Enantioselective synthesis and selective monofunctionalization of (4R,6R)-4,6-dihydroxy-2,8-dioxabicyclo[3.3.0]octane

Article abstract of DOI:10.1021/ol062431d

(Diagram presented) An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol unit.

Full text of DOI:10.1021/ol062431d

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5821-5824
Enantioselective Synthesis and Selective
Monofunctionalization of (4R,6R)-4,6-
Dihydroxy-2,8-dioxabicyclo[3.3.0]octane
Bruno Linclau,* Martin J. Jeffery,† Solen Josse,‡ and Cyrille Tomassi
UniVersity of Southampton, School of Chemistry,
Highfield, Southampton SO17 1BJ, U.K.
bruno.linclau@soton.ac.uk
Received October 3, 2006
ABSTRACT
An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol
unit.
The 2,8-dioxabicyclo[3.3.0]octane ring system (hexahydro-
furo[2,3-b]furan, also called bistetrahydrofuran or bis-THF)
is present in a limited number of natural products including
communiol D 1,1 the ATPase inhibitor asteltoxin 2,2 and
dihydroclerodin 3.3 The last is a member of the large
clerodane family, many of which were found to have
interesting biological activities, including antifeedant, anti-
viral, antitumor, and antibiotic activity (Figure 1).3 Benzan-
nulated bis-THF rings are found in aflatoxins,4 and they have
been used as a template for the development of cholinesterase
inhibitors.5
A particularly successful example of a bis-THF-containing
drug candidate is the nonpeptidic HIV-protease inhibitor
Figure 1. Examples of saturated bis-THF-containing compounds.
† Current address: Evotec (U.K.) Ltd., 114 Milton Park, Abingdon, Oxon
TMC-114 4,6 which has recently been approved by the FDA
for treatment against AIDS under the name Darunavir. This
compound was reported to be very active not only against
the wild-type virus but also against a series of mutant strains.7
OX14 4SD, U.K.
‡ Current address: Laboratoire des Glucides UMR6219, Universite´ de
Picardie Jules Verne, 33 rue Saint Leu, 80039 Amiens, France.
(1) (a) Che, Y.; Gloer, J. B.; Scott, J. A.; Malloch, D. Tetrahedron Lett.
2004, 45, 6891. (b) Enomoto, M.; Nakahata, T.; Kuwahara, S. Tetrahedron
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(2) Kruger, G. J.; Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Chem.
Commun. 1979, 441.
(3) Reviews: (a) van Beeck, T. A.; de Groot, Ae. Recl. TraV. Chim.
Pays-Bas 1986, 105, 513. (b) Merritt, A. T.; Ley, S. V. Nat. Prod. Rep.
1992, 9, 243.
(4) Reviews: (a) Schuda, P. F. Top. Curr. Chem. 1980, 91, 75. (b) Minto,
R. E.; Townsend, C. A. Chem. ReV. 1997, 97, 2537.
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W.; Tweedie, D.; Shafferman, A.; Lahiri, D. K.; Brossi, A.; Greig, N. H.
J. Med. Chem. 2006, 49, 2174.
10.1021/ol062431d CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/15/2006

With its low molecular weight, high degree of rigidity,
and association with biological activity, the bis-THF structure
is an interesting scaffold. Any substitution on a nonfused
bond position renders the bicycle chiral. There are two
H-bond acceptors, which, incidentally, play a crucial role in
the interaction of TMC-114 with the protease enzyme.
We were interested in the synthesis of the chiral 4,6-
disubstituted bis-THF 5 (Scheme 1) as a versatile intermedi-
Scheme 2. Cyanide Approach
Scheme 1. Retrosynthetic Analysis
targeted (Scheme 2). To this end, selective protection of
arabitol under kinetic conditions to the 1,2:4,5-diacetal 89
was followed by conversion to the triflate 9 and mesylate
10 in high yield (100% and 93%).10 However, reaction of 9
with NaCN in DMF at room temperature only returned
elimination products 12 and 13 in 80% combined yield. The
formation of the olefin isomers arises from unselective
cyanide attack of the diastereotopic â-protons. Attempting
to favor substitution over elimination by lowering the reaction
temperature (0 °C; -40 °C) only reduced the yield (63%;
59%). When the mesylate 10 was subjected to NaCN, no
reaction occurred at room temperature, and only 27% of
12/13 was obtained after 1 day at 110 °C.
ate for scaffold applications, in particular, toward the syn-
thesis of TMC-114 analogues with substitution at the exo-
6-position, where modeling has suggested that additional
interactions with the HIV-protease might be possible. To the
best of our knowledge, such analogues have not yet been
reported. An essential part of this work entailed the inves-
tigation toward a selective differentiation of the diastereotopic
alcohols. The synthesis and monofunctionalization of 5 is
reported herein.
Next, the synthesis of 6 was investigated via an alkene
hydroboration/oxidation sequence.8a Oxidation of 89a,b and
Wittig reaction led to 159b in excellent yield (Scheme 3).
The retrosynthetic analysis is shown in Scheme 1. Discon-
nections at the acetal center lead to 6. The acid-catalyzed
formation of a bis-THF ring via a central formyl group, or
from a preformed five-membered (hemi)-acetal, is known.8
Further disconnection as indicated leads to L-arabitol 7 as
starting material. Importantly for scaffold applications, both
arabitol enantiomers are commercially available at similar
cost.
Scheme 3. Synthesis of the Cyclization Precursor 6
A key feature in this approach is that, starting from
“pseudo-C2-symmetric” arabitol, the central carbon atom
remains nonstereogenic throughout the sequence, thus mini-
mizing diastereoselectivity issues. In addition, the selective
formation of a cis-fused bis-THF system was expected under
thermodynamic control.
The synthesis of the aldehyde 6 was first envisaged via
The subsequent hydroboration reaction proved to be an
eventful step (see below), but by using diethylborane as
reagent, a good yield of the alcohol 16 was obtained after
oxidative workup. Finally, Parikh-Doering oxidation11 of
16 gave 6 in excellent yield.
The hydroboration reaction was initially investigated with
BH3‚DMS as reagent which led to the formation of an acetal
reduction of a cyano group.8b Hence, the nitrile 11 was
(6) (a) Ghosh, A. K.; Shin, D. W.; Swanson, L.; Krishnan, K.; Cho, H.;
Hussain, K. A.; Walters, D. E.; Holland, L.; Buthod, J. Il Farm. 2001, 56,
29. (b) Ghosh, A. K.; Kincaid, J. F.; Cho, W.; Walters, D. E.; Krishnan,
K.; Hussain, K. A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.
Bioorg. Med. Chem. Lett. 1998, 8, 687.
(7) Surleraux, D. L. N. G.; Tahri, A.; Verschueren, W. G.; Pille, G. M.
E.; de Kock, H. A.; Jonckers, T. H. M.; Peeters, A.; De Meyer, S.; Azijn,
H.; Pauwels, R.; de Bethune, M.-P.; King, N. M.; Prabu-Jeyabalan, M.;
Schiffer, C. A.; Wigerinck, P. B. T. P. J. Med. Chem. 2005, 48, 1813.
(8) Selected examples toward saturated, monoacetal bis-THF via a formyl
group: (a) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1997, 38,
2187. (b) Vader, J.; Sengers, H.; De Groot, Ae. Tetrahedron 1989, 45, 2131.
(c) Roggenbuck, R.; Schmidt, A.; Eilbracht, P. Org. Lett. 2002, 4, 289.
Via acetal exchange: (d) Schreiber, S. L.; Satake, K. J. Am. Chem. Soc.
1984, 106, 4186. (e) Tadano, K.-I.; Yamada, H.; Idogaki, Y.; Ogawa, S.;
Suami, T. Tetrahedron Lett. 1988, 29, 655.
(9) (a) Linclau, B; Boydell, A. J.; Clarke, P. J.; Horan, R.; Jacquet, C.
J. Org. Chem. 2003, 68, 1821. (b) Maleczka, R. E., Jr.; Terrell, L. R.; Geng,
F.; Ward, J. S., III. Org. Lett. 2002, 4, 2841. See also: (c) Terauchi, T.;
Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh, N.; Nakata, M. Tetrahedron
Lett. 2000, 41, 2649.
(10) Boydell, A. J.; Jeffery, M. J.; Bu¨rkstu¨mmer, E.; Linclau, B. J. Org.
Chem. 2003, 68, 8252.
(11) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
5822
Org. Lett., Vol. 8, No. 25, 2006

Scheme 4. Diastereoselectivity of the Acetal Reduction
Table 1. Hydroboration Experiments of 15
yield %a
time 16 17b
temp
(°C)
entry
borane (equiv)
1
2
3
4
5
6
BH3‚DMS (5)c
rt
2 days 32 19
BH3‚DMS (5)c
BH3‚THF (5)
BH3‚THF (10)
50 2 days 26 41
rt
40 1 day
22 h
2 days 35
0
84
9
0
80
Et3B‚THF (3.0), BH3‚THF (1.0) rt
Et3B‚THF (3.0), BH3‚THF (0.5) rt
2 days 92
0
led to 17 as the only product in 84% yield (entry 4). Next,
the use of dialkylboranes was investigated, as after B-O
coordination (as in 23) the endo-R′ group would sterically
clash with the endo-ethyl group. Unfortunately, 9-BBN did
not react with 15, but use of Et2BH, formed in situ from
metathesis reaction with Et3B and BH3,13 led to the desired
16 in excellent yield after oxidative workup. An excess of
Et3B was necessary to completely remove BH3 from the
metathesis equilibrium reaction (Table 1, entries 5 and 6).
Hence, the hydroboration of the C2-symmetric alkene 15
was optimized for both reaction pathways.
a Isolated yield. b See Supporting Information for confirmation of relative
stereochemistry. c Toluene was used as solvent.
reduction byproduct 17 (entry 1, Table 1). When the reaction
was executed at elevated temperature, 17 was obtained in
higher yield (entry 2). Interestingly, a single diastereomer
was obtained representing an efficient desymmetrization of
the C2-symmetric 15.
Such a desymmetrization process starting from 18 has been
employed by Nakata in the synthesis of the C11-C23
segment of Swinholide A, in which the desymmetrized and
hydroborated products were obtained in a 2:1 ratio.12
Finally, the conversion of 6 to 5, which requires alcohol
deprotection followed by cyclic acetal formation, was
achieved in one pot (Table 2). Reaction in MeOH/H2O (22:1
Table 2. Deprotection/Cyclization toward the bis-THF 5
A rationale for the selective acetal reduction proposed
by Nakata12 fully explains our results, and is given in
Scheme 4.
Initial hydroboration leads to 19 which, after oxidative
workup, leads to the desired 16. However, intramolecular
B-O coordination initiates reductive acetal ring opening.
With the homotopic acetal groups of 15 now transformed
into diastereotopic groups, two possible diastereomeric
intermediates 20 and 21 can be formed, in which the
coordination effectively results in the formation of a [3.3.0]-
bicyclooctane ring system with the substituent R in the exo
position (20) or in the endo position (21). Steric factors result
in the formation of 20 being the preferred pathway, explain-
ing the observed diastereoselectivity.
yield (%)a
entry
conditions
time
44 h
5
24b
1
2
CSA (15 mol %), MeOH/H2O
CSA (15 mol %), THF, MeOH
(5 equiv), H2O (6.6 equiv)
62
78
25
0
13 days
3
DCM/TFA/H2O (100:10:1 v/v)
0.5 h
90
0
a Isolated yield. b Relative stereochemistry not determined.
v/v) with 15 mol % of CSA smoothly led to 5 in high yield
on a small scale. However, on a large scale, incomplete
reaction was observed (entry 1). In this case, a side product
24 was also isolated, resulting from trapping of the corre-
sponding oxocarbenium intermediate with MeOH (relative
stereochemistry not determined). When THF was introduced
as the solvent, the reaction time significantly increased, with
78% of 5 isolated after 13 days. Despite no 24 being formed,
Hence, it was envisioned that preventing B-O coordina-
tion would be key in maximizing the yield of 16. Indeed,
BH3‚THF in THF led to exclusive formation of 16 albeit in
low yield (entry 3). However, heating the reaction mixture
(12) Nakata, T.; Komatsu, T.; Nagasawa, K.; Yamada, H.; Takahashi,
T. Tetrahedron Lett. 1994, 35, 8225. With bis-p-methoxybenzylidene acetals
instead of acetonides, the corresponding diol was obtained in 88% yield.
See also: Horita, K.; Inoue, T.; Tanaka, K.; Yonemitsu, O. Tetrahedron
Lett. 1992, 33, 5537.
(13) Koster, R.; Binger, P. Inorg. Synth. 1974, 15, 141.
Org. Lett., Vol. 8, No. 25, 2006
5823

the reaction time was unacceptably long. Using TFA as acid,
the reaction rate was dramatically increased. Even on a large
scale (44 mmol), only bis-THF 5 was isolated in 90% yield
after a 30 min reaction time.
With a successful synthesis of 5 in hand, efforts were
directed toward a practical differentiation of the 1,3-diol
system, an essential requirement for scaffold applications.
It was anticipated that the bent shape of the bicyclo[3.3.0]-
octane system would enable selective monofunctionalization
of the diastereotopic alcohol groups, located on the endo and
the more accessible exo faces.14
was still isolated (entry 3), indicating that endo protection
commenced before all exo-OH had reacted. The reaction of
5 with pivaloyl chloride (1.1 equiv) was also not completely
exo selective (3:1 ratio), but no endo-product 26c was
observed (entry 4). The structure of 25b and 26b was proven
by X-ray crystallographic analysis of the corresponding
p-nitrophenolate derivatives (see Supporting Information).
To obtain the endo-protected scaffold, a two-step sequence
was investigated in which an exo-selective deprotection was
attempted starting from the bissilyl ethers 27b and 27d (Table
4), which were obtained by protection of 5 with excess
chlorosilane (76% resp 79%).
The use of TBAF/THF led to virtually unselective depro-
tection (not shown), but good selectivity was achieved with
the milder NH4F/MeOH system.15 Reaction at room tem-
perature was, as expected,15 sluggish, but selective exo
deprotection had taken place, next to full deprotection (entry
1). Halving the amount of NH4F, while increasing the
reaction temperature, led to a smaller amount of endo
deprotection, with a good yield of 26b in only 2.5 h (entry
2). Further lowering the number of NH4F equivalents while
increasing the reaction time eliminated any endo deprotec-
tion, but only a low conversion was achieved (entry 3). In
the event, TLC analysis is required to determine when to
terminate the reaction. Interestingly, the endo deprotection
was observed only when the exo-TBDPS group already
had reacted. In contrast, the deprotection of the corre-
sponding TBDMS-protected bis-THF 27d was much less
selective (entry 4).
Our initial results are given in Tables 3 and 4. Alcohol
differentiation was fully selective with the bulky TIPSCl
Table 3. Exo-Selective Protection Experiments
yield (%)a
entry
reagent R-Cl (equiv)
time (h)
25
26
27
1
2
3
4
a TIPS-Cl (1.5)
b TBDPS-Cl (1.5)
b TBDPS-Cl (1.0)
c Piv-Cl (1.1)b
22
22.5
24
80
55
63
57
0
0
5
0
0
45
11
19
25
a Isolated yield. b DIPEA was used instead of imidazole, and THF was
used instead of DMF.
In conclusion, an efficient, high-yielding synthesis of the
interesting scaffold 5 is reported, as well as a methodology
for selective differentiation of the alcohol groups. Research
toward the synthesis and biological evaluation of TMC-114
analogues is underway and will be reported in due course.
(Table 3, entry 1), with the exo-silyl ether 25a isolated in
excellent yield. Reaction with TBDPSCl was less selective
(entry 2), with bis-silylated 27b also formed. Interestingly,
when using 1 equiv, a small amount of endo-product 26b
Acknowledgment. We thank the EPSRC and NV Tibotec
for financial support and Dr. Dominique Surleraux and Dr.
Tim Jonckers (NV Tibotec) for helpful discussions. We wish
to acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.16
Table 4. Exo-Selective Deprotection Experiments
Supporting Information Available: Experimental pro-
1
cedures and spectral data, including copies of H and 13C
NMR spectra, for 5, 16, 17, 25a, and 26b; stereochemical
confirmation of 17; X-ray structures of 5; and the p-nitro-
phenolates of 25b and 26b. This material is available free
of charge via the Internet at http://pubs.acs.org.
yield (%)a
NH4F
OL062431D
entry
R
(equiv) temp
time
25 26
45 36
<1 50 <5
5
27b
(14) Related processes on dianhydroglucitol (selected examples): (a)
Buck, K. W.; Duxbury, J. M.; Foster, A. B.; Perry, A. R.; Webber, J. M.
Carbohydr. Res. 1966, 2, 122. (b) Stoss, P.; Merrath, P.; Schlu¨ter, G.
Synthesis 1987, 174. (c) Abenha¨ım, D.; Loupy, A.; Munnier, L.; Tamion,
R.; Marsais, F.; Que´guiner, G. Carbohydr. Res. 1994, 261, 255. (d) Enholm,
E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959. (e) Vogler, M.; Koert, U.;
Harms, K.; Dorsch, D.; Gleitz, J.; Raddatz, P. Synthesis 2004, 1211.
(15) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177.
(16) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput.
Sci. 1996, 36, 746.
1
2c
3
b TBDPS
b TBDPS
b TBDPS
d TBDMS
8
rt
4 days
0
0
d
4
1.2
1.2
reflux 2.5 h
reflux 24 h
reflux 22 h
0
34 <1 62
4
13 61 18
3e
a Isolated yield. b Recovered starting material. c Starting from the crude
reaction mixture after silylation. d Not determined (coeluted with excess
chlorosilane). e 27d.
5824
Org. Lett., Vol. 8, No. 25, 2006