a Palladium-Catalyzed Domino
Reaction**
Lutz F. Tietze,* Svenia-C. Duefert, Jꢀrꢁme Clerc, Matthias Bischoff, Christian Maaß, and
Dietmar Stalke
Dedicated to Professor Wolfgang A. Herrmann on the occasion of his 65th birthday
The natural product linoxepin (1) belongs to the aryldihy-
dronaphthalene lignans and contains a for this class of
compounds so far unprecedented benzonaphtho[1,8-bc]oxe-
pine moiety. It was first isolated by Schmidt et al. in 2007 from
Linum perenne L. (Linaceae), and its absolute configuration
was determined by CD spectroscopy in combination with
DFT calculations.[1] To date neither a synthetic approach nor
any biological studies have been reported. Owing to its close
structural resemblance to lignans showing interesting biolog-
Scheme 1. Retrosynthetic analysis of linoxepin (1).
ical profiles (such as podophyllotoxin and the clinically used
anticancer agents etoposide and teniposide), the novel lignan
is an attractive synthetic goal. To meet the requirements of
modern synthetic chemistry and fulfill the demand for an
ecologically and economically advantageous approach we
developed a novel Pd-catalyzed domino process[2] for its
synthesis, which is also suitable for the preparation of
analogues. Herein we describe the first total synthesis of
(+)- and (ꢀ)-linoxepin (1) in only ten steps and an overall
yield of 30% without the use of any protecting groups.
The retrosynthetic analysis of 1, based on a threefold Pd-
catalyzed domino process that consists of a Sonogashira
Scheme 2. a) MeOCH2PPh3Cl, KOtBu, THF, 08C!RT, 75 min, 97%;
b) 10% HCl (aq.), THF, 708C, 30 min, 82%, c) H3CPPh3Br, KOtBu,
THF, 08C, 75 min, 94%; d) lithium diisopropylamide (LDA), THF,
ꢀ788C, 30 min, then DMF, ꢀ788C, 14 h; e) NaBH4, EtOH, 08C!RT,
1 h, 84% over 2 steps; f) PBr3, CH2Cl2, RT, 18 h, 89%; g) K2CO3,
MeCN, 808C, 1 h, 91%.
reaction, a carbopalladation,[3] and a Heck-type reaction,
leads to substrates 2 and 3, where 2 is accessible from phenol 4
and benzylbromide 5 (Scheme 1).
The synthesis of 4 was accomplished in three steps from
the aldehyde 6 (Scheme 2).[4] Wittig reaction of 6 using
[*] Prof. Dr. L. F. Tietze, Dipl.-Chem. S.-C. Duefert, Dr. J. Clerc,
Dr. M. Bischoff
MeOCH2PPh3Cl and subsequent hydrolysis of the formed
methyl enol ether afforded aldehyde 7, which was trans-
formed into alkene 4 by another Wittig transformation in an
overall yield of 75%.[5] Benzyl alcohol 9 was prepared from
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: ltietze@gwdg.de
8
[6] by formylation and subsequent reduction.[7] Reaction of 9
Dipl.-Chem. C. Maaß, Prof. Dr. D. Stalke
Institut fꢀr Anorganische Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
with phosphorus tribromide led to benzyl bromide 5 in an
overall yield of 75%. Coupling of 4 and 5 under basic
conditions afforded the domino precursor 2 in 91% yield.[8]
Treatment of 2 and 3 with [Pd(PPh3)4] as catalyst and
TBAF·3 H2O as base at 808C in DME allowed us to perform
the envisioned domino Sonogashira/carbopalladation/Heck
reaction with 50% yield, but the final product was not the
expected compound 10 but the aromatic system 11, which is
probably formed from 10 under the employed reaction
conditions (Scheme 3).
[**] We thank the German Research Foundation (DFG), the Land
Niedersachsen, the Volkswagen Foundation, and the Fonds der
Chemischen Industrie for financial support. Special thanks to S. L.
Buchwald for providing a sample of the KenPhos ligand. S.-C.D.
thanks the Konrad Adenauer Foundation for a doctoral fellowship.
J.C. thanks the Alexander von Humboldt Foundation for a postdoc-
toral fellowship. C.M. thanks the Land Niedersachsen for providing
a fellowship in the Catalysis for Sustainable Synthesis (CaSuS) Ph.D.
program. The photograph in the graphical abstract was taken by
Thomas Hundtke.
The synthetic strategy was therefore adjusted by including
a silyl-terminated Heck reaction[9] as the last step of the
domino process employing an allysilane moiety to allow
a controlled elimination of a formal “PdSi” species. In this
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209868.
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desired terminal alkene 14a in 76% yield; in addition 13% of
the vinylsilane 14b was isolated. We used several other achiral
and also chiral ligands, such as BINAP and KenPhos,[10] as
well as different Pd sources. In all these cases the yields of the
desired compound 14a were lower. Moreover, when using the
chiral ligands an enantioselective reaction was not observed.
A final explanation for this result cannot be given yet.
For the completion of the total synthesis of linoxepin (1),
the alcohol 14a was oxidized in a two-step procedure using
the Dess–Martin periodinane and subsequently the Pinnick
oxidation to give the corresponding acid, which was trans-
formed into the methyl ester 17 by means of trimethylsilyl-
diazomethane in 91% yield over three steps. Controlled
ozonolysis in the presence of the dye solvent red 19 allowed
a selective cleavage of the vinyl group,[11] and finally reductive
work-up of the reaction mixture directly afforded racemic
linoxepin (1) in 80% yield.
Scheme 3. Domino Sonogashira/carbopalladation/Heck reaction:
a) [Pd(PPh3)4], tetrabutylammonium fluoride (TBAF)·3H2O, 1,2-dimeth-
oxyethane (DME), 808C, 24 h, 50%.
way a vinyl substituent, instead of the exo-methylene group as
in 10, would be formed, which should not undergo an
isomerization to give the corresponding undesired aromatic
system. The substrate for the Pd-catalyzed reaction is again
easily accessible (Scheme 4). Wittig reaction of aldehyde 7
with methyltriphenylphosphonium bromide and (iodometh-
yl)trimethylsilane afforded the allylsilane in 68% yield.
Alkylation with benzyl bromide 5 gave benzyl aryl ether 12.
Here we preferred to perform the Sonogashira reaction
separately, which is more reliable and gives better yields than
its inclusion into a threefold domino process. This is mainly
due to the fact that CuI cannot be used in the domino process,
since it inhibits the carbopalladation and the Heck reaction.
Treatment of 12 with propargyl alcohol (3) in the presence of
catalytic amounts of [Pd(PPh3)4] and CuI as well as Bu4NOAc
as base at 608C for 30 min provided alkyne 13 in 98% yield.
In the following domino carbopalladation/Heck reaction
best results were obtained by using Pd(OAc)2 with XPhos as
ligand and Bu4NOAc as base in DME at 808C to afford the
To prepare the two enantiomers (+)-(R)- and (ꢀ)-(S)-
linoxepin, the racemic alcohol 14a was resolved by chroma-
tography on chiral support using an IA column. The following
steps were identical with those used in the synthesis of the
racemic compound. The spectroscopic data of the final
products are in good agreement with those published by
Schmidt et al.[1] except the optical rotation, which with
22
½aꢁD ¼ + 96.1 is higher than the published value with
20
½aꢁD ¼ + 23. In contrast, the CD spectrum of the synthetic
(+)-linoxepin (1) corresponds very well with that of the
natural material.
To confirm the proposed absolute configuration of the
natural (+)-linoxepin (1) we analyzed crystals of the unnatu-
ral (ꢀ)-linoxepin (ent-1), which gave crystals of higher quality.
Owing to the lack of a heavy atom, the dataset was collected
using the Ka radiation of a copper rotating anode. The single-
crystal X-ray diffraction analysis showed that (ꢀ)-linoxepin
(ent-1) has the S configuration, thereby proving the R confi-
guration for the natural product (Figure 1).[12,13]
Figure 1. Crystal structure of (ꢀ)-(S)-linoxepin (ent-1). (Flack x parame-
ter: ꢀ0.05(8)).[14] The hydrogen atoms apart from H3 are omitted for
clarity, and the anisotropic displacement parameters are depicted at
the 50% probability level.
Scheme 4. Synthesis of linoxepin (1): a) Ph3PCH3Br, KOtBu,
ICH2SiMe3, THF, 08C, 3 days, 68%; b) 5, K2CO3, MeCN, 808C, 5 h,
99%; c) 3, [Pd(PPh3)4] (7 mol%), CuI (10 mol%), Bu4NOAc, dioxane,
608C, 30 min, 98%; d) Pd(OAc)2 (5 mol%), XPhos (7.5 mol%),
Bu4NOAc, DME, 808C, 1 h, 76% 14a and 13% 14b; e) Dess–Martin
periodinane, CH2Cl2, RT, 2 h, 92%; f) NaClO2, NaH2PO4·H2O in H2O,
2-methyl-2-butene, tBuOH/THF 4:1, RT, 2 days, 99%; g) TMSCHN2
(2 m in Et2O), benzene/MeOH 10:1, 08C, 15 min, quant.; h) O3,
solvent red 19 (0.05% in EtOH), EtOH, ꢀ788C, then NaBH4,
ꢀ788C!RT, 16 h, 80%.
In conclusion we have developed a highly elegant and
very robust synthesis, which includes multiple Pd-catalyzed
reactions, of the lignan linoxepin (1) by using a Sonogashira
reaction and a domino carbopalladation/Heck reaction of an
allylsilane. This synthesis offers a high degree of versatility in
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respect to aromatic substitution patterns and functional group
tolerance to also prepare analogues.
Received: December 10, 2012
Published online: February 12, 2013
Keywords: domino reactions · lignans · palladium ·
.
structure elucidation · total synthesis
Experimental Section
(11-Methoxy-7-vinyl-8,13-dihydro-7H-[1,3]dioxolo[4’,5’:3,4]benzo-
[1,2-e]naphtho[1,8-bc]oxepin-6-yl)methanol (14a): An oven-dried
flask was charged with alkyne 13 (1.00 g, 1.93 mmol, 1.00 equiv),
Pd(OAc)2 (21.7 mg, 96.5 mmol, 5.00 mol%), XPhos (69.1 mg,
145 mmol, 7.50 mol%), and tetrabutylammonium acetate (1.16 g,
3.86 mmol, 2.00 equiv). DME (20 mL) was added and the mixture was
heated to 808C for 1.5 h (preheated oil bath). The reaction mixture
was diluted with CH2Cl2 (30 mL), silica gel was added, and the solvent
was removed in vacuo. Column chromatography (SiO2, PE/EA =
4:1!3:1) yielded the desired product (535 mg, 1.47 mmol, 76%) as
a colorless foam in approximately 95% purity. In addition the vinyl
silane 14b (112 mg, 0.257 mmol, 13%) was isolated as by-product.
Rf = 0.23 (PE/EA = 2:1). UV(CH3CN): lmax (lge) = 200.0 nm (4.598),
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~
286.0 (4.041). IR (neat): n ¼3287, 2911, 1462, 1432, 1258, 1232, 1214,
1099, 1029, 1011 cmꢀ1. 1H NMR (300 MHz, CDCl3): d = 2.73 (dd, J =
14.9, 1.7 Hz, 1H, 8’-HA), 3.01 (ddd, J = 14.9, 5.7, 0.8 Hz, 1H, 8’-HB),
3.30 (t, J = 5.7 Hz, 1H, 7’-H), 3.79 (s, 3H, OCH3), 4.16 (q, J = 11.8 Hz,
2H, 1’-H2), 4.91 (ddd, J = 10.1, 1.6, 0.9 Hz, 1H, 2’’-HA), 5.09 (d, J =
12.3 Hz, 1H, 13-HA), 5.06–5.16 (m, 1H, 2’’-HB), 5.23–5.34 (m, 1H,
OH), 5.31 (d, J = 12.3 Hz, 1H, 13-HB), 5.74 (ddd, J = 17.3, 10.1,
7.4 Hz, 1H, 1’’-H), 5.98 (dd, J = 10.5, 1.4 Hz, 2H, 2’-H2), 6.65 (d, J =
8.1 Hz, 1H, 10’-H), 6.68–6.73 (m, 2H, 9’-H, 4’-H), 6.76 ppm (d, J =
7.9 Hz, 1H, 5’-H); 13C NMR (125 MHz, CDCl3): d = 35.5 (C-8’), 39.8
(C-7’), 56.0 (OCH3), 62.7 (C-1), 64.2 (C-13’), 101.5 (C-2’), 107.7 (C-4’),
109.7 (C-10’), 115.2 (C-2’’), 117.7 (C-13a’), 119.9 (C-9’), 121.8 (C-5b1’),
122.6 (C-5’), 128.0 (C-8a’), 133.2 (C-5a’), 133.6 (C-5b’), 137.3 (C-1’’),
139.6 (C-6), 144.7 (C-13b’), 146.0 (C-11a’), 147.4 (C-3a’), 148.6 ppm
(C-11’). MS (ESI): m/z (%) = 387.1 (64) [M+Na]+, 751.3 (100)
[2M+Na]+, 1115.4 (86) [3M+Na]+. HRMS (ESI): m/z calc. for
C22H20O5: 387.1203, found: 387.1203, [M+Na]+.
Linoxepin (1): Ester 17 (39 mg, 0.10 mmol, 1.0 equiv) was
dissolved in EtOH (10 mL) (ultrasonic bath), a solution of solvent
red 19 (0.05% in EtOH, 0.60 mL) was added and the red solution was
cooled to ꢀ788C. O3 was bubbled through the solution until the red
color vanished. Then Ar was bubbled through the solution to remove
excess O3. Sodium borohydride (15 mg, 0.40 mmol, 4.0 equiv) was
added and the mixture was allowed to warm to RT overnight. The
solution was separated from the yellow residue, poured into sat. aq.
NH4Cl sol. (30 mL) and extracted with CH2Cl2 (2 ꢀ 30 mL). The
yellow residue was dissolved in CH2Cl2 (10 mL), the organic phases
were combined and dried over MgSO4. After removal of the solvent
in vacuo, column chromatography (SiO2, CH2Cl2) afforded the
desired product (29 mg, 0.08 mmol, 80%) as a yellow solid. Rf =
0.21 (PE/EA = 2:1). 1H NMR (300 MHz, CDCl3): d = 2.64 (dt, J =
14.9, 1.1 Hz, 1H, 9-HA), 2.98 (dd, J = 14.6, 5.7 Hz, 1H, 9-HB), 3.26
(ddt, J = 14.6, 8.8, 5.7 Hz, 1H, 9a-H), 3.83 (s, 3H, OCH3), 4.01 (t, J =
8.7 Hz, 1H, 10-HA), 4.66 (t, J = 8.9 Hz, 1H, 10-HB), 5.12 (d, J =
12.5 Hz, 1H, 4-HA), 5.37 (d, J = 12.5 Hz, 1H, 4-HB), 6.01 (d, J =
1.9 Hz, 1H, 2-HA), 6.01 (d, J = 1.9 Hz, 1H, 2-HB), 6.72 (d, J =
8.0 Hz, 1H, 14-H), 6.78 (d, J = 8.2 Hz, 1H, 7-H), 6.83 (d, J = 8.2 Hz,
1H, 8-H), 6.85 ppm (d, J = 8.0 Hz, 1H, 13-H); 13C NMR (150 MHz,
CDCl3): d = 34.5 (C-9), 36.9 (C-9a), 56.2 (OCH3), 64.7 (C-4), 70.0 (C-
10), 101.8 (C-2), 108.1 (C-14), 111.8 (C-7), 116.5 (C-3b), 119.8 (C-8),
122.2 (C-5a1), 124.1 (C-13), 124.3 (C-12a), 128.1 (C-8a), 129.4 (C-12c),
144.7 (C-3a), 145.6 (C-12b), 148.5 (C-5a), 149.0 (C-14a), 149.4 (C-6),
168.7 ppm (C-12). MS (ESI): m/z (%) = 365.1 (46) [M+H]+, 387.1
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(98) [M+Na]+, 751.2 (100) [2M+Na]+ 1115.3 (17) [3M+Na]+.
,
HRMS (ESI): m/z calc. for C21H16O6: 365.1020, found: 365.1019,
[M+H]+.
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