Asymmetric One-Pot Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Component of Current HIV Protease Inhibitors

Article abstract of DOI:10.1021/acs.joc.6b02588

A concise and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key building block for several clinical and experimental HIV protease inhibitors including the highly important drug darunavir, was achieved via a one-pot procedure using furan and Cbz-protected glycol aldehyde as starting materials. A [2+2]-photocycloaddition between both reactants which can be prepared from wood-based starting materials according to the principles of xylochemistry, followed by hydrogenation and lipase-catalyzed kinetic resolution afforded the target compound in high yield and up to 99% ee.

Full text of DOI:10.1021/acs.joc.6b02588

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Note
An Asymmetric One-Pot Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-
b]furan-3-ol: A Key Component of Current HIV Protease Inhibitors
Adrian Sevenich, Gong-Qing Liu, Anthony J Arduengo, B. Frank Gupton, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02588 • Publication Date (Web): 20 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
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An Asymmetric One-Pot Synthesis of
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A
Key Component of Current HIV Protease
Inhibitors
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Adrian Sevenich§†, GongꢀQing Liu§†, Anthony J. Arduengo III ‡, B. Frank Gupton,ꢀ
and Till Opatz* †
† Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10–
14, 55128 Mainz, Germany
‡ Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, USA
ꢀDepartment of Chemistry, Virginia Commonwealth University, Richmond, VA
23284, USA
§ Both authors contributed equally.
Abstract Graphics
Abstract
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A concise and efficient synthesis of (3R,3aS,6aR)ꢀhexahydrofuro[2,3ꢀb]furanꢀ3ꢀol, a
key building block for several clinical and experimental HIV protease inhibitors
including the highly important drug Darunavir, was achieved via a oneꢀpot procedure
using furan and Cbzꢀprotected glycol aldehyde as starting materials. A
[2+2]ꢀphotocycloaddition between both reactants which can be prepared from
woodꢀbased starting materials according to the principles of xylochemistry, followed
by hydrogenation and lipaseꢀcatalyzed kinetic resolution afforded the target
compound in high yield and up to 99% ee.
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Acquired immunodeficiency syndrome (AIDS), caused by the human
immunodeficiency virus (HIV), is a degenerative disease of the immune system and
has become a pressing medical concern globally.1 Currently, highly active
antiretroviral therapy (HAART), a therapy combining protease inhibitors (PIs) and
reverse transcriptase inhibitors, is proven to be an effective treatment against AIDS.2
To this end, continuous efforts have been devoted to develop both new and existing
classes of HIV PIs due to resistance.3 Darunavir (1, Figure 1)4, brecanavir (2)5,
GSꢀ8374 (3)6 and SPIꢀ256 (4)7 are novel HIV PIs and have shown high efficacy in
treatment of multidrugꢀresistance HIV. A common structural feature of these
compounds is the (3R,3aS,6aR)ꢀhexahydrofuro[2,3ꢀb]furanꢀ3ꢀol (bisꢀTHF alcohol)
moiety. The significance of bisꢀTHF alcohol for combating drugꢀresistance is well
documented.8 It was shown that both oxygens of the bisꢀTHF ligand effectively form
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hydrogen bonds to the NH of Asp 30 and Asp 29 located in the S2 binding domain of
HIVꢀ1 protease.9 It turned out that ring size, position of the oxygens and
stereochemistry of the bisꢀTHF ligand are crucial.10
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Figure 1. Structures of HIVꢀprotease inhibitors 1ꢀ4
Various methods are available for the construction of the bisꢀTHF alcohol structure
owing to its importance in drug discovery.11 One representative strategy, first reported
by Ghosh and coꢀworkers,9 used the exꢀchiral pool approach which was also
employed in later syntheses based on
D
ꢀdiethyl malate,10
D
ꢀglucal12 and
D
ꢀglyceraldehyde derivatives.13 Another approach involves the synthesis of racemic
bisꢀTHF alcohol followed by enzymatic optical resolution.14 Other approaches
included the use of (1S,2R)ꢀ1ꢀtosylamidoꢀ2ꢀindanol as a chiral auxiliary,8 asymmetric
direct crossꢀaldol reaction of 4ꢀ(benzyloxy)butanal with benzyloxyacetaldehyde or
ethyl glyoxylate,15 and EvansꢀMukaiyama aldol reaction of benzyloxyacetaldehyde
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with a silyl ketene acetal16 as well as asymmetric oxyselenenylation of
2,3ꢀdihydrofuran.17
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In addition, oneꢀpot procedures were also reported as efficient methods for the
production of bisꢀTHF alcohol.18 Xie and coworkers have reported a synthesis using
the asymmetric Lewis acidꢀcatalyzed reaction of 2,3ꢀdihydrofuran with
glycolaldehyde dimer (Scheme 1).18b The formal cycloaddition was catalyzed by
Sn(OTf)2 and Evans’s BOX ligands in hexafluoroisopropanol at 0 °C and provided
bisꢀTHF alcohol in a 98:2 diastereoselectivity. A similar route was also described by
Yu and coworkers using Yb(fod)3 as the Lewis acid.18a This process, however,
required an oxidation (TEMPO, NaOCl) followed by NaBH4 reduction, acetylation
and lipase resolution (PSꢀC “Amano I”) to afford the bisꢀTHF alcohol in 97–98% ee
yields of 28–35%. Both routes make use of chiral BOX ligands to control the absolute
stereochemistry of the aldol reaction but suffered from low enantioselectivity so that
an additional enzymatic resolution step was required to obtain the target alcohol in
sufficient optical purity. Recently, Itoh and coꢀworkers reported a condensation of
2,3ꢀdihydrofuran with glycol aldehyde using Schreiner's thiourea catalyst.18c Again,
an enzymatic resolution was included to improve the enantioselectivity.
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Scheme 1. Strategies for the synthesis of bisꢀTHF alcohol.
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These syntheses, however, suffer to various extents from limitations such as multiple
steps, utilization of expensive metal catalysts and/or starting materials or low
diastereoꢀ or enantioselectivity requiring additional operations to achieve acceptable
values. Therefore, there is still a need for a highꢀyielding and scalable process to the
optically pure form of the bisꢀTHF alcohol. Herein, we report an efficient oneꢀpot
access to this compound involving photocycloaddition combined with hydrogenation
as well as enzymatic optical resolution (Scheme 1d).
Doan and coꢀworkers reported a novel strategy in a patented synthesis of (–)ꢀ5
(Scheme 2).19 They used the photocycloaddition of several protected glycol aldehydes
to furan to obtain the protected oxetane acetal. Hydrogenation followed by
acidꢀcatalyzed deprotection resulted in a racemic mixture of bisꢀTHF alcohol.
Acetylation, followed by resolution through lipase PSꢀ800 resulted in the formation of
the bisꢀTHF acetate, which was subsequently treated with potassium carbonate to
afford the desired product (–)ꢀ5 in 98% ee (no yield reported.
Scheme 2. Doan’s route to bisꢀTHF alcohol (–)ꢀ5.
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In comparison to Doan’s route we focused on maximizing costꢀefficiency and
environmental sustainability by using inexpensive, readily available and sustainable
starting materials, avoiding chlorinated solvents and minimizing waste and
purification steps. To fulfil these criteria, we optimized each step and assembled them
into a oneꢀpot procedure.
The photochemical [2+2] cycloaddition of aldehydes and ketones to furan is
wellꢀknown and has been used by Schreiber et al. as a key step to furnish the core of
Asteltoxin.20 Inspired by this seminal work, we envisioned that the target molecule
(–)ꢀ5 could be accessible via enzymatic resolution of (±)ꢀ5 which could be
constructed from oxetane 7 through hydrogenation and rearrangement (Scheme 3).
Ideally, reduction of the C=C double bond and removal of the protecting group of
compound 7 could be achieved in a single operation giving intermediate 6 which
would undergo subsequent rearrangement under thermodynamic control to give (±)ꢀ5.
Oxetane (±)ꢀ7 could be easily prepared from furan and a protected glycol aldehyde by
the [2+2] photocycloaddition, the latter being accessible from inexpensive ethylene
glycol. Ideally, the enzymatic resolution could be combined with the hydrogenation as
well as the photocycloaddition into an even simpler threeꢀstep oneꢀpot procedure.
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Scheme 3. Strategy for synthesis of bisꢀTHF alcohol.
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To test the feasibility of this strategy, Cbzꢀprotected glycol aldehyde 9 was used to
optimize reaction conditions. The carbobenzoxy group was chosen for Oꢀprotection
due to its ease of introduction, the removal under the conditions of double bond
hydrogenation as well as its economics. While the Oꢀbenzyl group should have the
same characteristics, its use is prohibited by an efficient Norrishꢀtype II reaction
leading to scission of the C–O bond. The intermolecular [2+2] cycloaddition of
aldehyde 9 proceeds readily, giving the exo product in almost quantitative yield in
furan without formation of the endo isomer (Table 1, entry 1). While Doan et al. used
furan as a solvent in their protocol, we aimed at reducing the required amount of this
component. First, the effect of changing the solvent in the reaction was investigated.
As shown in Table 1, the cycloaddition proceeds efficiently in polar solvents (entries
2–3 vs 4),. MTBE was finally chosen as the solvent for further studies due to its good
performance as well as its availability and low toxicity. Additionally, widespread
experience with MTBE in industrial processes and in lipase catalyzed
biotransformations exists.21 To further improve the reaction, the furan/aldehyde ratio
was optimized. When the reactions were carried out with 2 equiv. of furan, the
product was obtained in slightly higher yield compared to an equimolar ratio (cf. entry
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9
5 vs. 2ꢀ4). A further increase in the amount of furan to a 5:1 ratio led to complete
conversion of 9, and desired product 7 could be obtained in 93% isolated yield (entry
6). It is noteworthy that the purity of aldehyde 9 is crucial for the current [2+2]
photocycloaddition. When crude aldehyde 9 was used, only trace amounts of the
cycloaddition product (±)ꢀ7 were detected under various conditions. The low molar
extinction coefficient of aliphatic aldehydes in the n→π*ꢀabsorption band around 300
nm probably accounts for this behavior as even small quantities of UVꢀabsorbing
contaminants can prevent excitation.22 After purification of aldehyde 9 by vacuum
distillation, no problems were encountered.
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Table 1. Optimization of the reaction conditions a
entry solvent ratio 8:9 time (h) conv (%)b
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5
6
Furan
MTBE
CH2Cl2
Hexane
MTBE
MTBE
ꢀ
20
24
24
24
24
20
>99 (93)
90
1:1
1:1
1:1
2:1
5:1
90
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92
>99 (93)
a All reactions were performed in 1 mmol scale and 5 mL of degassed solvent under UV irradiation
b
1
(λmax= 306 nm). Conversion of 9 as determined by H NMR spectroscopy, isolated yield of (±)ꢀ7 in
brackets.
Having established optimal conditions for photocycloaddition, the hydrogenation step
was examined next. After extensive screening, the optimized reaction condition was
obtained as follows (Table 2): 10% Pd/C (2 mol%) and (±)ꢀ7 in MTBE under
hydrogen (ambient pressure) at room temperature. Reduction of the C=C double bond
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and Oꢀdeprotection could be realized via hydrogenation, providing the desired
product racemic bisꢀTHF aclohol (±)ꢀ5 in 90% isolated yield (Table 2, entry 1).
Screening of solvents revealed that MTBE was optimal for the hydrogenation. MeOH
and THF were also suitable for the reaction, but the yields were generally lower
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1
(entries 2–3). Oxetane (±)ꢀ6 was observed as a discrete intermediate by H NMR
spectroscopy when the reaction was performed in presence of a base like K2CO3
(entries 4–5). This intermediate was however unstable and rearranged readily during
purification by column chromatography or upon storage to form the
thermodynamically more stable bisꢀTHF alcohol (±)ꢀ5.23
Table 2. Hydrogenation of the photocycloaddition product a
Yield of 5
entry
reaction condition
(%)b
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3
4
5
see equation
solvent MeOH
90
84
solvent THF
27
1 equiv. K2CO3
67
solvent MeOH, 1 equiv. K2CO3
82
a All reactions were run at 1 mmol scale. b Yields of isolated product.
With racemic bisꢀTHF alcohol in hand, the enzymatic optical resolution was
optimized. To avoid the acylation of (±)ꢀ5 as an additional step, the enzyme should be
used for an enantioselective acylation of one enantiomer rather than a hydrolysis of
the racemic ester.19 First, the catalytic activity of different enzymes was examined
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(Table 3). As shown in table 3, Candida antarctica lipase A (CALꢀA) failed to give
optically pure bisꢀTHF alcohol due to complete acetylation of (±)ꢀ5 (Table 3, entry 1).
Candida antarctica lipase B (CALꢀB) provided the target compound with excellent
enantiomeric excess, but the reaction needs to be monitored carefully to prevent
overꢀacetylation of the desired enantiomer of the alcohol (entry 2). Rhizomucor
miehei lipase (RML), Thermomyces lanuginosa lipase (TLL) and Pseudomonas
fluorescens lipase (PFL) were able to produce enantioenriched alcohol 5, but low
stereoselectivites were observed (entries 3–5). The optical resolution using porcine
pancreatic lipase (PPL) and Pseudomonas cepacia lipase (PCL) was very efficient,
giving (–)ꢀ5 with 97% ee (entries 6–7). For both enzymes, the difference in the
reaction rates of both enantiomers is so large that the reaction ceases automatically at
50% conversion of the substrate.
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Table 3. Screening of different lipases a
ee
ee
s
#
lipase
conv.b (–)ꢀ5 acetate factor
(%) c
(%)c
d
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2
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5
6
7
CALꢀA
CALꢀB
RML
TLL
>99
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58
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76
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ꢀ
ꢀ
ꢀ
10
1
97
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57
61
97
97
47
<1
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25
95
7
PFL
3
PPL
165
>200
PCL
96
b
a All the reactions were run at 1 mmol scale, 50% w/w lipase. Conversion of (±)ꢀ5 as determined by
1H NMR. c ee determined by chiral GC. d stereoselectivity factor.
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Encouraged by these preliminary results, reactions with different acylating agents
were then carried out to find suitable conditions using the inexpensive PPL (Table 4).
Isopropenyl acetate as the acyl donor failed to give satisfactory conversion even at
long reaction times. This may be attributed to the steric hindrance of the acetylating
agent (Table 4, entry 1). The use of vinyl acetate or acetic anhydride offered good
enantioselectivities instead, but long reaction times were still needed to obtain
satisfactory conversions (entries 2–3). Longerꢀchain (propionyl, butyryl) acyl residues
were transferred more efficiently and with higher enantioselectivity by PPL (entries
4–5). (S)ꢀBisꢀTHF alcohol (–)ꢀ5 could be propionylated completely, resulting in >99%
ee of the (R)ꢀbisꢀTHF alcohol when reduced amounts of PPL and propionic anhydride
were used (entry 6). In addition, implementing the enzymatic resolution and
hydrogenation starting from compound (±)ꢀ7 into the oneꢀpot procedure had little
impact on the course of the reaction (entry 7). The use of butyric anhydride was not
further pursued due to unpleasant odor (entry 5).
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Table 4. Screening of acylating agents a
ee of
time covn.
#
reagent (equiv.)
(–)ꢀ5
(%)c
ꢀ
(h)
(%)b
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4
IPA (3.0)
VA (3.0)
160
95
5
50
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96
Ac2O (3.0)
(nPrCO)2O (3.0)
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6d
7d,f
(EtCO)2O (3.0)
(EtCO)2O (1.0)
(EtCO)2O (1.0)
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48 51(43)e
48 51
52
97
99
>99
7
a All reactions were run at 1 mmol scale. b Based on 1H NMR analysis of the crude reaction mixtures. c
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d
f
ee was determined by chiral GC. 10% w/w PPL was used. e Isolated yield of (–)ꢀ5. Oneꢀpot process
with hydrogenation step starting from (±)ꢀ7. IPA: Isopropenyl acetate, VA: Vinyl acetate.
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The success of above reactions prompted us to develop a larger scale oneꢀpot
procedure to prove the scalability of the current protocol, in which involved
photocycloaddition of furan and Cbzꢀprotected glycol aldehyde, hydrogenation as
well as enzymeꢀcatalyzed kinetic resolution (Scheme 4). Cbzꢀprotected glycol
aldehyde 7 (10.0 mmol, 1.94 g) and furan in MTBE were allowed to react in the
Rayonet photochemical reactor for 36 h. Excess furan was removed in vacuo and the
residue remaining in the vessel was redissolved in MTBE and treated with Pd/C and
H2 (balloon), followed by the addition of PPL and propionic anhydride. The
enzymatic optical resolution process was carried out at room temperature for 72 h.
The resulting mixture was filtered and concentrated in vacuo. The residue was
purified by silica gel column chromatography to give (–)ꢀ5 in 35% overall yield and
99% ee. For recycling of the hydrogenation catalyst, an additional filtration step can
be inserted prior to addition of the enzyme. Therefore, the current oneꢀpot procedure
is potentially interesting for industrial application. In addition, as furan, ethylene
glycol and toluene (required to produce CbzꢀCl) can be prepared from woody
biomass,24 the present route fulfills key criteria of xylochemistry.25
Scheme 4. Gramꢀscale oneꢀpot synthesis of enantiopure bisꢀTHF alcohol (–)ꢀ5.
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OH
H
H
PPL
Pd/C, H2
MTBE, r.t.
propionic anhydride
hv
OCbz
O
O
8
O
O
9
(−)−5
5 equiv.
10 mmol, 1.94g
35% isolated yield
99% ee
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In summary, a oneꢀpot procedure for the preparation of (−)ꢀbisꢀTHF alcohol 5 was
developed. The process involved a [2+2] photocycloaddition of furan and a protected
glycol aldehyde as a key step in which all three stereogenic centers were created in
the correct relative configuration and complete diastereoselectivity. In the subsequent
hydrogenation, the C=C double bond and the carbobenzoxy group could be removed
simultaneously, giving a labile oxetane acetal which directly rearranged to the desired
product. Addition of PPL and propionic anhydride to the resulting reaction mixture
produced the desired enantiopure bisꢀTHF alcohol. This current protocol is highly
practical due to (1) mild conditions and easyꢀtoꢀoperate oneꢀpot features, (2)
inexpensive and readily available reagents, and is (3) environmentally friendly and
should be amenable to production on a larger scale. It represents the shortest and
simplest route to this important intermediate reported so far.
Experimental Section
General Information: All reagents were obtained from commercial suppliers and
used without further purification unless stated otherwise. Except for PPL, all enzymes
were immobilized on polymeric beads to increase their stability. Anhydrous
dichloromethane was distilled from calcium hydride. Anhydrous ethyl acetate was
dried over molecular sieves. Anhydrous furan, MTBE and THF were distilled from
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sodium and benzophenone under nitrogen. Solvents used for photocycloaddition
reactions were degassed by argon sparging (30 min). Reactions requiring anhydrous
conditions were performed in dried glassware under an atmosphere of argon or
nitrogen. Photochemical reactions were performed in quartz glassware using a
photochemical reactor equipped with a Rayonetꢀtype circular array of 16 UV lamps
(λmax = 306 nm, 7.2 W each), a magnetic stirrer and a cooling fan. Flash
chromatography was performed on silica gel (35–70 µm) using the specified eluent
mixtures given as a volumetric ratio of components. NMR spectra were recorded with
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a 300 MHz spectrometer (300 MHz H and 75 MHz 13C) or with a 400 MHz
spectrometer (400 MHz 1H and 100 MHz 13C). All 13C NMR spectra were broadband
1Hꢀdecoupled. The chemical shifts (δ) are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS) and were referenced to the residual solvent
signal (e.g. for CDCl3: δ = 7.26 ppm for 1H and δ = 77.16 ppm for 13C NMR spectra).
Coupling constants (J) are given in Hertz (Hz) using the conventional abbreviations
(br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and
combinations thereof). ESIꢀHRMS was performed on a QꢀTOF instrument with a dual
source and a suitable external calibrant. Thinꢀlayer chromatography (TLC) was
carried out on 0.25 mm silica gel plates with a fluorescence indicator. Chiral GCꢀMS
analysis was carried out on using an Astec Chiraldex βꢀcyclodextrin trifluoroacetyl
(BTA) capillary column (20 m × 0.25 mm × 0.12 µm) and EI ionization (70 eV). The
chromatography to separate both enantiomers of the bisꢀTHF alcohol was conducted
using the following parameters: flow rate of the carrier gas (helium) 1.0 mL/min, inlet
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temperature 50 °C, transfer line temperature 180 °C, ion source temperature 200 °C
and an initial oven temperature of 90 °C for 3 min with a temperature ramp of
3 °C/min to 140 °C followed by 5 min hold and a coolꢀdown of 15 °C/min back to
90 °C followed by 2 min hold. (3R,3aS,6aR)ꢀbisꢀTHF alcohol: tR = 21.5 min,
(3S,3aR,6aS)ꢀbisꢀTHF alcohol: tR = 21.2 min. The optical rotations were measured at
546 nm and 578 nm. The data were extrapolated to a wavelength of λ = 589 nm using
the Drude equation.26
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Benzyl (2-oxoethyl) carbonate (9). To a solution of ethylene glycol (12.4g, 200
mmol) and pyridine (1.74 g, 22 mmol) in dry ethyl acetate, benzyl chloroformate
o
(3.42 g, 20 mmol) was added at 0 C. The mixture was warmed to room temperature
and stirred overnight, the mixture was washed with 1N HCl, dried and concentrated to
give Cbzꢀprotected glycol, which was used in the subsequent step without further
purification.
Method 1: Trichloroisocyanuric acid (4.87 g, 21 mmol) was added to a solution of the
Cbzꢀprotected glycol (3.92 g, 20 mmol) in CH2Cl2, and the solution was stirred and
o
maintained at 0 C, followed by addition of TEMPO (31 mg, 0.2 mmol). After the
addition, the mixture was warmed to room temperature and stirred for 15 min and
then filtered on Celite, and the solvent was evaporated to yield crude aldehyde 9,
which was purified by column chromatography or distillation (105 °C / 0.2 mbar) to
give pure Cbzꢀprotected glycol aldehyde 9 (2.37g, 61%, 2 steps) as a colorless oil.27
Method 2: To a solution of oxalyl chloride (3.05 g, 24 mmol) in CH2Cl2 cooled at
−78 °C was added dropwise a solution of DMSO (1.72 g, 22 mmol) in CH2Cl2. After
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5 min, a solution of Cbzꢀprotected glycol (3.92 g, 20 mmol) in CH2Cl2 was added.
The reaction mixture was then stirred for 15 min at −78 °C and triethylamine (12.1 g,
120 mmol) was added in 1 portion. After 10 min at −78 °C, the mixture was allowed
to warm to room temperature and diluted with CH2Cl2. The organic layer was
successively washed with a saturated aqueous solution of NH4Cl. The combined
organic extracts were dried and concentrated to give crude aldehyde, which was
purified by column chromatography or distillation (105 °C/0.2 mbar) to give pure
Cbzꢀprotected glycol aldehyde 9 (2.79g, 72%, 2 steps) as a colorless oil.28
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Method 3: To a solution of glycerol (18.4g, 200 mmol) and pyridine (1.74 g, 22 mmol)
o
in dry ethyl acetate, benzyl chloroformate (3.42 g, 20 mmol) was added at 0 C. The
mixture was warmed to room temperature and stirred overnight, the mixture was
washed with 1N HCl, dried and concentrated to give Cbzꢀprotected glycol, which was
used in the subsequent step without further purification.
To a solution of Cbzꢀprotected glycerol (3.92 g, 20 mmol) in methanol, NaIO4 (6.42 g,
o
30 mmol) was added at 0 C, and the resulting mixture was stirred at room
temperature for overnight. The formed precipitate was removed by filtration. Most of
the solvent was removed by a rotary evaporator to give residual oil, which was
purified by column chromatography or distilled under reduced pressure (105 °C / 0.2
mbar) to give aldehyde 9 (2.60 g, 67%, 2 steps) as a colorless oil.29
1H NMR (300 MHz, CDCl3) δ/ppm = 9.65 (s, 1H), 7.48 – 7.35 (m, 5H), 5.24 (s, 2H),
4.71 (s, 2H). 13C NMR (75 MHz, CDCl3) δ/ppm =195.4, 154.7, 134.6, 128.8, 128.7,
128.4, 71.2, 70.7. Spectral data are in agreement with literature values.30
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exo-2,7-Dioxabicyclo[3.2.0]hept-3-en-6-ylmethyl benzyl carbonate ((±)ꢀ7).
Cbzꢀprotected glycol aldehyde 9 (194 mg, 1.00 mmol) and furan 8 (340 mg, 5.00
mmol) in MTBE (5 mL) were mixed in a 10ꢀmL photolysis flask equipped with a
magnetic stirrer bar and placed in the Rayonetꢀtype photochemical reactor. Nitrogen
was sparged throughout the duration of the reaction, and the solution was stirred
vigorously. TLC analysis indicated completion of the reaction after 20 h. The reaction
mixture was concentrated to give a crude residue, which was purified by flash column
chromatography (cyclohexane/EtOAc = 5/1) to give (±)ꢀ7 as colorless oil (244 mg,
93%). 1H NMR, COSY (400 MHz, CDCl3) δ = 1H NMR (300 MHz, CDCl3) δ/ppm =
7.45 – 7.35 (m, 5H, ArꢀH), 6.67 – 6.63 (m, 1H, Hꢀ3), 6.33 (d, J = 4.3 Hz, 1H, Hꢀ1),
5.35 (t, J = 2.9 Hz, 1H, H4), 5.22 (s, 2H, ꢀCH2ꢀPh), 4.73 (dt, J = 3.5, 1.8 Hz, 1H, Hꢀ6),
4.44 (dd, J = 12.0, 3.5 Hz, 1H, CHaHb), 4.32 (dd, J = 12.0, 3.5 Hz, 1H, CHaHb), 3.72
– 3.65 (m, 1H, Hꢀ5).13CꢀNMR, HSQC, HMBC (100 MHz, CDCl3): δ/ppm = 155.1
(C=O), 148.5 (Cꢀ3), 135.0 (ArꢀC1’), 128.7 (ArꢀC3’, ArꢀC5’), 128.7 (ArꢀC4’), 128.4
(ArꢀC2’, ArꢀC6’), 107.9 (Cꢀ1), 103.6 (Cꢀ4), 87.9 (Cꢀ6), 70.0 (ꢀCH2Ph), 68.8 (ꢀCH2ꢀ),
46.6 (Cꢀ5). HRMS–ESI (m/z): [M+Na]+ calcd for C14H14O5, 285.0739; found:
285.0742.
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anti-Hexahydrofuro[2,3-b]furan-3-ol ((±)ꢀ5). The compound (±)ꢀ7 (262 mg, 1.00
mmol), 10% Pd/C (21 mg, 0.02 mmol), and MTBE (10 mL) were combined, and the
reaction vessel was evacuated and backꢀfilled with hydrogen (balloon). The reaction
mixture was stirred under hydrogen for 24h. The catalyst was filtered off using Celite,
and the filtrate was evaporated to give a crude residue which was purified by flash
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column chromatography (cyclohexane/EtOAc = 1/1) to give (±)ꢀ5 as colorless oil
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(117 mg, 90%). HꢀNMR, COSY (300 MHz, CDCl3): ꢀ/ppm = 5.66 (d, J = 5.2 Hz,
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1H, Hꢀ6a), 4.41 (pseudoꢀq, ³J ≈ 7.2 Hz, 1H, Hꢀ3), 4.02–3.79 (m, 3H, Hꢀ2a,5), 3.60
(dd, J = 9.1, 7.2 Hz, 1H, Hꢀ2b), 2.84 (dddd, J = 10.1, 7.2, 5.2, 2.6 Hz, 1H, Hꢀ3a), 2.49
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(s, 1H, OH), 2.30 (ddꢀpseudoꢀt, ²J = 12.9 Hz, J = 5.8 Hz, J ≈ 2.6 Hz, 1H, Hꢀ4a),
1.85 (dꢀpseudoꢀtd, ²J = 12.9 Hz, J ≈ 10.1 Hz, J = 8.4 Hz, 1H, Hꢀ4b). 13CꢀNMR,
HSQC, HMBC (75 MHz, CDCl3): ꢀ/ppm = 109.6 (Cꢀ6a), 73.1 (Cꢀ2), 70.9 (Cꢀ3),
70.0 (Cꢀ5), 46.6 (Cꢀ3a), 25.0 (Cꢀ4). Spectral data are in agreement with literature
values.18c
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(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol ((–)ꢀ5). To a stirred solution of (±)ꢀ5
(130 mg, 1.00 mmol) in MTBE (10 mL) was added PPL (13 mg, 10% w/w) and the
propionic anhydride (130 mg, 1.00 mmol). The reaction mixture was stirred for 22 h
at room temperature. And then the mixture was filtered through a pad of Celite. The
filtrate was concentrated in vacuo, and the resulting residue was purified by flash
column chromatography (cyclohexane/EtOAc = 1/1) to give (–)ꢀ5 as colorless oil
(49.5 mg, 43%). [α]2D6 = −11.5 (c = 1.25, MeOH), (lit10: [α]D26 = −11.9, c = 1.24, MeOH).
ee = 99%. The NMR data corresponded to those of the racemic compound (±)ꢀ5. The
enantiomeric excess of 5 was determined by chiral GC analysis using an Astec
Chiraldex βꢀcyclodextrin trifluoroacetyl (BTA) capillary column: major isomer
(3R,3aS,6aR): tR = 21.5 min; minor isomer (3S,3aR,6aS): tR = 21.2 min.
General
One-Pot
Procedure
for
the
Synthesis
of
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol ((–)-5): Cbzꢀprotected aldehyde 9
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(1.94 g, 10 mmol), furan (3.40 g, 50 mmol) and MTBE (20 mL) were placed in a
quartz roundꢀbottomed flask (50 mL) equipped with a magnetic stirrer bar and placed
in the Rayonet photochemical reactor. The reaction mixture was kept under nitrogen
atmosphere and irradiated until TLC indicated complete consumption of the starting
akdehyde (usually 36 h). Excess furan was removed in vacuo on a rotary evaporator.
Palladium on activated charcoal (212 mg, 0.20 mmol) was added and the reaction
vessel was evacuated and backꢀfilled with hydrogen (balloon) at room temperature
and ambient pressure for 36 h. After this time, the hydrogen balloon was removed,,
PPL (194 mg, 10% w/w) and the acetylating agent, in this case propionic anhydride
(1.30 g, 10 mmol), were added. The reaction vessel was flushed with argon and the
reaction mixture was stirred at room temperature. After 72 h, the suspension was
filtered (paper, washed with CH2Cl2) and evaporated to dryness in vacuo. The
resulting residue was purified by flash column chromatography (cyclohexane/EtOAc
= 1/1) to give (–)ꢀ5 as colorless oil (455 mg, 35%). [α]3D0 = −11.5 (c = 1.25, MeOH),
(lit10: [α]2D6 = −11.9, c = 1.24, MeOH). ee = 99%. The NMR data corresponded to those
of the racemic compound (±)ꢀ5. The enantiomeric excess of 5 was determined by
chiral GC analysis using an Astec Chiraldex βꢀcyclodextrin trifluoroacetyl (BTA)
capillary column: major isomer (3R, 3aS, 6aR): tR = 21.5 min; minor isomer (3S, 3aR,
6aS): tR = 21.2 min.
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Acknowledgements
We thank Philipp Klein (Mainz) for GC assistance, and Dr. Johannes C. Liermann and
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Dr. Norbert Hanold (both Mainz) for NMR spectroscopy and mass spectrometry.
Financial support by the Bill & Melinda Gates Foundation (The Medicines for All
Initiative, grant number OPP1128257) is gratefully acknowledged. AJA
acknowledges support through a University of Alabama Research Award: RG14648
“Technology for a Sustainable Chemical Economy” ꢀ STANCE.
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Supporting Information
Copies of NMR spectra for all synthesized compounds and GCꢀMS data of compound
(–)ꢀ5. Detailed comparison of the reported procedures with the ones in the literature.
These materials are available free of charge via the Internet at http: //pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: opatz@uniꢀmainz.de
Notes
The authors declare no competing financial interest.
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