Asymmetric synthesis of tetrasubstituted tetrahydrofuran, 2- epigoniothalesdiol, employing stereoselective hydrogenation

Article abstract of DOI:10.1055/s-1999-2993

An efficient and stereodefined process is described for the preparation of a 3,4-dihydroxy-2,5-disubstituted tetrahydrofuran ring with the contiguous stereogenic centers and the asymmetric synthesis of 2-epigoniothalesdiol is also reported by featuring the elaboration of the functionalized homochiral lactone derived from C₂-imide.

Full text of DOI:10.1055/s-1999-2993

LETTER
1969
Asymmetric Synthesis of Tetrasubstituted Tetrahydrofuran, 2-
Epigoniothalesdiol, Employing Stereoselective Hydrogenation
Hidemi Yoda,* Takahiro Shimojo, Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Fax +81 53 478 1150; E-mail: yoda@mat.eng.shizuoka.ac.jp
Received 24 September 1999
OCH3
Abstract: An efficient and stereodefined process is described for
the preparation of a 3,4-dihydroxy-2,5-disubstituted tetrahydrofu-
ran ring with the contiguous stereogenic centers and the asymmetric
synthesis of 2-epigoniothalesdiol is also reported by featuring the
elaboration of the functionalized homochiral lactone derived from
C2-imide.
O
HO
OCH3
H3CO
H3CO
O
Magnone A (1a): R = H
Magnone B (1b): R = OCH3
R
Key words: goniothalesdiol, tetrasubstituted tetrahydrofuran, ste-
reoselective deoxygenation, hemiketal, trisubstituted γ-lactone
H3CO
OCH3
HO
OH
5
2
H3CO
H3CO
O
O
COOCH3
O
O
Tetrahydrofuran backbone is among the most common
heterocyclic units found in natural products and structur-
ally complex ones feature in many biologically potent
compounds such as pheromones,1 polyether antibiotics,2
and marine epoxylipids.3 Due to their interesting activity
as well as unique structural characteristics, they have been
the subject of an extensive synthetic effort which has cul-
minated in numerous syntheses.4 Noteworthy members
among this class of compounds are optically active tet-
rahydrofuran derivatives with tri- and tetrasubstituents
serving as good templates for the construction of pharma-
cologically important furanoid groups and exhibiting var-
ious degrees of potency and specificity (Figure).5 In this
connection we have also recently reported a novel and ste-
reoselective conversion of lactones to polysubstituted cy-
clic ethers6a employing nucleophilic addition of Grignard
reagents in the presence of CeCl3 followed by the Lewis
acid-induced deoxygenation and the first total synthesis of
tetrasubstituted tetrahydrofuran, (-)-virgatusin (2).6b Ste-
reochemical outcome obtained from the deoxygenation
reaction using trisubstituted lactones with α,β-dibenzyl-
oxymethyl and γ-aryl substituents evidently depends on
the γ-substituent.6
Virgatusin (2)
Goniothalesdiol (3)
Figure
as the configurations at the corresponding C(2) and C(3)
of D-tartaric acid. Further we envisioned that the stereo-
genic center of C(5) could originate from the nucleophilic
addition to the C2-imide obtained from D-tartaric acid fol-
lowed by reduction based on our previous reports.8 The
remaining C(2) stereogenic center of 3 would have to be
independently set in an asymmetric hydrogenation ac-
cording to the strategy mentioned above.
As shown in Scheme 1, N-benzyl-C2-imide 4 obtained
from D-tartaric acid was treated with octylmagnesium
bromide followed by reduction of the α-hydroxylactam
intermediate with NaBH4, leading to the corresponding
hydroxyamide 5a in 67% yield with exclusive stereose-
lectivity.8 Accompanying formation of the other stereoi-
somer 5b was observed in mere trace amounts after
isolation using silica gel column chromatography. Then,
5a was cyclized under acidic conditions to give the dihy-
droxylactone 6. Whereas the use of BnBr-Ag2O for the
protection of the dihydroxyl functions in 6 brought about
unsatisfactory racemization at C-5 in 7a, the reaction with
TBSCl-imidazole in DMF provided the disilylated com-
pound 7b as a single isomer (determined by 13C NMR) in
almost quantitative yield.
On the other hand, another type of dihydroxlated tetrahy-
drofuran, goniothalesdiol (3), was isolated in 1998 from
the bark of the Malaysian tree Goniothalamus borneensis
(Annonaceae). This was revealed to have significant cyto-
toxicity against P388 mouse leukemia cells and insecti-
cidal activities,5c and a new addition to the styryl-type
lactone series.7 Taking advantage of these successive re-
actions of nucleophilic addition and stereoselective hy-
drogenation of its ketal derivative, we wish to
communicate our synthetic efforts for the 3,4-dihydroxy-
2,5-disubstituted tetrahydrofuran, such as goniothalesdiol
(3), from C2-imide.
Next, we investigated the direct conversion of 7b to the
corresponding substituted tetrahydrofuran via Lewis acid-
induced reductive deoxygenation. Thus, 7b was subjected
to reaction with the second Grignard reagents (alkyl- and
arylmagnesium bromide) at -78 °C in the presence of
CeCl3 as reported previously,6 followed by BF3∑OEt2-pro-
moted hydrogenation with Et3SiH9 of the hemiketal inter-
mediates 8 at the same temperature. The reactions in both
In formulating the synthetic plan for 3, we recognized that
the absolute configurations at C(3) and C(4) are the same
Synlett 1999, No. 12, 1969–1971 ISSN 0936-5214 © Thieme Stuttgart · New York

1970
H. Yoda et al.
LETTER
cases proceeded within 10 minutes to afford the deoxy- 1.45, EtOH), with a butenyl side chain was easily and ste-
genated tetrasubstituted furans 9a and 9b, respectively, in reoselectively prepared according to the above method in
good yields with complete stereoselectivity (determined an enantiomerically pure form from 4 in 65% yield (4
by 13C NMR and HPLC analysis). No other stereoisomer steps). Treatment of 7c with phenylmagnesium bromide at
or ring-opened diol type product resulting from the attack -78 °C in the presence of CeCl3 furnished the labile
of excess
hemiketal intermediate 8c, which was readily effected by
BF3∑OEt2-induced deoxygenation with Et3SiH at the
same temperature with care (the use of excess Et3SiH par-
tially hydrogenated the olefinic part in 8c as well as the
deoxygenation reaction of the hemiketal skeleton), to lead
cleanly to the tetrasubstituted furan 9c, [α]D28+46.0° (c
1.05, EtOH), also as a sole stereoisomer (determined by
13C NMR) in 91% yield. Then, the double bond in 9c was
cleaved via dihydroxylation with OsO4 to the aldehyde
10. This was successively oxidized with bromine in
MeOH10 to the methyl ester 11, [α]D30+36.9° (c 0.57,
EtOH), in 83% yield, followed by final deprotection of the
silyl groups to complete the total synthesis of (+)-2-epigo-
niothalesdiol (12),11 [α]D29+66.6° (c 0.74, EtOH), in 37%
overall yield from C2-imide 4.
SBTO
O
OTBS
O
OH
ref. 8
a
HOOC
COOH
N
OH
CH2Ph
4
OTBS
OH
OTBS
O
O
C8H17
C8H17
+
PhH2CHN
PhH2CHN
SBTO
SBTO
OH
5a
5b
b
RO
OR
6: R = H
c
O
7a: R = Bn
7b: R = TBS
C8H17
O
SBTO
O
OTBS
O
SBTO
O
OTBS
4 steps
SBTO
OTBS
SBTO
R
OTBS
a
d
e
HO
R
7b
N
O
C8H17
O
C8H17
O
CH2Ph
4
7c
9a: R = C8H17
9b: R = Ph
8a: R = C8H17
8b: R = Ph
SBTO
OTBS
SBTO
OTBS
b
c
Reagents and conditions: (a) 1. C8H17MgBr, THF, 0 ºC; 2, NaBH4,
EtOH; 67% (5a) (2 steps); trace (5b) (2 steps) ; (b) 10% HCl-dioxane
(1 : 1), 80 ºC; 95%; (c) BnBr-Ag2O, CH3COOEt; 51% (7a); TBSCl,
imidazole, DMF; 97% (7b); (d) 1. C8H17MgBr, CeCl3, THF, -78 ºC
(8a); PhMgBr, CeCl3, THF, -78 ºC (8b); 2. Et3SiH, BF3∑OEt2,
CH2Cl2, -78 ºC; 64% (9a) (2 steps); 66% (9b) (2 steps).
HO
O
O
9c
8c
SBTO
OTBS
RO
OR
d
Scheme 1
2
5
O
O
CHO
COOCH3
10
Grignard reagent to 7b was observed. Stereochemistry of
the new asymmetric center in 9a was unambiguously de-
termined to be S, since it possesses a C2-axis of symmetry.
9b was also estimated to have the same configuration
based on the similarity of its spectral data. In contrast to
our previous reports,6 it could proceed through the exclu-
sive attack of Et3SiH to the oxocarbenium ion intermedi-
ate from the opposite site of the α-OTBS group
independent of the γ-substituent. Presumably a manifesta-
tion of productlike steric destabilization of the transition
state leading to the cis 2,3-stereochemistry is being ob-
served.9a
11: R = TBS
12: R = H (2-epigoniothalesdiol)
e
Reagents and conditions: (a) PhMgBr, CeCl3, THF, -78 ºC; (b)
Et3SiH, BF3∑OEt2, CH2Cl2, -78 ºC; 91% (2 steps); (c) 1. OsO4, NMO,
acetone-H2O (1 : 1); 99%; 2. NaIO4, Et2O-H2O (1 : 1); (d) Br2,
NaHCO3, MeOH-H2O (9 : 1); 83% (2 steps); (e) cat. p-TsOH, MeOH;
77%.
Scheme 2
In summary, this work constitutes the first asymmetric
synthesis of 2-epigoniothalesdiol from D-tartaric acid
based on the stereoselective Lewis acid-promoted hydro-
genation, and verifies the structure proposed in the litera-
ture for this natural product, since no report concerning
the total synthesis of goniothalesdiol has been appeared to
date.
With above stereochemical outcome in hand, we turned
our attention to the asymmetric synthesis of 2-epigonio-
thalesdiol since the preparation of unnatural epimers and
other structural analogs of styryllactone groups has gener-
ated much interest. This is based on the fact that the bio-
logical activity of these molecules varies substantially
with the number, position and stereochemistry of the
functional groups into the furan skeleton. As summarized
in Scheme 2, the homochiral lactone 7c, [α]D30 -62.2° (c
Acknowledgement
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
Synlett 1999, No. 12, 1969–1971 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Tetrasubstituted Tetrahydrofuran, 2-Epigoniothalesdiol
1971
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Article Identifier:
1437-2096,E;1999,0,12,1969,1971,ftx,en;Y17999ST.pdf
Synlett 1999, No. 12, 1969–1971 ISSN 0936-5214 © Thieme Stuttgart · New York