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DOI: 10.1055/s-0029-1219371
Synthesis of Nemorosone via a Difficult Bridgehead Substitution Reaction
Publication History
Publication Date:
08 February 2010 (online)
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Abstract
The synthesis of nemorosone, a polyprenylated acylphloroglucinol isolated from Clusia rosea, was achieved by means of a bridgehead substitution process, involving initial iodination and subsequent lithium-iodine exchange followed by acylation. The difficulties in the bridgehead substitution are discussed, and a probable explanation proposed, based on molecular modelling.
Key words
nemorosone - bridgehead substitution - iodine-lithium exchange - B3LYP calculations
- For a comprehensive review, see:
-
1a
Ciochina R.Grossman RB. Chem. Rev. 2006, 106: 3963 -
1b See also:
Verotta L. Phytochem. Rev. 2002, 1: 389 - For syntheses, see:
-
2a
Kuramochi A.Usuda H.Yamatsugu K.Kanai M.Shibasaki M. J. Am. Chem. Soc. 2005, 127: 14200 -
2b
Siegel DR.Danishefsky SJ.
J. Am. Chem. Soc. 2006, 128: 1048 -
2c
Rodeschini V.Ahmad NM.Simpkins NS. Org. Lett. 2006, 8: 5283 -
2d
Ahmad NM.Rodeschini V.Simpkins NS.Ward SE.Blake AJ. J. Org. Chem. 2007, 72: 4803 -
2e
Nuhant P.David M.Pouplin T.Delpech B.Marazano C. Org. Lett. 2007, 9: 287 -
2f
Qi J.Porco JA. J. Am. Chem. Soc. 2007, 129: 12682 -
2g
Tsukano C.Siegel DR.Danishefsky SJ. Angew. Chem. Int. Ed. 2007, 46: 840 - For very recent synthetic efforts, and further leading references, see:
-
3a
Couladouros EA.Dakanali M.Demadis KD.Vidali VP. Org. Lett. 2009, 11: 4430 -
3b
Mitasev B.Porco JA. Org. Lett. 2009, 11: 2285 -
3c See also:
Rodeschini V.Simpkins NS.Wilson C.
J. Org. Chem. 2007, 72: 4265 - 4
Ahmad NM.Rodeschini V.Simpkins NS.Ward SE.Wilson C. Org. Biomol. Chem. 2007, 5: 1924 - Nemorosone - corrected structure:
-
5a
Cuesta-Rubio O.Velez-Castro H.Frontana-Uribe BA.Cárdenas J. Phytochem. 2001, 57: 279 - Cytotoxicity studies:
-
5b
Cuesta-Rubio O.Frontana-Uribe BA.Ramirez-Apan T.Cárdenas J. Z. Naturforsch., C: Biosci. 2002, 57: 372 -
5c
Diaz-Carballo D.Malak S.Bardenheuer W.Freistuehler M.Reusch HP. J. Cell. Mol. Med. 2008, 12: 2598 -
5d
Diaz-Carballo D.Malak S.Freistuehler M.Elmaagacli A.Bardenheuer W.Reusch HP. Int. J. Clin. Pharm. Ther. 2008, 46: 428 -
5e
Diaz-Carballo D.Seeber S.Strumberg D.Hilger RA. Int. J. Clin. Pharm. Ther. 2003, 41: 622 -
6a
Schönwälder K.-H.Kollat P.Stezowski JJ.Effenberger F. Chem. Ber. 1984, 117: 3280 -
6b Our approach was inspired
by a paper from the Stoltz group, see:
Spessard SJ.Stoltz BM. Org. Lett. 2002, 4: 1943 - 11
Hayes CJ.Simpkins NS.Kirk DT.Mitchell L.Baudoux J.Blake AJ.Wilson C. J. Am. Chem. Soc. 2009, 131: 8196 - 12
Computational
Methods
Geometry optimisations were performed using
the B3LYP/6-31G* level of theory using Spartan
04 (Windows), and zero-point vibrational energies were calculated
for all structures, and the absence of imaginary frequencies was used
to characterise the structures as minima on their potential energy
surfaces. NBO calculations were performed on all anionic species
using the NBO keyword in Spartan 04 (Windows):
Kong J.White CA.Krylov AI.Sherrill D.Adamson RD.Furlani TR.Lee MS.Lee AM.Gwaltney SR.Adams TR.Ochsenfeld C.Gilbert ATB.Kedziora GS.Rassolov VA.Maurice DR.Nair N.Shao Y.Besley NA.Maslen PE.Dombroski JP.Daschel H.Zhang W.Korambath PP.Baker J.Byrd EFC.Van Voorhis T.Oumi M.Hirata S.Hsu C.-P.Ishikawa N.Florian J.Warshel A.Johnson BG.Gill PMW.Head-Gordon M.Pople JA. J. Comput. Chem. 2000, 21: 1532
References and Notes
Preparation of
10
LTMP (22.6 mL of a freshly prepared 0.5 M solution
in THF, 11.3 mmol) was added dropwise to
a solution of O-methylated trione 9 (1.95
g, 5.7 mmol) in THF (60 mL) at
-78 ˚C.
The reaction mixture was stirred for 5 min before addition of TMSCl
(2.87 mL, 22.6 mmol). The reaction mixture was stirred and allowed
to warm to -40 ˚C over 2 h. The reaction was quenched
with NH4Cl solution (30 mL), and the product was extracted
with Et2O (3 × 40 mL). The combined
organic extracts were dried (MgSO4), and the solvent
was removed under reduced pressure. Purification of the residue
by flash column chromatography (10% Et2O in PE)
afforded vinylsilane 10 as a white solid
(2.21 g, 94%); mp 46-48 ˚C; R
f
= 0.34
(10% EtOAc in PE). ¹H NMR (500 MHz,
CDCl3): δ = 4.96-4.92
(m, 2 H), 3.73 (s, 3 H), 3.22 (s, 1 H), 2.40 (dd, J = 14.3,
7.7 Hz, 1 H), 2.32 (dd, J = 14.3,
7.7 Hz, 1 H), 2.04 (dd, J = 13.2,
5.1 Hz, 1 H), 1.91 (dd, J = 13.2, 4.0
Hz, 1 H), 1.66 (s, 3 H), 1.63 (s, 3 H), 1.60 (t, J = 13.2
Hz, 1 H), 1.59 (s, 3 H), 1.53 (s, 3 H), 1.54-1.51 (m, 1
H), 1.28 (app. t, J = 12.8
Hz, 1 H), 1.09 (s, 3 H), 0.94 (s, 3 H), 0.16 (s, 9 H). ¹³C
NMR (125 MHz, CDCl3): δ = 208.4,
201.9, 177.9, 133.6, 133.2, 123.5, 122.3, 119.6, 63.7, 61.1, 55.8,
42.8, 41.0, 39.4, 29.6, 27.9, 25.8, 25.73, 25.72, 20.9, 18.0, 17.8, 0.33.
ESI-HRMS (TOF): m/z calcd for
C25H40O3Si [M + H]+: 417.2820;
found: 417.2823. IR: ν = 2975 (s), 2911 (s), 1731 (s),
1641 (s), 1560 (s), 1447 (m), 1219 (s), 1057 (w), 842 (s) cm-¹.
Preparation of 11
LDA (4.9 mL
of a freshly prepared 0.5 M solution in THF, 2.44 mmol) was added
dropwise to a solution of TMS-protected enone 10 (253
mg, 0.61 mmol) and TMSCl (0.31 mL, 2.44 mmol) in THF (2 mL) at -78 ˚C.
The reaction mixture was stirred at -78 ˚C
for 10 min before removal of the cold bath and warming to 0 ˚C
over 30 min. The reaction mixture was then cooled to -78 ˚C,
and a solution of iodine (709 mg, 5.5 mmol) in THF (2 mL) was added.
The reaction mixture was stirred at -78 ˚C for
10 min before stirring at 0 ˚C for 30 min. The reaction
mixture was diluted with EtOAc (20 mL) before washing with Na2SO3 solution
(3 × 10 mL) and brine (3 × 10
mL). The organic layer was separated, and the solvent was removed
under reduced pressure. The residue was subjected to flash column
chromatography (5% EtOAc in PE) to afford bridgehead iodide 11 as a white solid (214 mg, 65%);
mp 59-61 ˚C; R
f
= 0.5
(10% EtOAc in PE). ¹H NMR (500 MHz,
CDCl3): δ = 5.04
(t, J = 7.2 Hz, 1 H), 4.95 (t, J = 7.2 Hz,
1 H), 3.92 (s, 3 H), 2.46-2.38 (m, 2 H), 2.17 (dd, J = 13.4,
5.3 Hz, 1 H), 1.80-1.73 (m, 2 H), 1.69-1.63 (m,
1 H), 1.62 (s, 3 H), 1.60 (s, 3 H), 1.51 (s, 6 H), 1.39 (app. t, J = 14.3 Hz,
1 H), 1.23 (s, 3 H), 0.88 (s, 3 H), 0.22 (s, 9 H). ¹³C
NMR (125 MHz, CDCl3): δ = 200.0,
199.9, 178.9, 134.0, 133.4, 125.2, 122.2, 119.6, 86.0, 65.6, 65.5,
47.7, 40.9, 38.9, 30.4, 30.2, 29.0, 25.8, 25.6, 20.6, 17.9, 17.8,
0.3. ESI-HRMS (TOF): m/z calcd
for C25H39IO3Si [M + H]+: 543.1791;
found: 543.1779. IR: ν = 2976
(m), 1734 (s), 1654 (s), 1548 (s), 1437 (m), 1250 (s), 1034 (w),
848 (s), 758 (s) cm-¹.
Preparation of 12
n-BuLi (0.17 mL of a 2.5 M solution in
hexanes, 0.43 mmol) was added dropwise to a solution of bridgehead
iodide 11 (196 mg, 0.36 mmol) in THF (3
mL) at -78 ˚C. The reaction mixture was stirred
at -78 ˚C for 5 min before adding benzoyl chloride
(50 µL, 0.43 mmol) dropwise at this temperature. The reaction
mixture was stirred for 1 h at -78 ˚C and at r.t.
for 30 min. The reaction was quenched with NH4Cl solution
(10 mL), and the product was extracted into Et2O (3 × 15
mL). The combined organic layers were dried (MgSO4),
and the solvent was removed under reduced pressure. Purification
of the residue by flash column chromatography (10% Et2O
in PE) gave the bridgehead benzoylated product, ready for the desilylation
(117 mg, 63%). A solution of TBAF (0.33 mL of a 1 M solution
in THF, 0.33 mmol) was added to a solution of the product obtained
above (117 mg, 0.22 mmol) in THF (3 mL) at -78 ˚C.
The reaction mixture was allowed to warm to r.t. over 1.5 h before
quenching with NH4Cl solution (10 mL). The product was
extracted into Et2O (3 × 15
mL), and the combined organic layers were dried (MgSO4).
Removal of the solvent under reduced pressure and purification of
the residue by flash column chromatography (100% CH2Cl2) gave
the benzoylated product 12 as a white solid
(80 mg, 81%); mp 141-142 ˚C
(subl.); R
f
= 0.40
(20% EtOAc in PE). ¹H NMR (500 MHz,
CDCl3): δ = 7.59
(d, J = 7.3
Hz, 2 H), 7.42 (t, J = 7.3
Hz, 1 H), 7.27 (app. t, J = 7.9
Hz, 2 H), 5.94 (s, 1 H), 5.00 (t, J = 7.0
Hz, 1 H), 4.96 (t, J = 7.0
Hz, 1 H), 3.50 (s, 3 H), 2.56 (dd, J = 14.3,
7.0 Hz, 1 H), 2.44 (dd, J = 14.2,
7.2 Hz, 1 H), 2.12 (dd, J = 13.2,
5.1 Hz, 1 H), 1.98 (dd, J = 13.2,
4.4 Hz, 1 H), 1.79-1.72 (m, 1 H), 1.71-1.62 (m,
1 H), 1.66 (s, 3 H), 1.65 (s, 3 H), 1.64 (s, 3 H), 1.55 (s, 3 H),
1.45 (app. t, J = 13.0
Hz, 1 H), 1.34 (s, 3 H), 1.18 (s, 3 H). ¹³C
NMR (125 MHz, CDCl3): δ = 207.3,
196.1, 192.5, 173.8, 137.0, 134.4, 133.3, 132.1, 127.92, 127.91,
122.3, 119.5, 106.5, 72.4, 65.6, 56.5, 47.5, 42.6, 42.5, 29.0, 27.7, 25.9,
25.8, 24.3, 18.1, 17.8, 15.8. ESI-HRMS (TOF): m/z calcd
for C29H36O4 [M + H]+:
449.2692; found: 449.2691. IR: ν = 2931
(m), 1720 (s), 1655 (s), 1606 (s), 1445 (w), 1344 (m), 1237 (s),
1218 (s) cm-¹.
Preparation
of Nemorosone (4)
LTMP (5.8 mL of a freshly prepared
0.1 M solution in THF, 0.58 mmol) was added to a solution of enone 12 (130 mg, 0.29 mmol) in THF (8 mL) at -78 ˚C.
The reaction mixture was stirred for 30 min before addition of Li(2-Th)CuCN
(5.8 mL of a freshly prepared 0.1 M solution in THF, 0.58 mmol). The
reaction mixture was stirred at -78 ˚C for 5 min
and at -40 ˚C for 30 min. The reaction
mixture was then cooled
to -78 ˚C and
prenyl bromide (0.17 mL, 1.45 mmol) was added. The reaction mixture
was warmed to -30 ˚C over 1.5 h before quenching
with NH4Cl/NH4OH solution (10% w/w, 20
mL). The product was extracted with Et2O (3 × 20
mL), and the combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. Purification by flash column
chromatography (CH2Cl2-PE, 1:1) afforded
O-methylated nemorosone as a white solid (83 mg, 55%).
This intermediate (41 mg, 79 µmol) and LiCl (29 mg, 0.68
mmol) were dissolved in DMSO-d
6 (0.75
mL) and heated to 120 ˚C for 2 h. The reaction mixture
was then cooled to r.t., diluted with H2O (5 mL) and
extracted with Et2O (3 × 5
mL). The combined organic layers were washed with brine (5 mL) and dried
(MgSO4). The solvent was removed under reduced pressure
to afford nemorosone (4), which did not
require further purification (39 mg, quant.). ¹H
NMR (500 MHz, MeOH-d
4): δ = 7.58
(d, J = 8.4
Hz, 2 H), 7.47 (t, J = 7.3
Hz, 1 H), 7.29 (t, J = 7.7
Hz, 2 H), 5.12 (t, J = 7.3
Hz, 1 H), 5.06-5.02 (m, 2 H), 3.17 (dd, J = 14.7,
7.3 Hz, 1 H), 3.12 (dd, J = 14.7,
7.3 Hz, 1 H), 2.57 (dd, J = 14.3,
7.0 Hz, 1 H), 2.52 (dd, J = 14.3,
7.0 Hz, 1 H), 2.21-2.17 (m, 1 H), 2.06 (dd, J = 13.6,
3.7 Hz, 1 H), 1.82-1.74 (m, 2 H), 1.72 (s, 3 H), 1.693
(s, 3 H), 1.685 (s, 9 H), 1.63 (s, 3 H), 1.47 (app. t, J = 13.2 Hz,
1 H), 1.37 (s, 3 H), 1.14 (s, 3 H). The resonance for the hydroxy
proton could not be identified in the ¹H NMR
spectrum. ¹³C NMR (125 MHz, MeOH-d
4): δ = 209.5, 195.1,
138.4, 135.3, 134.3, 133.7, 133.2, 129.7, 128.9, 124.1, 122.4, 121.3,
121.0, 78.2, 62.1, 49.1 (masked by MeOH signal), 44.8, 42.4, 30.6,
28.4, 26.4, 26.18, 26.16, 24.5, 22.5, 18.5, 18.3, 18.1, 16.4. The
resonances for C-2 and C-4 could not be identified in the ¹³C
NMR spectrum (tautomeric exchange). ESI-HRMS (TOF): m/z calcd for C33H42O4 [M + H]+:
503.3161; found: 503.3159.
The Danishefsky group reported a low
yield for their final
O-demethylation leading to nemorosone,
and noted the ‘chemical frailty’ of the natural
product. We found nemorosone to be considerably more stable in either
MeOH or DMSO than in CHCl3, making these the solvents
of choice for NMR work.
Our synthesis is about the same length as the Danishefsky route and proceeds in similarly modest overall yield of about 1-2%.
10
Typical Procedure - Preparation
of 13
t-BuLi (160 µL
of a 1.7 M solution in pentane) was added dropwise to a solution
of bridgehead iodide 11 (75 mg, 0.14 mmol)
in THF (2 mL) at -100 ˚C. The resulting strongly yellow
reaction mixture was stirred at -100 ˚C for 20
min before adding dropwise the electrophile methyl chloro-formate
(53 µL, 0.69 mmol) followed by warming of the reaction
mixture to -78 ˚C. After 2 h the reaction was quenched
at -78 ˚C using NH4Cl solution (15
mL). The product was extracted into Et2O (3 × 20
mL), and the combined organic layers were washed with H2O
(3 × 10 mL) and brine (3 × 10
mL) then dried (MgSO4). The solvent was removed under
reduced pressure, and purification of the residue by flash column
chromatography (5% EtOAc in PE) gave bridgehead ester 13 as a colourless oil (33 mg, 50%); R
f
= 0.39
(10% EtOAc in PE). ¹H NMR (300 MHz,
CDCl3): δ = 5.06
(t, J = 6.9
Hz, 1 H), 4.97 (t, J = 7.9
Hz, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H), 2.39 (app. d, J = 6.8 Hz,
2 H), 2.12 (dd, J = 11.2,
5.6 Hz, 1 H), 1.76 (dd, J = 13.0,
4.0 Hz, 1 H), 1.68-1.58 (overlapping m, 2 H), 1.65 (s,
6 H), 1.63 (s, 3 H), 1.54 (s, 3 H), 1.43 (app. t, J = 12.8
Hz, 1 H), 1.27 (s, 3 H), 1.10 (s, 3 H), 0.27 (s, 9 H). ¹³C
NMR (100 MHz, CDCl3): δ = 204.4, 199.9,
179.5, 168.0, 133.7, 133.4, 125.7, 122.3, 119.9, 74.9, 64.9, 64.8,
51.8, 45.1, 42.8, 40.0, 29.3, 27.6, 25.9, 25.7, 24.1, 18.0, 17.8,
16.0, 0.5. ESI-HRMS (TOF): m/z calcd
for C27H42O5Si [M + Na]+:
497.2699; found: 497.2694. IR: ν = 2951
(w), 1755 (m), 1728 (s), 1651 (m), 1565 (s), 1247 (s), 844 (s),
752 (s) cm-¹.
Data
for Compounds 14-16
Compound 14 was
obtained using TFAA as the electrophile. Colourless oil (25 mg,
59%); R
f
= 0.32
(5% EtOAc in PE). ¹H NMR (300 MHz,
CDCl3): δ = 5.02-4.88
(m, 2 H), 3.96 (s, 3 H), 2.54-2.31 (m, 2 H), 2.19-2.04
(m, 1 H), 1.86 (dd, J = 13.2,
3.9 Hz, 1 H), 1.70-1.52 {m, 14 H, including [1.67 (s,
3 H), 1.63 (s, 6 H), 1.55 (s, 3 H)}, 1.41 (app. t, J = 12.9 Hz,
1 H), 1.25 (s, 3 H), 1.07 (s, 3 H), 0.30 (s, 9 H). ¹9F
NMR (282 MHz, CDCl3): δ = -74.7
(s). ¹³C NMR (100 MHz, CDCl3): δ = 205.8,
199.4, 188.9 (q, ²
J
C-F = 33.8
Hz), 176.3, 134.2, 133.9, 122.2, 121.9, 119.2, 115.0 (q, J
C-F = 294.8
Hz), 75.5, 64.9, 64.1, 46.6, 42.7, 40.9, 29.1, 27.4, 25.8, 25.7,
23.9, 18.0, 17.8, 15.8, 1.1. ESI-HRMS (TOF): m/z calcd
for C27H39O4F3Si [M + Na]+:
535.2467; found: 535.2473. IR: ν = 2917
(m), 1768 (m), 1723 (m), 1655 (s), 1561 (s), 1233 (s), 1163 (s),
844 (s), 720 (s) cm-¹.
Compound 15 was obtained as a single diastereomer
using acetaldehyde as the electrophile. Colourless oil (48.4 mg, 58%); R
f
= 0.47
(20% EtOAc in PE). ¹H NMR (500 MHz, CDCl3): δ = 5.00
(t, J = 6.6
Hz, 1 H), 4.95 (t, J = 5.9
Hz, 1 H), 4.50 (app. sext, J = 6.3
Hz, 1 H), 3.95 (s, 3 H), 3.65 (d, J = 12.0
Hz, 1 H), 2.42 (dd, J = 14.5,
7.7 Hz, 1 H), 2.34 (dd, J = 14.5,
6.4 Hz, 1 H), 2.10-2.07 (m, 1 H), 1.82 (dd, J = 13.2, 4.2 Hz, 1 H), 1.66
(s, 3 H), 1.64 (s, 3 H), 1.62 (s, 3 H), 1.70-1.58 (overlapping
m, 1 H), 1.54 (s, 3 H), 1.52-1.48 (overlapping m, 1 H),
1.40 (dd, J = 13.0
Hz, 1 H), 1.28 (d, J = 6.3
Hz, 3 H), 1.23 (s, 3 H), 1.11 (s, 3 H), 0.22 (s, 9 H). ¹³C
NMR (125 MHz, CDCl3): δ = 214.6,
200.2, 185.0, 133.9, 133.1, 124.8, 122.5, 119.8, 69.0, 67.5, 65.2,
63.3, 46.2, 44.1, 41.2, 29.9, 27.7, 25.9, 25.8, 23.9, 21.8, 18.4,
18.0, 17.9, 0.8. ESI-HRMS (TOF): m/z calcd
for C27H44O4Si [M + Na]+:
483.2907; found: 483.2902. IR: ν = 3529
(w), 2969 (m), 1710 (m), 1649 (m), 1227 (s), 1107 (w), 843 (s),
754 (s) cm-¹.
Compound 16 was obtained as a single diastereomer
using isobutyraldehyde as the electrophile. Colourless oil (18.8 mg,
51%); R
f
= 0.52
(20% EtOAc in PE). ¹H (300 MHz, CDCl3): δ = 4.92
(br s, 2 H), 4.56 (d, J = 11.8
Hz, 1 H), 4.26 (dd, J = 11.8,
2.0 Hz, 1 H), 3.95 (s, 3 H), 2.45 (dd, J = 14.0, 8.3
Hz, 1 H), 2.31 (dd, J = 14.0,
5.8 Hz, 1 H), 2.07 (d, J = 12.3
Hz, 1 H), 1.88 (dd, J = 12.2,
3.4 Hz, 2 H), 1.73-1.51 {m, 14 H, including [1.66
(s, 6 H), 1.58 (s, 3 H), 1.53 (s, 3 H)}, 1.34 (dd, J = 12.5 Hz,
1 H), 1.25 (s, 3 H), 1.15 (s, 3 H), 1.02 (d, J = 6.8
Hz, 3 H), 0.65 (d, J = 6.9
Hz, 3 H), 0.22 (s, 9 H). ¹³C NMR (100
MHz, CDCl3): δ = 216.2,
199.9, 185.0, 134.0, 133.1, 124.0, 122.5, 119.7, 65.7, 65.6, 63.0,
48.0, 44.3, 42.7, 32.0, 30.0, 29.7, 27.8, 25.9, 25.8, 24.3, 22.2,
18.7, 18.0, 17.9, 17.3, 0.7. ESI-HRMS (TOF): m/z calcd
for C29H48O4Si [M + Na]+:
511.3220; found: 511.3228. IR: ν = 3484
(w), 2958 (m), 1707 (m), 1649 (s), 1548 (s), 1421 (w), 1229 (s),
1017 (w), 844 (s), 756 (s) cm-¹.