An acyl-claisen approach to tetrasubstituted tetrahydrofuran lignans: Synthesis of fragransin A2, talaumidin, and lignan analogues

Article abstract of DOI:10.1055/s-0029-1218363

A simple and stereocontrolled synthesis of racemic 2,3,4,5-tetrasubstituted tetrahydrofurans was achieved from acyl-Claisen derived syn-disubstituted amides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218363

LETTER
3315
An Acyl-Claisen Approach to Tetrasubstituted Tetrahydrofuran Lignans:
Synthesis of Fragransin A2, Talaumidin, and Lignan Analogues
An
Acyl-Claisen
l
A
pproac
h
to
T
etra
i
substit
r
uted
T
etr
e
ahydrofurans E. Rye, David Barker*
Department of Chemistry, The University of Auckland, 23 Symonds St, Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: d.barker@auckland.ac.nz
Received 14 August 2009
ic steps, giving defined stereochemistry at the 2- and 5-
positions in the final tetrahydrofuran.
Abstract: A simple and stereocontrolled synthesis of racemic
2,3,4,5-tetrasubstituted tetrahydrofurans was achieved from acyl-
Claisen derived syn-disubstituted amides.
Amides 4 can be prepared using a Lewis acid catalysed
acyl-Claisen rearrangement (which has also been named a
Zwitterionic aza-Claisen)8 of tertiary allylic amines 5 and
acid chlorides 6. The benefit of using this methodology is
that both reaction components can be easily obtained and
thus a wide variety of amides can be prepared. Further-
more, the rearrangement is generally high yielding and
highly stereospecific, giving syn-substituted products 4
when E-allylic amines 5 are used.8 This is in contrast to
other methods that have been used for the preparation of
similarly disubstituted amides where the level of diastereo-
selectivity and the range of substituents is often lower.9
Whilst the syn-selectivity and functional group tolerance
of the acyl-Claisen reaction has been investigated,8 there
have been very few reports on the use of the amide prod-
ucts in synthesis.10 We therefore report on the use of acyl-
Claisen derived substituted amides 4 to efficiently prepare
tetrasubstituted tetrahydrofurans with high levels of stereo-
selectivity.
Key words: tetrahydrofurans, acyl-Claisen reaction, aza-Claisen
reaction, lignans, stereospecific synthesis
Tetrasubstituted tetrahydrofurans are a common structural
motif found in many natural and synthetic compounds.
One compound class containing this motif is the tetra-
hydrofuran lignans of which there are a large number of
biologically active members (Figure 1),1 including fra-
gransin A2 (1),2 talaumidin (2)3 and manassantin A (3).4 In
many cases the stereochemistry of the substituents has
been found to be important for biological activity,1d–g for
example, isomers of manassantin A (3), which are
changed only with respect to the configuration of the sub-
stituents in the tetrahydrofuran ring, were found to be con-
siderably less active than the isomer with natural
stereochemistry.4c
Many bioactive tetrahydrofuran lignans, such as fra-
gransin A2 (1), have a trans-relationship between the sub-
stituents at the 3- and 4-positions (Figure 1). Many
previous syntheses have employed an oxidative coupling
of allyl phenols5 or acetophenones,6 or used radical cycli-
sation processes,7 however, all these approaches result in
mixtures of diastereomers at these positions. With the aim
of carefully controlling the stereochemistry at these posi-
tions we envisaged that the stereochemistry could be de-
rived from a suitably substituted 2,3-syn-disubstituted
prop-4-enamide 4. The stereochemistry at these two posi-
tions could then be used to control the subsequent synthet-
Whilst numerous similar methods have been reported for
the acyl-Claisen reaction,8 we found the combination of
10 mol% aluminium chloride with diisopropylethylamine
in dichloromethane to be the most efficient. Thus (E)-
crotylamines11 5a and 5b were reacted with acid chlorides
6a–c to give amides 4a–f in 24–88% yield, with the mor-
pholine amides being prepared in higher yield
(Scheme 1). The rearrangement was completely selective
for the syn-stereoisomer, with less than one percent of the
anti-isomer observed in the product by 1H NMR. We ini-
tially envisaged that amides 4 could be reduced using a
hydride reagent to give the corresponding aldehyde,12
MeO
HO
OMe
OMe
O
O
O
O
OH
OH
(–)-talaumidin (2)
(+)-fragransin A2 (1)
MeO
MeO
O
OMe
O
OMe
OMe
O
MeO
OH
OH
manassantin A (3)
Figure 1 Structures of naturally occurring tetrahydrofuran lignans 1–3
SYNLETT 2009, No. 20, pp 3315–3319
x
x
.x
x
.2
0
0
9
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218363; Art ID: D22009ST
© Georg Thieme Verlag Stuttgart · New York

3316
C. E. Rye, D. Barker
LETTER
R4
R3
Li
O
R1
R1
O
R1
O
R4
R3
N
AlCl3 (10 mol%)
i-Pr2NEt, CH2Cl2
R2
N
8a–d
Cl
R2
R2
R1
THF, –78 °C
6a, R2 = Me
6b, R2 = Et
6c, R2 = Bu
4a, N(R1)2 = mor, R2 = Me (88%)
4b, N(R1)2 = pyr, R2 = Me (68%)
4c, N(R1)2 = mor, R2 = H (62%)
4d, N(R1)2 = pyr, R2 = H (24%)
4e, N(R1)2 = mor, R2 = Pr (38%)
4f, N(R1)2 = pyr, R2 = Pr (40%)
8a, R3 = OMe, R4 = H
8b, R3 = R4 = OMe
8c, R3, R4 = -OCH2O-
7a, R2 = Me, R3 = OMe, R4 = H (96/43%)
7b, R2 = Me, R3 = R4 = OMe (66/57%)
7c, R2 = Me, R3, R4 = -OCH2O- (86/57%)
8d, R3 = OMOM, R4 = OMe 7d, R2 = Me, R3 = OMOM, R4 = OMe (77/43%).
7e, R2 = H, R3 = OMe, R4 = H (65/46%)
5a, N(R1)2 = morpholine (mor)
5b, N(R1)2 = pyrrolidine (pyr)
7f, R2 = Pr, R3 = OMe, R4 = H (66/56%)
Scheme 1 Synthesis of ketones 7a–f; final yields of ketones 7 refer to the those obtained from from the corresponding morpholine amides
(4a,4c,4f) or pyrrolidine amides (4b,4d,4f)
however, regardless of the reagents employed, we found temperature of the reaction was allowed to warm from
this approach to be unreliable because it gave mixtures of 0 °C to room temperature overnight. However, despite the
products. Thus, we turned our attention to the addition of elevated temperatures and longer reaction times, the re-
aryl organometallic reagents in an attempt to obtain ke- ductions in these cases were still completely selective,
tones 7a–f. We discovered that the use of Grignard re- giving alcohols 9b–d in 78–91% yields. Using the Felkin–
agents were ineffective, giving only starting materials, Anh model, the stereochemistry of the resultant alcohol
whilst addition of the organocerium reagents was also un- group in 9a–f was expected to be anti to the neighbouring
successful. We therefore turned to the use of aryl lithium methyl group and was tentatively assigned as such by
reagents 8a–d, which were prepared from the correspond- comparison to similar literature compounds;4b this was
ing bromide using n-butyllithium for 8a, or tert-butyllith- later confirmed by determination of the stereochemistry in
ium for reagents 8b–d. The addition of aryl lithiums 8a–d the final tetrahydrofuran product (see below). After exper-
to morpholine amides 4a, 4c and 4e occurred efficiently, imenting with a number of groups, we protected alcohols
giving ketones 7a–f in 65–96% yields; the pyrrolidine 9a and 9d as the corresponding MOM ethers.13 We then
amides 4b, 4d and 4f were less reactive and gave the ke- wished to convert the terminal alkene into an aldehyde
tones in reduced yields. Different conditions were re- prior to addition of a second organometallic reagent. Ozo-
quired for the stereoselective reduction of ketones 7a–f. In nolysis of the alkene proved unsuccessful, giving only de-
the case of mono-aryl substituted, 4-methoxyphenyl ke- composition products. However, dihydroxylation using
tones such as 7a, reduction of the ketones was relatively osmium tetroxide and NMO, followed by diol cleavage
rapid (5 h) and careful control of the temperature was re- using sodium periodate in MeOH–water (3:1) gave alde-
quired because reduction at elevated temperatures led to a hydes 10a and 10b in excellent yield over two steps. Pre-
distereoisomeric mixture of alcohols (Scheme 2).
vious studies2b,4b on the addition of aryl Grignard reagents
to similar aldehydes resulted in a diastereomeric mixture
of alcohols being produced, however, we found that addi-
tion of a second aryl lithium 8a–d gave alcohols 11a–d in
25–63% yields, furthermore, we found that a single dia-
stereomer could be obtained if the temperature of addition
was kept at –78 °C. The final step in the synthesis of the
Thus, reduction of ketones 7a, 7e and 7f with sodium
borohydride at –78 °C, in MeOH, was completely selec-
tive and gave alcohols 9a, 9e and 9f in 70–95% yields. Re-
duction of the di-aryl substituted ketones 7b–d was
considerably slower (18–24 h) and successful reduction
was only achieved using sodium borohydride when the
OH
O
i) MOMCl, i-Pr2NEt
ii) OsO4 (10 mol%)
NMO, t-BuOH–H2O
MOMO
NaBH4
MeOH
R2
R1
R2
R1
R2
R1
see text
O
iii) NaIO4
MeOH–H2O
7a, R1 = OMe, R2 = H
9a, R1 = OMe, R2 = H (92%)
10a, R1 = OMe, R2 = H (61% over 3 steps)
7d, R1 = OMOM, R2 = OMe
9d, R1 = OMOM, R2 = OMe (78%)
10b, R1 = OMOM, R2 = OMe (66% over 3 steps)
R4
Li
R3
MOMO
i) MsCl (1.3 equiv)
R3
R2
R1
R2
R1
R4
R4
Et3N (1.6 equiv), CH2Cl2
8a–d
THF, –78 °C
O
OH
ii) for 12b, 1 and 2 only,
2 M HCl
R3
11a, R1 = R3 = OMe, R2 = R4 = H (63%)
12a, R1 = R3 = OMe, R2 = R4 = H (80%)
11b, R1 = OMOM, R2 = R3 = R4 = OMe (48%)
11c, R1 = OMOM, R2 = OMe, R3, R4 = -OCH2O- (61%)
11d, R1 = R3 = OMOM, R2 = R4 = OMe (25%)
12b, R1 = OH, R2 = R3 = R4 = OMe, (81% over 2 steps)
12c (rac-2), R1 = OH, R2 = OMe, R3, R4 = -OCH2O- (65%, over 2 steps
12d (rac-1), R1 = R3 = OH, R2 = R4 = OMe (67%, over 2 steps)
Scheme 2 Synthesis of tetrasubstituted tetrahydrofuran lignans
Synlett 2009, No. 20, 3315–3319 © Thieme Stuttgart · New York

LETTER
An Acyl-Claisen Approach to Tetrasubstituted Tetrahydrofurans
3317
tetrahydrofuran ring was to convert the unprotected sec- the epimer of 11a, differing at the unprotected benzylic al-
ondary alcohol into a good leaving group which, upon cohol. Dess–Martin oxidation of 11a followed by selec-
deprotection of the MOM-ether, would be expected un- tive reduction, again using sodium borohydride at –78 °C
dergo SN2 attack by the resultant alcohol to give the de- in MeOH, gave alcohol 11f in 75% over two steps. Cycli-
sired product 12a–d. We found that conversion of sation of 11f using the conditions reported above gave the
alcohols 11a–d into the corresponding tetrahydrofurans trans,trans,cis-tetrahydrofuran 12f in 39% yield with
12a–d could be achieved by transformation of the second- 24% of 12a also being produced (Scheme 3). This type of
ary alcohol into a mesylate. Thus, addition of 1.3 equiva- benzylic epimerisation has previously been seen in other
lents of methanesulfonyl chloride along with 1.6 compounds containing para-oxygenated aromatic substit-
equivalents of triethylamine activated the alcohol, depro- uents, with the reason being that electron-donation from
tected the alkyl MOM ether and gave (after deprotection the para-oxygenated substituent results in the formation
of the phenolic MOM ethers for 12b–d) the cyclised tet- of a planar quinoid intermediate with subsequent loss of
rahydrofuran 12a–d in good yields in a single synthetic stereochemistry.2b To investigate this proposed mecha-
step. Importantly, the use of fewer equivalents of base nism, we decided to cyclise alcohol 11g, which has no
during this step resulted in mixtures of diastereoisomers para-substituent on the aromatic ring adjacent to the
of the tetrahydrofuran being formed.
formed mesylate. Alcohol 11g was synthesised by addi-
tion of phenyl lithium to aldehyde 10a followed by Dess–
Martin oxidation and NaBH4 reduction, in a manner sim-
ilar that described for 11f above. Cyclisation of 11g using
the same conditions used for 11a–e, gave the desired
trans,trans,cis-tetrahydrofuran 12g in 69% yield with
only 17% of the trans,trans,trans-tetrahydrofuran being
formed (Scheme 3). This result confirms that electron-
donating para-substituents can effect cyclisations of this
kind.
Those tetrahydrofurans that contained a MOM-protected
phenol were converted into fully deprotected compounds
12b–d using 2 M HCl in methanol in 80–83% yields.
To explore the application of these procedures for the syn-
thesis of tetrasubstituted tetrahydrofuran lignan ana-
logues, we decided to convert ketone 7f into
tetrahydrofuran 12e. Thus, after careful reduction of 7f to
ketone 9f (see above) and following the same procedures
as outlined in Scheme 2, we obtained alcohol 11e, which
was cyclised to give tetrahydrofuran 12e as a single dia-
stereoisomer in 68% yield (Scheme 3).
In conclusion, we have synthesised a number of tetrasub-
stituted tetrahydrofurans including the natural lignans fra-
gransin A2 (1), talaumidin (2) and dimethyl-4-epi-
larreatricin (12a). We have also synthesised compound
12d, which has recently been used to explore the effect of
stereochemistry in the biological activity of manassantin
A,4c and tetrasubstituted tetrahydrofuran lignan analogues
12e–g. The acyl-Claisen methodology allows the synthe-
sis of a wide variety of substituted amides 4, which we
have shown can be stereospecifically converted into a
range of tetrasubstituted tetrahydrofuran products.15,16 We
are currently investigating a general asymmetric acyl-
Claisen rearrangement and intend to report on its use in
the synthesis of complex tetrahydrofurans in due course.
The stereochemistry of the substituents around the formed
tetrahydrofurans 12a–e was determined to be, as expect-
ed, trans,trans,trans by comparison with literature com-
pounds,1–4 thus confirming the expected cyclisation
mechanism and the stereochemistry of the initially formed
alcohols 9a–f. The spectroscopic data for 12d, 12c and
12a matched those reported for the natural compounds
fragransin A2 (1),2 talaumidin (2)3 and dimethyl-4-epi-lar-
reatricin,14 respectively.
To explore the mechanism of the cyclisation step further,
we decided to investigate the cyclisation of 11f, which is
OMe
MOMO
MsCl (1.3 equiv)
Et3N (1.6 equiv), CH2Cl2
68%
OH
O
MeO
MeO
MeO
OMe
OMe
11e
11f
12e
OMe
MOMO
MsCl (1.3 equiv)
Et3N (1.6 equiv), CH2Cl2
O
39%
OH
MeO
12f
MOMO
MsCl (1.3 equiv)
Et3N (1.6 equiv), CH2Cl2
O
69%
OH
MeO
MeO
11g
12g
Scheme 3 Synthesis of tetrahydrofuran lignan analogues 12e–g
Synlett 2009, No. 20, 3315–3319 © Thieme Stuttgart · New York

3318
C. E. Rye, D. Barker
LETTER
J. W.; Nubbemeyer, U. Tetrahedron 2002, 58, 1317.
(11) (E)-Crotylamines were prepared from (E)-crotonaldehyde,
by LAH reduction and PBr3 bromination to give (E)-crotyl
bromide. Amine 5a was prepared by amination with
morpholine at 0 °C in CH2Cl2, whilst amine 5b was prepared
using the sodium hydride derived sodium salt of pyrrolidine
and TBAI in THF.
Acknowledgment
We would like to acknowledge the Royal Society of New Zealand
Marsden Fund for funding this research and The University of
Auckland for additional financial assistance and a doctoral scholar-
ship for C.E.R.
(12) (a) Concellon, J. M.; Rodriguez-Solla, H.; Mejica, C.;
Blanco, E. G.; Garcia-Granda, S.; Diaz, M. R. J. Org. Chem.
2008, 73, 3828. (b) Olivella, A.; Rodriguez-Escrich, C.;
Urpi, F.; Vilarrasa, J. J. Org. Chem. 2008, 73, 1578.
(c) Concellon, J. M.; Rodriguez-Solla, H.; Diaz, P. J. Org.
Chem. 2007, 72, 7974.
(13) We found that the TES groups were cleaved during the
dihydroxylation step to give extremely polar triols and the
use of TBDMS groups was unsatisfactory as they did not
spontaneously cleave during the cyclization step and,
instead, gave unwanted products.
(14) Konno, C.; Lu, Z. Z.; Xue, H. Z.-g.; Erdelmeier, C. A. J.;
Meksuriyen, D.; Che, C. T.; Cordell, G. A.; Soejarto, D. D.;
Waller, D. P.; Fong, H. H. S. J. Nat. Prod. 1990, 53, 396.
(15) General Procedure for the Synthesis of Amides 4: To a
stirred suspension of AlCl3 (0.1 mmol) in CH2Cl2 (5 mL)
under an atmosphere of N2, a solution of (E)-4-(but-2-
enyl)amine 5 (1 mmol) in CH2Cl2 (5 mL) was added
dropwise, followed by diisopropylethylamine (1.5 mmol)
dropwise. The resultant mixture was stirred at r.t. for 15 min,
then a solution of acid chloride 6 (1.2 mmol) in CH2Cl2 (5
mL) was added dropwise and the reaction mixture was
stirred at r.t. for 24 h. Aq NaOH (10 mL) was added, the
layers were separated and the aqueous layer was further
extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4)
and the solvent was removed in vacuo. The crude product
was purified by flash chromatography to give the amides 4
in 24–88% yields.
References and Notes
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Rep. 2005, 22, 696. (b) Ward, R. S. Nat. Prod. Rep. 1999,
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2001, 64, 772. (h) Fernandes, A. M. A. P.; Barata, L. E. S.;
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C.; Pezzella, A.; Evidente, A.; Napolitano, A.; D’Ischia, M.
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General Procedure for the Synthesis of Ketones 7: To a
solution of aryl bromide (1.2 mmol) in THF (20 mL) under
an atmosphere of N2 at –78 °C, was added, either n-BuLi
(1.2 mmol for 8a) or t-BuLi (2.4 mmol for 8b–d) and the
resultant solution was stirred for 10 min. A solution of amide
4 (1 mmol) in THF (5 mL) was then added dropwise and the
mixture was stirred at –78 °C and slowly warmed to r.t. over
2–18 h. Sat. NH4Cl solution (20 mL) was added and the
aqueous mixture was extracted with EtOAc (3 × 30 mL).
The combined organic extracts were dried (MgSO4) and the
solvent was removed in vacuo. The crude product was
purified by flash chromatography to give the ketones 7 in
43–96% yields.
(6) Biftu, T.; Gamble, N. F.; Doebber, T.; Hwang, S.-B.; Shen,
T.-Y.; Snyder, J.; Springer, J. P.; Stevenson, R. J. Med.
Chem. 1986, 29, 1917.
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General Procedure for the Synthesis of
Tetrahydrofurans 12: To a solution of alcohol 11 (1 mmol)
and Et3N (1.6 mmol) in CH2Cl2 (25 mL) under an
atmosphere of N2 was added MsCl (1.3 mmol) and the
reaction mixture was stirred for 1–2 h. Sat NaHCO3 solution
(10 mL) was added, the layers were separated and the
aqueous layer was further extracted with CH2Cl2 (3 × 15
mL). The combined organic extracts were dried (Na2SO4)
and the solvent was removed in vacuo. The crude product
was purified by flash chromatography to give the
tetrahydrofurans 12 in 63–81% yields.
(16) Spectroscopic Data for Selected Products:
( )-Dimethoxy-4-epi-larreatricin (12a): 1H NMR (400
MHz, CDCl3): d = 1.01 (m, 6 H, CHCH3), 1.78 (m, 2 H, CH),
3.78 (s, 6 H, OMe), 4.63 (d, J = 9.0 Hz, 2 H, OCH), 6.87 (d,
(10) (a) Raubo, P.; Giuliano, C.; Hill, A. W.; Huscroft, I. T.;
London, C.; Reeve, A.; Seward, E. M.; Swain, C. G.;
Kulagowski, J. J. Synlett 2006, 600. (b) Xu, Q.; Rozners, E.
Org. Lett. 2005, 7, 2821. (c) Laabs, S.; Munch, W.; Bats,
J = 8.7 Hz, 4 H, 2¢-Ar), 7.31 (d, J = 8.4 Hz, 4 H, 3¢-Ar). 13
C
NMR (100 MHz, CDCl3): d = 13.7 (2 × CH3), 51.0 (2 × CH),
55.2 (OCH3), 88.0 (2 × CH), 113.6 (2 × CH), 127.4
Synlett 2009, No. 20, 3315–3319 © Thieme Stuttgart · New York

LETTER
An Acyl-Claisen Approach to Tetrasubstituted Tetrahydrofurans
3319
(2 × CH), 134.5 (q), 159.0(q). IR (film): 2954, 2833, 1609,
13C NMR (75 MHz, CDCl3): d = 13.8 (2 × CH3), 50.8 (CH),
51.1 (CH), 56.0 (OCH3), 88.2 (CH), 88.4 (CH), 106.6 (CH),
107.9 (CH), 108.6 (CH), 114.0 (CH), 119.4 (CH), 119.7
(CH), 134.1 (q), 136.9 (q), 145.1 (q), 146.9 (q). IR (film):
3451, 2958, 2926, 1772, 1607, 1515, 1460, 1247, 1036
cm–1. MS (ESI): m/z (%) = 343 (100) [M + H]+, 321 (6), 301
(8), 292 (10), 259 (60). Anal. Calcd for C20H23O5: 343.1545
[M – H+]. Found: 343.1536. The 1H- and 13C-NMR data
were in agreement with the literature values.2b
2,5-Di(4-methoxyphenyl)-3-methyl-4-propyltetrahydro-
furan (12e): 1H NMR (400 MHz, CDCl3): d = 0.83 (m, 3 H,
CH2CH2CH3), 1.23 (m, 2 H, CH2CH2CH3), 1.34 (d, J = 6.8
Hz, 3 H, 3-CH3), 1.51 (m, 2 H, CH2CH2CH3), 2.09 (m, 1 H,
4-H), 2.45 (m, 1 H, 3-H), 3.82 (s, 6 H, OMe), 4.84 (d, J = 9.6
Hz, 2 H, 2- and 5-H), 6.90 (d, J = 8.4 Hz, 4 H, Ar-H), 7.26
(d, J = 8.8 Hz, 4 H, Ar-H). 13C NMR (100 MHz, CDCl3):
d = 14.2 (CH3), 14.7 (CH3), 20.3 (CH2), 33.3 (CH2), 42.0
(CH), 51.7 (CH), 55.3 (OCH3), 85.2 (2 × CH), 114.0
(2 × CH), 128.3 (2 × CH), 140.2 (q), 160.0(q). IR (film):
2958, 2339, 1773, 1613, 1516, 1462, 1299, 1251, 1171,
1034, 988, 833 cm–1. MS (ESI): m/z (%) = 363 (3) [M + Na]+,
303 (4), 271 (100). Anal. Calcd for C22H28O3Na: 363.1931
[M + Na+]. Found: 363.1926.
2-(4-Methoxyphenyl)-3,4-dimethyl-5-phenyl tetrahydro-
furan (12g): 1H NMR (400 MHz, CDCl3): d = 0.63 (d, J = 6.0
Hz, 3 H, 4-CH3), 1.04 (d, J = 6.0 Hz, 3 H, 3-CH3), 1.78 (m,
1 H, 3-H), 2.25 (m, 1 H, 4-H), 3.83 (s, 3 H, OCH3), 4.40 (d,
J = 9.0 Hz, 1 H, 2-H), 5.17 (d, J = 9.0 Hz, 1 H, 5-H), 6.93 (d,
J = 9.0 Hz, 2 H, Ar-H), 7.28–7.35 (m, 5 H, Ar-H), 7.43 (d,
J = 9.0 Hz, 2 H, Ar-H). 13C NMR (100 MHz, CDCl3): d =
15.0 (CH3), 15.3 (CH3), 45.9 (CH), 48.5 (CH), 55.3 (OCH3),
83.0 (CH), 87.3 (CH), 113.8 (CH), 127.0 (CH), 127.8 (CH),
127.9 (CH), 132.9 (q), 141.0(q), 162.6 (q). IR (film): 2958,
2836, 1613, 1515, 1454, 1222, 1036, 825, 704 cm–1. MS
(ESI): m/z (%) = 283 (100) [M + H]+, 265 (42), 177 (19), 149
(16), 121 (36). Anal. Calcd for C19H23O2: 283.1693 [M + H+].
Found: 283.1680.
1584, 1507, 1454, 1299, 1239, 1169, 1025, 821, 726 cm–1.
MS (EI+): m/z (%) = 312 (8) [M+], 176 (100), 161 (60), 135
(12), 77 (6). Anal. Calcd for C20H24O3 [M+]: 312.17254.
Found: 312.17286. The 1H NMR data was in agreement with
the literature values.14
( )-2-(3,4-Dimethoxyphenyl)-3,4-dimethyl-5-(3-methoxy-
4-hydroxyphenyl)tetrahydrofuran (12b):
1H NMR (400 MHz, CDCl3): d = 1.12 (d, J = 6.4 Hz, 6 H, 3-
and 4-CH3), 1.95–2.02 (m, 2 H, 3- and 4-H), 3.91 (s, 9 H,
OMe), 4.75 (d, J = 10.0 Hz, 2 H, 2- and 5-H), 5.69 (br s, 1 H,
OH), 6.81–6.92 (m, 6 H, Ar-H). 13C NMR (100 MHz,
CDCl3): d = 14.3 (2 × CH3), 47.8 (2 × CH, C-3 and C-4),
56.0 (3 × OCH3), 86.4 (2 × CH, C-2 and C-5), 108.3
(2 × CH), 114.1 (2 × CH), 119 (2 × CH), 129.1 (q), 140.1
(q), 146.1 (q), 146.8 (q). IR (film): 3426.6, 2967.1, 1766,
1607.1, 1519, 1459.9, 1380.0, 1275.8, 1237.2, 1176, 1033
cm–1. MS (ESI): m/z (%) = 381 (11) [M + Na]+, 359 (8)
[M + H]+, 259 (83), 237 (100), 191 (22). Anal. Calcd for
C21H27O5: 359.1858 [M + H+]. Found: 359.1864.
( )-Talaumidin (rac-2, 12c): 1H NMR (400 MHz, CDCl3):
d = 1.03 (m, 6 H, 3- and 4-CH3), 1.78 (m, 2 H, 3- and 4-H),
3.91 (s, 3 H, OCH3), 4.61 (d, J = 5.2 Hz, 2 H, 2- and 5-H),
5.59 (br s, 1 H, OH), 5.94 (s, 2 H, OCH2O), 6.77–6.93 (m, 6
H, Ar-H). 13C NMR (100 MHz, CDCl3): d = 13.8 (CH3), 50.8
(CH), 51.1 (CH), 55.9 (OCH3), 88.2 (CH), 88.4 (CH), 100.9
(CH2), 106.5 (CH), 107.9 (CH), 108.5 (CH), 114.0 (CH),
119.4 (CH), 119.6 (CH), 134.1 (q), 136.5 (q), 145.1 (q),
146.5 (q). IR (film): 3468.5, 2959, 1770, 1609, 1515, 1488,
1447, 1365, 1273, 1243, 1036, 934 cm–1. MS (ESI): m/z (%)
= 343 (100) [M + H]+, 339 (8), 325 (17). Anal. Calcd for
C20H23O5: 343.1545 [M + H+]. Found: 343.1551. The 1H-
and 13C NMR data were in agreement with the literature
values.2b
( )-Fragransin A2 (rac-1, 12d): 1H NMR (300 MHz,
CDCl3): d = 1.05 (d, J = 6.3 Hz, 6 H, 3- and 4-CH3), 1.76 (m,
2 H, 3- and 4-H), 3.91 (s, 6 H, OCH3), 4.61 (d, J = 9.3 Hz, 2
H, 2- and 5-H), 5.55 (s, 2 H, OH), 6.78–6.94 (m, 6 H, Ar-H).
Synlett 2009, No. 20, 3315–3319 © Thieme Stuttgart · New York

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