CHAPTER 3
Stereodivergent synthesis of enantiomerically pure diastereoisomeric carba
analogs of glycal-derived vinyl epoxides and corresponding N-acetyl
aziridines: a new access to carbasugars
3.1. Sterodivergent synthesis of vinyl epoxides (-)-1.17α and (-)-1.17β
The synthetic strategies adopted to obtain carbapyranoses can be broadly classified as: i) synthetic methods which employ non-carbohydrates as starting materials,1-3 ii) protocols which utilize
carbohydrates as the precursors.4,5 In this framework, the use of carbohydrates provides important advantages to the preparation of their carbacyclic analogs mostly because the enantiomeric purity of the target carbasugars is guaranteed by the enantiomeric purity of the starting material. Chiral vinyl carba epoxides (-)-1.17α and (-)-1.17β were thought to be valid tools to the construction of enantiomerically pure carbasugars. As a consequence the realization of an effective synthetic procedure to both vinyl epoxides (-)-1.17α and (-)-1.17β was considered valuable and following an
ii-type synthetic strategy, tri-O-acetyl-D-glucal [(+)-3.6] was found as the easily available
precursor. The most significant features of our protocol to enantiomerically pure epoxides are the synthesis of the carbocyclic system (-)-3.3 by way of a new application of the known Claisen rearrangment of glycals, described by Nagarajan and Sudha in 1998,6 to glycal derivative (-)-3.1. In
this way, the glycal system constituted by primary alcohol (-)-3.1 is switched, after transformation to terminal olefin (+)-3.2, into the corresponding carba analogue constituted by primary alcohol
(-)-3.3, in which a methylene group replaces the originally present endocyclic oxygen. The second
feature is the synthesis of an advanced, efficient carba-type precursor, the trans diol (+)-1.21, from which both vinyl epoxides (-)-1.17α and (-)-1.17β are independently prepared following completely stereoselective pathways (Scheme 3.1).
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Scheme 3.1. Retrosynthetic analysis for trans diol (+)-1.21, the synthetic intermediate of both epoxides (-)-1.17α and (-)-1.17β.
The 3,4-di-(p-methoxybenzyl) [di-(OPMB)] protection used in our synthetic protocol and necessarily present in compound (+)-3.2 submitted to the thermal Claisen rearrangement, is different from the corresponding 3,4-di-OBn protection used in the original procedure described by Nagarajan and Sudha, in which the glucal-derived system 3.4 is switched into carbacycle-3.5 (Scheme 3.2). This difference was due to the necessity to have at C(3) and C(4) carbons O-protective groups which could be removed, without affecting the 1,2-double bond, necessary for further functionalizations: this is a very fundamental step for the synthesis of vinyl epoxides
(-)-1.17α and (-)-1.17β and their derivatives. The –OPMB protection corresponded to what required,
because, differently from the benzyl group for which reducing conditions are commonly used for deprotection (H2/Pd-C), it can be removed under oxidative conditions (DDQ), in which the olefinic
carbon-carbon double bond is stable.
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Scheme 3.2. Transformation of glycal system 3.4 into carba system 3.5 by means of thermal Claisen
rearrangement.
The first part of the synthesis was the preparation of primary alcohol (-)-3.1, the stable precursor of terminal olefin (+)-3.2, the substrate designed for the thermal Claisen rearrangement (Scheme 3.3).
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Scheme 3.3. Synthesis of primary alcohol (-)-3.1.
The synthetic pathway started from the commercially available tri-O-acetyl-D-glucal [(+)-3.6] which was subjected to regioselective deprotection of the primary hydroxy functionality by Lipase from Candida Cylindracea7,8 (CCL, 2.0 unit/mg activity) at pH = 7.0 affording the primary alcohol
(+)-3.7 easily and in good yield. Recently, Sigma-Aldrich, the chemical company supplying the original CCL, substituted it with the more active Lipase from Candida Rugosa (CRL, 700.0 unit/mg activity). The enhanced activity of the new Lipase made possible the development of a modified protocol consisting of the use of a lesser amount of phosphate buffer with beneficial effects on the final work-up, yields are substantially the same with both Lipases (90-92%). Primary alcohol (+)-3.7 was selectively protected by treatment with 3,4-dihydro-2H-pyran in the presence of pyridinium p-toluen sulfonate (PPTS) to give O-THP-derivative 3.8. Subsequent saponification of 3.8 by NaOMe/MeOH afforded trans diol (+)-3.9, the first key intermediate of our synthetic process. Elaboration of trans diol 3.9 into 3,4-di-O-PMB-D-glucal 3.10 was easily obtained by alkylation of 3.9 with p-methoxybenzyl chloride and sodium hydride in DMF for 12 h at room temperature. Deprotection of acetal 3.10 with 1.5:2:1 AcOH/THF/H2O mixture for 12 h at 45°C
afforded primary alcohol (-)-3.19 in good yield (65%) after flash chromatography. The deprotection
turned out to be particularly sensible to the temperature which cannot exceed 50°C and to acid concentration to the point that if the conditions don’t correspond strictly to those described above, complex reaction mixtures are obtained due to the degradation of the glycal-derived alcohol (-)-3.1 under the acid reaction conditions (Scheme 3.3).10
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Scheme 3.4. Synthesis of trans diol (+)-1.21.
Alcohol (-)-3.1 was oxidized to aldehyde 3.11 through a very clean reaction by using freshly prepared 2-iodoxy benzoic acid (IBX), as the oxidant (Scheme 3.5).
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Scheme 3.5. Synthesis of IBX, precursor of the known DMP.
IBX, mild and versatile oxidant, is well-known also because is the precursor of Dess-Martin reagent (DMP) (Scheme 3.5). Its preparation is not simple and harmless, but, recently, Figerio et al. have reported an extremely effective procedure which provides oxidation of 2-iodo-benzoic acid with Oxone®(2KHSO5-KHSO4-K2SO4) for 3 h at 70°C.11b In this way, IBX is obtained in good
yield (80%) and with a high purity degree (>95%). The treatment of alcohol (-)-3.1 with dry IBX in anhydrous CH3CN at 45°C gave the desired aldehyde 3.11, so pure to be used in the next step
without any purification (Scheme 3.4). Scale-up of this protocol [until 5 g of alcohol (-)-3.1] was successful, but, also in this transformation, particular attention had to be given to the reaction temperature. Actually, reaction temperatures above the indicated 45°C determined the formation of the desired aldehyde 3.11, but unfortunately accompanied by different amounts (until 50%, depending on the temperature) of p-methoxy benzaldehyde (3.14) with a drastic reduction of the yield. The formation of p-methoxy benzaldehyde (3.14) under these conditions derives from an
attack of the oxidant on the C-H bond of the benzylic methylene of the protective group, strongly activated toward the oxidation process by the conjugative effect of p-methoxy group (Scheme 3.6).
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Scheme 3.6. Oxidation by IBX protocol of prymary alcohol (-)-3.1 when the temperature exceeds 40°C. Aldehyde 3.11 was immediately subjected to Wittig C-1 extension by using Ph3PCH3I and
KHMDS in THF affording the glycal-derived 6-exocyclic olefin (+)-3.2 in a mixture with triphenylphosphine oxide (Ph3PO). Separation of olefin (+)-3.2 from this mixture was
advantageously carried out by filtration on silica gel-Fluorisil® pad with a 7:3 hexane:AcOEt
mixture. Evaporation of the organic solution afforded olefin (+)-3.2 in good yield (88%) without any residual of Ph3PO. Thermal Claisen rearrangement is a [3,3] sigmatropic rearrangement in
which a vinyl allyl ether, or a related structure, is transformed into a γ,δ-unsaturated carbonyl compound, as schematically shown in Figure 3.1.
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Figure 3.1. [3,3] sigmatropic rearrangement.
In the present case, glycal-derived terminal olefin (+)-3.2 with one endocyclic and one exocyclic double bonds is the necessary starting vinly allyl ether which, subjected to the thermal rearrangement, leads to the formation of carba aldehyde 3.12. In this process, depicted in Scheme 3.7, the formyl carbon C(1) of aldehyde 3.12 derives from C(1) of the endocyclic double bond of the glycal-derived olefin (+)-3.2. Aldehyde 3.12 is immediatey reduced (NaBH4) to the stable
primary alcohol (-)-3.3, which can be purified by flash chromatography (Scheme 3.7). Initially, the rearrangement was carried out by warming a solution of olefin (+)-3.2 (0.5 g) in 1,3-dichlorobenzene at 240°C in sealed vial for almost 1 h. In order to obtain the required high temperature and to keep it stable for all the time necessary for the transformation be completed, we made use, as an alternative to the sand bath described by other authors, of a silicone oil (AP 100, from Aldrich) perfectly suitable for the purpose, because stable and not flammable at the required
temperature. However, the potential risk present in the new protocol (oil at 240°C), stimulated us to find a safer and more sustainable procedure. With this intention, we evaluated the feasibility of carrying out the rearrangement process by using microwaves. Under these new reaction conditions, the reaction successfully progressed by radiating a solution of olefin (+)-3.2 (0.5 g) in 1,3-dichlorobenzene (4.0 mL) at 300 W power, 100 Psi pressure and one minute ramp time (CEM Discover instrument). After 20 minutes, the reaction was completed (TLC) and, as usual, the obtained aldehyde 3.12 was not isolated but directly reduced with NaBH4 in a THF/EtOH mixture
to primary carba alcohol (-)-3.3, then purified by flash chromatography [68% yield from olefin
(+)-3.2]. Following these modified conditions, 1.5 g of (+)-3.2 were rearranged in 1 h (3 x 0.50 g
portions) with a consistent reduction of the reaction times with respect to the initially used standard protocol by which the rearrangment of the same quantity would have required more then 3 h.
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Scheme 3.7. Claisen rearrangement of glucal (+)-3.2 into carba system 3.12.
The presence of p-OPMB protective groups at C(3) and C(4) in the rearranged carbacyclic primary alcohol (-)-3.3 (Scheme 3.4) is particularly appropriate because, once the primary –OH group is orthogonally protected as a benzyl ether, the two secondary -OPMB protected alcoholic functionalities can be deprotected and the free hydroxy functionalities elaborated to the desired epoxides (-)-1.17α and (-)-1.17β, without affecting the O-benzyl protected primary alcoholic group and the C(1)-C(2) double bond. Actually, primary alcohol (-)-3.3 was treated with BnBr/NaH protocol in DMF to yield all-protected unsaturated carbacycle (+)-3.13 (>99%), sufficiently pure to be used in the next step without any purification (Scheme 3.4). Deprotection of the two -OPMB ether groups of (+)-3.13 was carried out by using an electron transfer system (SET) with 2,3-dichloro-5,6-dicyano benzoquinone (DDQ), as the oxidant in a 18:1 CH2Cl2/H2O mixture. The
mechanism involves the formation of an oxonium ion that is captured by water. Subsequent formation of an hemiacetal leads to the free alcohol [in this case the trans diol (+)-1.21] with the
contemporary formation of p-methoxy benzaldehyde 3.14 (Schemes 3.4 and 3.8).12 !"# $ # !"# %# #$ $ %#$ !"# $ #% & $'# ($& !"# $ #% # )* )* #$ )+ )+ !"# $ #% # )* )* #( )+ )+ !"# #% # )* )* # )+ )+ & ,-. & $ & )* )* #$ )+ )+ # )* )* #$ )+ )+ #$ &$& !"#$ %%&
Scheme 3.8. Mechanism of the DDQ-promoted deprotection of an –OPMB ether functionality.
As for epoxide (-)-1.17β, the synthetic protocol has been modified with respect to the one previously adopted for the corresponding racemic version (see Scheme 1.6, Chapter 1). Actually, in the new modified version, trans diol (+)-1.21 is treated, by following Kishi procedure,13 with the
bulky PivCl which selectively protects the allyl secondary hydroxy group, affording pivaloyl derivative (-)-3.15. Pivaloate (-)-3.15 is mesylated to the fully protected 3-O-pivaloyl-4-O-mesyl derivative (-)-3.16. The subsequent saponification/cyclization of (-)-3.16 under basic conditions (MeONa/CH3CN), gives vinyl epoxide (-)-1.17β with 88% overall yield (3 steps starting from trans diol (+)-1.21) with a substantial increase with respect to the overall yield obtained by means
of the original procedure [66% yield for 4 steps, starting from the same precursor, trans diol
(+)-1.21], as shown in Scheme 3.9. !" "! #$! !%&' "! #$! !%&' ()! #$! #$! ! %&'*+ ,(-%.%/ *"0*+0 1223 ()*+ .%/ 443 (5!67 *"8*6 1223 !"#"$%&'
!(#"&%)& !"#"$%&* !"#"&%&+!
As for epoxide (-)-1.17α, a new, straightforward procedure was envisaged. We had always thought, and in some cases directly experimented, that allyl mesylate could not be prepared due to their enhanced reactivity/instability. However, it was recently found in the literature that secondary aliphatic allyl mesylates (SAAM) could be prepared in spite of their reactivity, provided that mesyl anhydride is used as the mesylating agent instead of the commonly used mesyl chloride.14 By
following this precise indication, the treatment of trans diol (+)-1.21 with Ms2O (1 equiv) in
anhydrous THF in the presence of Et3N and Py at 0°C afforded, after 2 h stirring at room
temperature, a crude reaction mixture consisting of allyl mesylate 3.17 accompanied by some amounts of the unreacted starting diol (almost 20%, 1H NMR). The allyl mesylate 3.17 is not
separated and the reaction mixture is directly treated with t-BuOK (2 equiv), which determines the formation of homoallyl alcoholate and subsequent cyclization, by intramolecular SN2 reaction on
the vicinal carbon bearing the good methansulfonate leaving group. In this way chiral epoxide
(-)-1.17α, is obtained in good yield (60%) after separation (flash chromatography) by the unreacted
trans diol (+)-1.21 which can be advantageously recycled. If an excess of Ms2O (1.2 equiv) is
initially used, unreacted diol (+)-1.21 is not present in the reaction mixture, but the allyl mesylate
3.17 is now accompanied by a small amount of 3,4-di-O-mesyl derivative (3.17-diMs) of trans diol
(+)-1.21 (15%). Under these modified conditions, after treatment with t-BuOK, epoxide (-)-1.17α is recovered pure in 75% overall yield by flash chromatography. In both of cases, epoxide
(-)-1.17α can be easily separated by flash chromatography from the other components of the crude
reaction mixture. However a comparison of the two possible protocols would indicate that the use of only 1 equiv of Ms2O is more convenient, even if the epoxide is obtained with a lower yield,
because the unreacted trans diol (+)-1.21 can be easily recovered and recycled, whereas the
3,4-di-O-mesyl derivative 3.17-diMs, present when 1.2 equiv of Ms2O are used, cannot be recycled and
therefore is not synthetically useful (Scheme 3.10).
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Scheme 3.10. Synthesis of vinyl epoxide (-)-1.17α.
Enantiopure vinyl epoxides (-)-1.17α and (-)-1.17β were then tested as pseudoglycosyl donors in nucleophilic addition reactions with two nucleophiles such as 1,2;3,4-di-O-isopropyliden-α-D -galoctopyranose and cyclohexanemethanol, which were used as O-nucleophile models for the possible synthesis of carba disaccharides.
In accordance with the results obtained with racemic epoxides (±)-1.17α and (±)-1.17β,15 the
reaction of enantiopure epoxide (-)-1.17β with 1,2;3,4-di-O-isopropyliden-α-D-galoctopyranose (6 equiv) in 5.10-3 N TsOH in CH
2Cl2, afforded, through a complete 1,2-regio- and
anti-stereoselective process, the 3-O-(6-D-galactopyranosyl)-carbagulal (+)-3.18 (anti-1,2-addition product), as the only reaction product (Scheme 3.11).10
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Scheme 3.11. Reaction of epoxide (-)-1.17β with 1,2;3,4-di-O-isopropyliden-α-D-galoctopyranose.
On the basis of the high 1,4-regio and syn-stereoselectivity observed in the methanolysis of epoxide
1.17α carried out in 1:1 CH2Cl2/[bimim][BF4] in the presence of 2.10-3 N TsOH (76%
syn-1,4-addition product, Chapter 1, Table 1.4, entry 3), we have applied the same protocol by using cyclohexanemethanol, as the O-nucleophile. Actually in these conditions, the reaction of enantiopure vinyl epoxide (-)-1.17α with cyclohexanemethanol (3 equiv), under acidic conditions (2.10-3 N TsOH in CH
2Cl2), gave a crude reaction product mainly consisting of syn-1,4-addition
product (+)-3.19 (1H NMR). Purification of this mixture by preparative TLC afforded pure
syn-1,4-addition products (+)-3.19. It is worth noting that the structure of the purified syn-1,4-syn-1,4-addition product 3.19 corresponds to that of an homogenous simplified α-O-linked-1,6-carba-disaccharide (Scheme 3.12). ! "#! $%&%!"!#! $'&%$"!% "#! (! ! !( )(*)+*, *-./%0,12!( 34565673"897
Scheme 3.12. Reaction of epoxide (-)-1.17α with cyclohexanemethanol.
3.2. Synthesis of N-acetyl aziridines (-)-1.18α-Ac and (-)-1.18β-Ac
(±)-1.18β-Ns in nucleophilic addition reactions, previously described in Chapter 2, and the increased
importance of aminocyclitols in Medicinal Chemistry had directed our next project to the enantioselective synthesis of corresponding chiral vinyl aziridines. At this purpose, we thought appropriate to direct our efforts toward enantiopure N-acetyl aziridines (-)-1.18α-Ac and
(-)-1.18β-Ac, because, if compared with the previously used N-nosyl group, the N-acetyl group is diffuse and
biologically interesting in Nature. As a consequence, having systems, as N-acetyl aziridines
(-)-1.18α-Ac and (-)-1.18β-Ac, leading to products containing the N-acetyl group can be
advantageous to the point that the subsequent deprotection to free amino group, indispensable with the N-nosyl group, could be not necessary.
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Scheme 3.13. Synthesis of vinyl N-acetyl aziridine (-)-1.18α-Ac.
As previously described for the racemic N-nosyl aziridines 1.18α-Ns and 1.18β-Ns, the synthesis of the new N-acetyl aziridines (-)-1.18α-Ac and (-)-1.18β-Ac starts from the corresponding vinyl epoxide of opposite configuration (-)-1.17α and (-)-1.17β, respectively (see Chapter 2). The first step consists in the azidolysis of epoxide (-)-1.17β by NaN3/THF-H2O protocol to the trans azido
alcohol (+)-2.1, as the only reaction product. Trans azido alcohol (+)-2.1 was reduced by means of PS-PPh3 resin to the corresponding trans amino alcohol (+)-2.3. At this point, the treatment of
trans amino alcohol (+)-2.3 with CH3COCl (1 equiv) in CH2Cl2 at 0°C affords N-acetyl derivative
(+)-3.20, in a regioselective process, due to the greater nucleophilicity of the allyl amino group with respect to the homoallyl hydroxy functionality at C(4). N-acetyl derivative (+)-3.20 was mesylated to the fully protected derivative (+)-3.21, which on treatment with t-BuOK in anhydrous benzene affords the desired N-acetyl aziridine (-)-1.18α-Ac, as a pure enantiomer [56% overall yield, for 5 steps starting from epoxide (-)-1.17β] (Scheme 3.13).
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Scheme 3.14. Synthesis of vinyl N-acetyl aziridine (-)-1.18β-Ac.
A corresponding procedure starting from epoxide (-)-1.17α was followed for the synthesis of aziridine (-)-1.18β-Ac, as shown in Scheme 3.14. Epoxide (-)-1.17α was treated with NaN3 in 1:1
THF/H2O mixture affording, as the only reaction product, the trans azido alcohol (-)-2.6. By using
the PS-PPh3 in THF/H2O reducing protocol, trans amino alcohol (+)-2.7 was obtained pure, then
subjected to the previously described reactions sequence: regioselective acetylation to give N-acetyl derivative (+)-3.22, followed by O-mesylation with the formation of trans N- N-acetyl-O-mesylate (+)-3.23. The treatment trans N-acetyl-O-N-acetyl-O-mesylate (+)-3.23 with t-BuOK in anhydrous benzene afforded N-acetyl aziridine (-)-1.18β-Ac, as a pure enantiomer [49% overall yield for 5 steps starting from epoxide (-)-1.17α]. Surprendently, chiral N-acetyl aziridines (-)-1.18α-Ac and (-)-1.18β-Ac turned out to be not stable and easily degraded even if maintained at -15°C. As a consequence, due also to the small amount of chiral aziridines available at the end of the synthetic sequences, no addition reactions could be carried out.
In conclusion, we have developed a stereodivergent synthesis of enantiomerically pure vinyl epoxides 1.17α and 1.17β and corresponding N-acetyl aziridines 1.18α-Ac and
(-)-1.18β-Ac by using tri-O-acetyl-D-glucal (+)-3.6, as the chiral starting material. As for N-acetyl aziridines (-)-1.18α-Ac and (-)-1.18β-Ac, these studies have also indicated that their use as useful tools for the construction of enantiopure N-(acetylamino)-substituted carbasaccharides and/or pseododisaccharides is subjected to appropriate considerations and attention due to their unexpected instability.
3.3. Experimental
General Procedures. See Chapter 1.
Materials. Tri-O-acetyl-D-glucal, lipase from Candida Rugosa type VII CRL, pyridinium p-toluen sulfonate PPTS, PMBCl, Ph3PMeI, potassium hexamethyldisilazide (KHMDS), NaBH4, BnBr,
NaH, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), MsCl, Ms2O, t-BuOK,
1,2;3,4-di-O-isopropyliden galactopyranose, and 3-cyclohexane-1-methanol were purchased from Aldrich and used without purification. 2-Iodoxybezoic acid (IBX) was synthesized according to the literature methods.11 Et
3N, Ac2O, and were distilled from CaH2, tetrahydrofuran (THF) was distilled from
Na/benzophenone. Anhydrous N,N-dimethylformamide (DMF), CH3CN, CH2Cl2 and pyridine were
purchased from Aldrich. AcOH, MeOH, anhydrous CH2Cl2 over molecular sieves, anhydrous
CH3CN over molecular sieves, anhydrous pyridine over molecular sieves, anhydrous DMF over
molecular sieves and anhydrous acetone were purchased from Aldrich and used without purification, DHP was purchased from Fluka and used without purification. Benzene, toluene, Et2O
and THF were distilled from sodium/benzophenone.
Instrumentation. See Chapter 1.
Synthesis of trans diol (+)-1.21 3,4-Di-O-acetyl-D-glucal (+)-3.7
A solution of tri-O-acetyl-D-glucal (+)-3.6 (10.0 g, 36.73 mmol)7,8 in (i-Pr)
2O (15.0 mL), phosphate
buffer (pH 7.0, 60 mL) and anhydrous acetone (15.0 mL) was treated with lipase CRL (lipase from
Candida Rugosa type VII activity >700 unit/mg) (1.4 g) and the reaction mixture was stirred for 12
h at room temperature. Extraction with AcOEt of the filtered (Celite®) reaction mixture and
evaporation of the washed (brine) organic extracts afforded a crude reaction product (7.73 g, 91% yield) consisting of alcohol practically pure alcohol (+)-3.7 (1H NMR), which was used in the next step without any purification.
(+)-3.7: a liquid: Rf = 0.26 (1:1 hexane/AcOEt). 1H NMR (CDCl3) δ 6.49 (dd, 1H, J
= 6.1, 1.2 Hz), 5.41-5.50 (m, 1H), 5.22 (dd, 1H, J = 9.0, 6.5 Hz), 4.81 (dd, 1H, J = 5.9, 2.9 Hz), 3.98-4.09 (m, 1H), 3.66-3.86 (m, 2H), 2.13 (s, 3H), 2.07 (s, 3H). 13C
NMR (CDCl3) δ 170.8, 170.6, 145.9, 99.1, 76.7, 68.4, 67.9, 60.6, 21.2, 20.9.
Anal.Calcd for C10H14O6: C, 52.17; H, 6.13. Found: C, 52.23; H, 6.41.i !
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6-O-(2-Tetrahydropyranyl)-3,4-di-O-acetyl-D-glucal (3.8)
A solution of PPTS (0.540 g, 2.15 mmol) in anhydrous CH2Cl2 (150.0 mL)7,8 was added dropwise
at room temperature to a stirred solution of alcohol (+)-3.7 (4.95 g, 21.50 mmol) in DHP (2.92 mL, 32.2 mmol) and the reaction mixture was stirred at same temperature for 16 h. Dilution with CH2Cl2 and evaporation of the washed (saturated aqueous NaHCO3 and saturated aqueous NaCl)
organic solution afforded a crude reaction product (6.70 g, >99% yield) consisting of 6-OTHP protected diacetate 3.8, as a mixture of diastereoisomers.
3.8: a liquid: Rf = 0.16 (8:2 hexane/AcOEt); FTIR (neat film) ν 1743, 1471, 1238,
1033 cm-1. 1H NMR (CDCl
3) δ 6.48 (dt, 1H, J = 6.0, 1.3 Hz), 5.17-5.38 (m, 2H),
4.75-4.85 (m, 1H), 4.53-4.70 (m, 1H), 4.17-4.30 (m, 1H), 3.69-4.00 (m, 2H), 3.40-3.68 (m, 2H), 2.06 and 2.07 (two singlets corresponding to two diastereoisomers, 3H), 2.03 and 2.04 (two singlets corresponding to two diastereoisomers, 3H), 1.43-1.92 (m, 6H). 13C NMR (CDCl
3) δ 170.4, 169.5, 145.8, 99.3, 99.2,
98.6, 98.4, 75.3, 75.1, 74.9, 74.7, 67.7, 67.4, 65.3, 64.8, 62.1, 61.7, 30.3, 25.3, 21.0, 20.8, 19.2, 19.0. Anal. Calcd for C15H22O7: C, 57.32; H, 7.05. Found: C, 57.38; H, 7.23.
6-O-(2-Tetrahydropyranyl)-D-glucal (3.9)
A solution of diacetate 3.9 (0.377 g, 1.20 mmol)7,8 in MeOH (4.3 mL) was treated with MeONa
(0.009 g, 0.167 mmol) and the reaction mixture was stirred for 12 h at room temperature. Evaporation of the filtered organic solution afforded a crude liquid product (0.248 g, 90% yield) consisting of trans diol 3.9, practically pure, as a liquid.
3.9: a liquid: Rf = 0.10 (8:2 CH2Cl2/AcOEt); FTIR (neat film) n 3398, 1647, 1350,
1232, 1126, 1080, 1026 cm-1. 1H NMR (CDCl 3) d 6.27 (dt, 1H, J = 6.0, 1.9 Hz), 4.65 (dt, 1H, J = 6.0, 1.5 Hz), 4.45-4.62 (m, 1H), 3.37-4.31 (m, 9H), 1.38-1.84 (m, 6H). 1H NMR (CD 3CN) d 6.29 (d, 1H, J = 6.0 Hz), 4.65 (dd, 1H, J = 6.0, 1.6 Hz), 4.54-4.60 (m, 1H), 4.13-4.38 (m, 9H), 1.41-1.80 (m, 6H). 13C NMR (CDCl3) d 144.3, 144.2, 103.2, 102.8, 100.8, 100.7, 99.4, 77.5, 77.1, 76.6, 69.6, 69.5, 69.4, 66.7, 66.4, 64.4, 62.6, 31.1, 30.8, 30.4, 25.3, 25.1, 21.3, 20.6, 19.5. 13C NMR (CD 3CN) d 144.4, 144.3, 104.7, 104.6, 103.7, 103.5, 102.4, 100.1, 78.7, 78.6, 78.5, 78.0, 75.2, 69.5, 68.6, 67.3, 66.8, 65.6, 65.4, 63.4, 62.8, 31.9, 31.8, 31.4, 31.2, 26.1, 26.0, 20.6, 20.3. Anal.Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 56.99; H, 7.95. ! !"# "#! $%&! !"# ! !" "! #"$! !"#
3,4-Di-O-(p-methoxybenzyl)-6-O-(2-tetrahydropyranyl)-D-glucal (3.10)
A solution of trans diol 3.9 (1.18 g, 5.13 mmol)7,8 in anhydrous DMF (15 mL) was added dropwise
at 0°C to a suspension of 60% NaH in mineral oil (1.03 g, 25.6 mmol, 5.0 equiv) in anhydrous DMF (15 mL). After stirring at room temperature for 30 min, the suspension was cooled at 0°C and
p-methoxybenzylchloride (PMBCl) (1.7 mL, 12.8 mmol, 2.5 equiv.) was added dropwise. The
reaction mixture was allowed to warm to room temperature and stirred for further 12 h. Dilution with Et2O and evaporation of the washed (brine) and dried (MgSO4) organic solution afforded
3,4-di-O-para-methoxybenzyl (PMB)-derivative 3.10 (2.47 g, >99% yield), practically pure as a yellow oil, which was used in the next step without any further purification;
3.10: Rf = 0.20 (8:2 hexane/AcOEt); [α]20D -0.3 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.17–7.36 (m, 4H), 6.78–6.97 (m, 4H), 6.40 (ddd, 1H, J = 6.2, 3.1, and 1.3 Hz), 4.84 (ddd, 1H, J = 6.2, 2.7, 0.9 Hz), 4.55–4.82 (m, 2H), 4.77 (d, 1H, J = 10.8 Hz), 4.68 (d, 1H, J = 10.8 Hz), 4.49 (dd, 1H, J = 11.3 and 1.9 Hz), 4.13–4.22 (m, 1H), 3.95–4.12 (m, 2H), 3.65–3.93 (m, 3H), 3.80 (s, 6H), 3.42–3.55 (m, 1H), 1.41–1.92 (m, 6H). 13C NMR (62.5 MHz, CDCl 3) (2 diastereoisomers) δ 159.4, 144.8, 130.6, 129.7, 129.6, 113.9, 100.2, 100.0, 99.4, 99.2, 75.8, 75.6, 74.3, 73.6, 73.5, 70.4, 62.5, 62.2, 55.5, 30.7, 25.6, 19.7, 19.5. Anal. Calcd for C27H34O7: C, 68.92; H, 7.29. Found: C, 69.24; H,
7.55.
3,4-Di-O-(p-methoxybenzyl)-D-glucal (-)-(3.1)
3,4-Di-O-PMB-derivative 3.10 (2.0 g, 4.26 mmol) was dissolved in a 1.5:2:1 AcOH/THF/H2O
mixture (70 mL),9 and the reaction mixture was stirred for 12 h at 50°C. After dilution with Et 2O
and neutralization with solid NaHCO3, evaporation of the washed (saturated aqueous NaHCO3 and
saturated aqueous NaCl) and dried organic solution afforded a crude solid product (2.35 g) consisting of primary alcohol (-)-3.1, which was purified by recrystallization from hexane/AcOEt (1.07 g, 65% yield), m.p. 67–69°C: (-)-3.1: Rf = 0.14 (7:3 hexane/AcOEt); [α]20D −21.7 (c 0.6, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.21–7.32 (m, 4H), 6.84–6.92 (m, 4H), 6.39 (dd, 1H, J = 6.2, 1.2 Hz), 4.87 (dd, 1H, J = 6.2, 2.7 Hz), 4.78 (d, 1H, J = 11.1 Hz), 4.64 (d, 1H, J = 11.1), 4.60 (d, 1H, J = 11.1 Hz), 4.50 (d, 1H, J = 11.1 Hz), 4.16–4.22 (m, 1H), 3.87–3.96 (m, 1H), 3.82–3.86 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.76 (dd, 1H, J = 8.4, 6.5 Hz); 13C NMR (62.5 MHz, CDCl 3) δ 159.5, 159.4, 144.6, 130.3, 130.2, 129.9, 129.6, 114.0, 100.4, 77.4,
75.3, 74.3, 73.5, 70.5, 62.0, 55.4. Anal. Calcd for C22H26O6: C, 68.38; H, 6.78. Found: C, 68.82; H, ! !"#$ "#$! %&"! !"#$ ! !"#$ "#$! %! !"#"$%&
6.53.
2-Formyl-3,4-di-(p-methoxybenzyloxy)-3,4-dihydro-2H-pyrane (3.11)
IBX (2.18 g, 7.77 mmol, 3.0 equiv)11a was added to a solution of primary alcohol (-)-3.1 (1.0 g,
2.59 mmol) in anhydrous CH3CN (60 mL), and the reaction mixture was stirred at 45°C for 5 h.
After cooling, the reaction mixture was filtered on a pad of Celite® that was further eluted with AcOEt. Evaporation of the filtered solution afforded aldehyde 3.11 (0.93 g, 94% yield), pure as a liquid, which was used in the next step without any further purification:
3.11: Rf = 0.22 (7:3 hexane/AcOEt); 1H NMR (250 MHz, CDCl3) δ 9.53 (d, 1H, J = 0.6 Hz), 7.20–7.34 (m, 2H), 7.09–7.17 (m, 2H), 6.79–6.93 (m, 4H), 6.65 (d, 1H, J = 6.2 Hz), 5.00–5.09 (m, 1H), 4.62 (d, 1H, J = 11.7 Hz), 4.55 (d, 1H, J = 11.7 Hz), 4.51–4.59 (m, 1H), 4.29 (s, 2H), 4.01–4.06 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72–3.78 (m, 1H). 13C NMR (62.5 MHz, CDCl 3) δ 198.9, 159.6, 159.5,
145.0, 129.7, 129.6, 129.4, 114.2, 114.0, 100.5, 79.4, 72.2, 71.6, 69.4, 66.9, 55.5. Anal. Calcd for C22H24O6: C, 68.74; H, 6.29. Found: C, 69.02; H, 6.11.
1,5-Anhydro-di-O-(p-methoxybenzyl)-2,6,7-trideoxy-D-arabino-hept-1,6-dienitol (+)-(3.2) A solution 0.5M of KHMDS in THF (6.8 mL, 3.40 mmol, 1.4 equiv) was added dropwise to a solution of Ph3PMe+I− (1.47 g, 3.65 mmol, 1.5 equiv)6 in anhydrous THF (15 mL) at −78°C, and
the mixture was stirred at the same temperature for 30 min and at 0°C for 1 h. After cooling at – 78°C, a solution of aldehyde 3.11 (0.93 g, 2.43 mmol) in anhydrous THF (15 mL) was added dropwise, and the reaction mixture was stirred at r.t. for 5 h. Dilution with Et2O and filtration on
Fluorisil®-silica gel pad afforded an organic solution, which was washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, and saturated aqueous NaCl) and dried. Evaporation of the
organic solution afforded a crude product which was filtered again on Fluorisil®-silica gel pad using a 1:1 hexane/AcOEt mixture as the eluant. Evaporation of the filtered solution afforded olefin (+)-3.2, practically pure as a solid, m.p. 35–37°C (0.817 g, 88% yield):
(+)-3.2: Rf = 0.43 (7:3 hexane/AcOEt); [α]20D +1.1 (c 0.10, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.17–7.37 (m, 4H), 6.79–6.97 (m, 4H), 6.41 (d, 1H, J = 6.2 Hz), 6.03 (ddd, 1H, J = 17.2, 10.5 and 6.5 Hz), 5.41 (d, 1H, J = 17.2 Hz), 5.30 (d, 1H, J = 10.5 Hz), 4.85 (dd, 1H, J = 6.2 and 2.7 Hz), 4.70 (d, 1H, J = 10.7 Hz), 4.60 (d, 1H, J = 10.7), 4.57 (d, 1H, J = 11.3 Hz), 4.51 (d, 1H, J = 11.3 Hz), 4.29 (t, 1H, J = 7.7 Hz), 4.12–4.20 (m, 1H), 3.80 (s, 6H), 3.56 (dd, 1H, J = 8.5 and 6.2 Hz). 13C NMR (62.5 MHz, CDCl3) δ 159.5, 159.4, 144.6, 134.6, 130.7, 130.4, 129.8, 129.5, 118.4, 113.9, 100.7, 78.2, 78.1, ! !"#$ "#$! ! !"## ! !"#$ "#$! !"#$%&'
75.3, 73.6, 70.6, 55.4. Anal. Calcd for C23H26O5: C, 72.23; H, 6.85. Found: C, 72.82; H, 6.73.
3,4-Di-O-(p-methoxybenzyl)-5a-carba-D-glucal (-)-(3.3)
Olefin (+)-3.2 (0.5 g, 1.31 mmol) was dissolved in 1,3-dichlorobenzene (4.0 mL)6 and radiated in a
microwave apparatus (CEM Discover instrument) at 300 W power, 100 Psi pressure and one minute ramp time. After 20 minutes, the obtained aldehyde 3.12 was not isolated but directly reduced with NaBH4 (0.075 g, 1.965 mmol, 1.5 equiv) in a 1:1 THF/EtOH mixture (3.0 mL) to
primary carba alcohol (-)-3.3, which was subjected to flash chromatography. Elution with a 1:1 hexane/AcOEt mixture afforded primary alcohol (-)-3.3 (0.342 g, 68% yield), pure as a pale yellow solid, m.p. 46–48°C: (-)-3.3: Rf = 0.28 (1:1 hexane/AcOEt); [α]20D −14.6 (c 0.52, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.19–7.39 (m, 4H), 6.80–6.95 (m, 4H), 5.62–5.81 (m, 2H), 4.91 (d, 1H, J = 11.0 Hz), 4.67 (d, 1H, J = 11.0 Hz), 4.66 (d, 1H, J = 11.2 Hz), 4.58 (d, 1H, J = 11.2 Hz), 4.15–4.25 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.49–3.67 (m, 3H), 1.57–2.22 (m, 3H). 13C NMR (62.5 MHz, CDCl3) δ 159.5, 159.4, 130.6, 130.1, 129.7, 128.9, 128.2, 127.0, 126.2, 114.1, 114.0, 82.1, 81.1, 74.1, 71.2, 66.0, 55.4, 40.7, 28.2. Anal. Calcd for C23H28O5: C, 71.85; H, 7.34. Found: C, 72.02; H, 7.43. 6-O-Benzyl-3,4-di-O-(p-methoxybenzyl)-5a-carba-D-glucal (+)-(3.13)
Primary alcohol (-)-3.3 (0.483 g, 1.26 mmol) in anhydrous DMF (4 mL) was added dropwise at 0°C to a suspension of 60% NaH in mineral oil (0.15 g, 3.78 mmol, 3.0 equiv) in anhydrous DMF (4 mL), and the resulting reaction mixture was stirred at room temperature for 40 min. After cooling at 0°C, BnBr (0.37 mL, 3.15 mmol, 2.5 equiv) was added dropwise, and the mixture was stirred at room temperature for 2 h. Evaporation of the washed (saturated aqueous NaCl) and dried organic layer, afforded a crude reaction mixture (0.631 g), which was subjected to flash chromatography. Elution with an 8:2 hexane/AcOEt mixture afforded monobenzyl-derivative
(+)-3.13, pure as a liquid (0.602 g, >99% yield):
(+)-3.13: Rf= 0.36 (8:2 hexane/AcOEt); [α]20D +2.9 (c 0.83, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.15–7.40 (m, 9H), 6.80–6.92 (m, 4H), 5.61–5.81 (m, 2H), 4.81 (d, 1H, J = 10.5 Hz), 4.62 (s, 2H); 4.55 (d, 1H, J = 10.5 Hz), 4.50 (s, 2H), 4.10–4.21 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.53–3.71 (m, 3H), 2.20–2.31 (m, 2H), 1.99–2.15 (m, 1H). 13C NMR (62.5 MHz, CDCl 3) δ 159.3, 138.8, 138.4, 132.4, 132.2, 129.8, 129.6, 129.2, 128.9, 128.6, 127.9, 127.8, 127.6, 113.9, 81.0, 79.4, 74.2, 73.2, 71.3, 70.7, 55.5, 39.5, !"#$ "#$! %! !"#"$%$ !"#$ "#$! $%! !"#$%&'%
29.0. Anal. Calcd for C30H34O5: C, 75.92; H, 7.22. Found: C, 76.04; H, 7.53.
6-O-Benzyl-5a-carba-D-glucal (+)-(1.21)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.405 g, 1.79 mmol, 1.5 equiv) was added at room temperature to a solution of benzyl derivative (+)-3.13 (0.567 g, 1.19 mmol) in 18:1 CH2Cl2/H2O mixture (34 mL) and the reaction solution was stirred at the same temperature for 3 h.
After dilution with CH2Cl2, evaporation of the washed (saturated aqueous NaHCO3 and saturated
aqueous NaCl) and dried organic solution, afforded a crude product (0.35 g), which was subjected to flash chromatography. Elution with 1:1 hexane/AcOEt mixture afforded trans diol (+)-1.21, pure as a liquid (0.181 g, 65% yield):
(+)-1.21: Rf = 0.18 (1:1 hexane/AcOEt); [α]20D +40.8 (CHCl3, c 0.13). 1H NMR
(250 MHz, CDCl3) δ 7.19–7.49 (m, 5H), 5.42–5.71 (m, 2H), 4.55 (s, 2H), 4.12–
4.24 (m, 1H), 3.49–3.76 (m, 3H), 1.85–2.24 (m, 3H). 13C NMR (62.5 MHz,
CDCl3) δ 137.8, 128.7, 128.5, 128.1, 127.9, 127.0, 77.4, 74.0, 73.7, 73.5, 38.4,
28.4. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 72.02; H, 7.43.
Synthesis of carba-epoxides (-)-1.17α and (-)-1.17β 6-O-Benzyl-3-O-pivaloyl-5a-carba-D-glucal (-)-(3.15)
A solution of trans diol (+)-1.21 (0.909 g, 3.885 mmol) in anhydrous CH2Cl2 (45.6 mL) was
treated with DMAP (0.095 g, 0.777 mmol, 0.2 equiv), pyridine (2.5 mL, 31.08 mmol, 8.0 equiv) and dropewise with PivCl (0.48 mL, 3.885 mmol, 2.0 equiv). After stirring 24 h at room temperature, dilution with AcOEt, evaporation of the washed (saturated aqueous NaHCO3 and
brine) organic layer afforded a crude reaction product (1.23 g, >99% yield) consisting of the pivaloyl derivative (-)-3.15, pure as a yellow liquid, which was used in the next step without any further purification. (-)-3.15: Rf = 0.40 (8:2 hexane/AcOEt); [α]20D -0.76 (c 9.1, CHCl3); 1H NMR (CDCl3) δ 7.27-7.37 (m, 5H), 5.74 (ddd, 1H, J = 10.1, 4.5, 2.1 Hz), 5.41 (unresolved d, 1H, J = 10.1 Hz), 5.25-5.33 (m, 1H), 4.54 (d, 1H, J = 12.0 Hz), 4.48 (d, 1H, J = 12.0 Hz), 3.79 (dd, 1H, J = 10.3, 7.7 Hz), 3.58-367 (m, 2H), 1.93-2.27 (m, 3H), 1.23 (s, 9H). 13CNMR (CDCl 3) δ 179.5, 138.1, 129.3, 128.6, 127.9, 127.8, 125.4, 73.6, 73.5, 72.5, 39.6, 39.1, 28.2, 27.4. !" "! #$" %&'(!"#! !"#$ %! &'! ()*)!"#$
6-O-Benzyl-4-O-mesyl-3-O-pivaloyl-5a-carba-D-glucal (-)-(3.16)
A solution of pivaloyl derivative (-)-3.15 (1.75 g, 5.50 mmol) in anhydrous pyridine (8.0 mL) was treated with MsCl (0.85 mL, 11.0 mmol, 2.0 equiv) at 0°C and the reaction mixture was stirred at the same temperature for 12 h. Dilution with Et2O and evaporation of the washed (10% aqueous
HCl and ice, saturated aqueous NaHCO3 and brine) organic solution afforded a crude reaction
product (1.52 g) consisting of O-mesyl derivative (-)-3.16, which was subjected to flash chromatography. Elution with a 8:2 hexane/AcOEt mixture afforded pure O-mesyl-O-pivaloyl derivative (-)-3.16 (1.92 g, 88% yield), as a yellow oil.
(-)-3.16: Rf = 0.40 (8:2 hexane/AcOEt); [α]20D -0.76 (c 9.1, CHCl3); 1HNMR (CDCl3) δ 7.27-7.39 (m, 5H), 5.80-5.91 (m, 1H), 5.50 (dt, 1H, J = 7.0, 2.1 Hz), 5.42 (dt, 1H, J = 9.9, 2.1 Hz), 5.02 (dd, 1H, J = 9.9, 7.2 Hz), 4.58 (d, 1H, J = 11.7 Hz), 4.47 (d, 1H, J = 11.7 Hz), 3.63 (dd, 1H, J = 9.5, 4.8 Hz), 3.54 (dd, 1H, J = 9.5, 2.3 Hz), 2.98 (s, 3H), 2.21-2.41 (m, 3H), 1.22 (s, 9H). 1HNMR (CDCl 3) δ 178.4, 138.2, 130.0, 128.6, 128.0, 127.9, 124.1, 80.0, 73.3, 72.6, 38.8, 38.5, 28.1, 27.3. 6-O-Benzyl-3,4-anhydro-5a-carba-D-galactal (-)-1.17β
MeONa (1.13 g, 20.96 mmol, 16.0 equiv) was added in three times (10.0 equiv initially, 3.0 equiv after 24 h and 3.0 equiv after 30 h) to a solution of O-mesyl-O-pivaloyl derivative (-)-3.16 (0.52 g, 1.31 mmol) in CH3CN (32.0 mL) at room temperature, and the reaction mixture was stirred for 48
h. Dilution with CH2Cl2 and evaporation of the washed (distilled water and brine) organic solution
afforded a crude reaction product consisting of epoxide (-)-1.17β (0.29 g, >99% yield) practically pure as a pale yellow oil, which was used in the next step without any further purification:
(-)-1.17β: Rf = 0.40 (8:2 hexane/AcOEt); [α]20D −3.9 (c 0.13, CHCl3). 1H NMR
(250 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 5.87–6.02 (m, 2H), 4.62 (d, 1H, J = 12.0
Hz), 4.55 (d, 1H, J= 12.0 Hz), 3.52–3.70 (m, 3H), 3.28–3.33 (m, 1H), 2.02–2.27 (m, 2H), 1.70–1.84 (m, 1H). 13C NMR (62.5 MHz, CDCl
3) δ 138.4, 132.7, 128.5,
127.7, 123.2, 73.4, 73.0, 56.5, 47.8, 33.7, 24.7. Enantiomeric excess (ee) >99%. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.86; H, 7.31.
6-O-Benzyl-3,4-anhydro-5a-carba-D-allal (-)-(1.17α)
Et3N (70.0 µL, 0.553 mmol, 6.5 equiv), pyridine (1.0 µL, 0.01 mmol), and a solution of Ms2O
(0.015 g, 0.085 mmol, 1.0 equiv)14 in anhydrous THF (0.5 mL) were successively added to a
solution of trans diol (+)-1.21 (0.020 g, 0.085 mmol) in anhydrous THF (0.5 mL) at 0°C, and the
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reaction mixture was stirred at the same temperature for 30 min. The completeness of the mesylation was monitored by TLC analysis and after that, the mixture was treated in situ with t-BuOK (0.019 g, 0.170 mmol, 2.0 equiv) and stirred at room temperature for 2 h. Dilution with CH2Cl2 and evaporation of the filtered organic solution afforded a crude reaction product (0.020 g)
consisting of epoxide (-)-1.17α together with a small amount (15%) of the starting diol (+)-1.21 (1H NMR). The crude product was subjected to flash chromatography. Elution with an 8:2
hexane/AcOEt mixture afforded epoxide (-)-1.17α (0.15 g, 60% yield), pure as a liquid.
(-)-1.17α: Rf= 0.39 (8:2 hexane/AcOEt); [α]20D −1.5 (c 0.11, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.28–7.40 (m, 5H), 5.84–5.97 (m,1H), 5.71–5.82 (m, 1H), 4.52 (s, 2H), 3.42–3.51 (m, 1H), 3.45 (dd, 1H, J = 9.0 and 7.1 Hz), 3.35 (dd, 1H, J = 9.0 and 7.6 Hz), 3.19 (td, 1H, J = 4.0 and 1.7 Hz), 2.61–2.78 (m, 1H), 2.13–2.29 (m, 1H), 1.95–2.11 (m, 1H). 13C NMR (62.5 MHz, CDCl 3) δ 138.3, 131.1, 128.5, 127.8, 127.7,
123.2, 73.3, 70.3, 56.3, 46.8, 31.9, 23.9. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C,
77.71; H, 7.23.
Reaction of epoxide (-)-1.17β with 1,2;3,4-di-O-(isopropyliden)-D-galactal under 5.10-3 N
TsOH.H2O/CH2Cl2 protocol
Epoxide (-)-(1.17β) (0.014 g, 0.065 mmol) was added to a solution of
1,2;3,4-di-O-(isopropyliden)-D-galactal (0.101 g, 0.39 mmol, 6.0 equiv), TsOH (0.0012 g, 0.006 mmol, 0.1 equiv) in anhydrous CH2Cl2 (0.44 mL) [epoxide:1,2;3,4-di-(O-isopropyliden)-D-galactal: TsOH 1:6:0.05], and the
reaction mixture was stirred at room temperature for 2 h. After dilution with CH2Cl2, solid
NaHCO3 was added and stirring was prolonged for 15 min. Evaporation of the washed (brine) and
filtered organic solution afforded a crude reaction product (0.069 g), consisting of corresponding
anti-1,2-addition product (+)-3.18 and the excess of 1,2;3,4-di-O-(iso-propyliden)-D-galactal,
which was subjected to preparative TLC (an 8:2 hexane/(i-Pr)2O mixture was used as the eluant).
Extraction of the more intense band afforded 3-O-[6-(1,2:3,4-di-O-isopropyliden-α- D-galactopyranosyl)]-6-O-benzyl-5a-carba-D-gulal (+)-(3.18) (anti-1,2-addition product) (0.030 g,
87% yield), pure as a yellow oil.
(+)-3.18: Rf = 0.16 [8:2 hexane/(i-Pr)2O]; [α]20D +4.4 (c 0.52, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.27–7.40 (m, 5H), 5.89 (dt, 1H, J = 10.6, 3.9 Hz), 5.68–5.78 (m, 1H), 5.52 (d, 1H, J = 5.1 Hz), 4.62 (dd, 1H, J = 5.9, 2.4 Hz), 4.53 (s, 2H), 4.34 (dd, 1H, J = 5.4, 2.4 Hz), 4.18– 4.28 (m, 1H), 4.03–4.10 (m, 1H), 3.58–3.38 (m, 6H), !"# $# # # # # # # !"# $%&%!"!#! #
1.90–2.28 (m, 3H), 1.50 (s, 3H), 1.43 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H). 13C NMR (62.5 MHz,
CDCl3) δ 138.2, 130.5, 128.6, 127.9, 127.8, 124.6, 109.4, 108.8, 96.5, 73.6, 72.2, 71.8, 71.2, 70.9,
70.8, 68.2, 68.1, 66.1, 35.4, 29.9, 26.2, 26.0, 25.4, 24.7. Anal. Calcd for C26H36O8: C, 65.53; H,
7.61. Found: C, 65.71; H, 7.25.
Reaction of epoxide (-)-1.17α with cyclohexanemethanol under 0.01 N CH2Cl2/TsOH.H2O
protocol
Following the typical procedure previously described in Chapter 1, epoxide (-)-1.17α (0.020 g, 0.093 mmol) was added to a solution of cyclohexanemethanol (0.032 g, 0.279 mmol, 3.0 equiv) in CH2Cl2 (0.4 mL) containing TsOH (0.0017 g, 0.009 mmol, 0.1 equiv)
(epoxide:3-cyclohexane-1-methanol:TsOH = 1:3:0.1) and [bimim][BF4] (0.4 mL) and the reaction mixture was stirred at room
temperature for 20 h. After dilution with Et2O, solid NaHCO3 was added and stirring prolonged for
15 min. Evaporation of the washed (brine) and filtered organic solution afforded a crude reaction product (0.032 g) mainly consisting of syn-1,4-addition product (+)-3.19 and an excess of 3-cyclohexene-1-methanol, which was subjected to preparative TLC (an 9:1:1 CH2Cl2
/hexane/(i-Pr)2O mixture was used as the eluant). Extraction of the most intense band afforded pure
cyclohexanemethyl 6-O-benzyl-2,3-dideoxy-5a-carba-α-D-erithro-hex-2-enopyranoside (+)-3.19. (+)-3.19: Rf = 0.08 [9:1:1 CH2Cl2/hexane/(i-Pr)2O]; [α]20 D +19.2 (c 0.26, CHCl3);1H NMR (CDCl3) δ 7.28-7.39 (m, 5H), 5.82-5.88 (m, 2H), 4.56 (s, 2H), 4.03-4.15 (m, 1H), 3.54-3.75 (m, 3H), 3.44 (d, 1H, J = 6.3 Hz), 3.24 (d, 1H, J = 6.3 Hz), 2.07-2.22 (m, 1H), 1.57-1.83 (m, 7H), 1.11-1.41 (m, 6H). 13C NMR (CDCl 3) δ 138.0, 134.5, 134.4, 128.7, 128.1, 127.9, 126.9, 126.4, 75.4, 73.7, 73.6, 72.2, 70.4, 38.5, 37.1, 30.4, 30.3, 29.7, 28.6, 28.1, 26.8.
Synthesis of aziridine (-)-1.18α-Ac
6-O-Benzyl-3-deoxy-3-azido-5a-carba-D-gulal (+)-(2.1)
Trans azido alcohol (+)-2.1 was prepared as previously described in Chapter 2 for
the corresponding racemic compound: [α]20
D +172.5 (c 1.7, CHCl3). !" #$ %&" '()*!"# !"#$!"#$ %&' (' '
6-O-Benzyl-3-deoxy-3-amino-5a-carba-D-gulal (+)-(2.3)
Trans amino alcohol (+)-2.3 was prepared as previously described in Chapter 2
for the corresponding racemic compound: [α]20
D +21.1 (c 1.2, CHCl3).
6-O-Benzyl-3-deoxy-3-N-(acetylamino)-5a-carba-D-gulal (+)-(3.20)
A solution of trans amino alcohol (+)-2.3 (0.133 g, 0.572 mmol) in anhydrous CH2Cl2 (4.6 mL)
was treated at 0°C with Et3N (0.086 mL, 0.669 mmol, 1.2 equiv) and AcCl (0.04 mL, 0.572 mmol,
1.0 equiv) and the reaction mixture was stirred 1 h at the same temperature. Dilution with CH2Cl2
and evaporation of the washed (saturated aqueous NaHCO3 and brine) organic solution afforded a
crude residue consisting of N-aceyl derivative (+)-3.20 (0.151 g, 96% yield), as a yellow viscous liquid, sufficiently pure to be directly used in the next step without any purification.
(+)-3.20: Rf = 0.42 (9:1 AcOEt/ MeOH); [α]20 D +65.5 (c 1.14, CHCl3);1H NMR (CDCl3) δ 7.40-7.27 (m, 5H), 5.93-5.82 (m, 1H), 5.68-5.48 (m, 2H), 4.55 (d, 1H, J = 11.97 Hz), 4.48 (d, 1H, J = 11.97 Hz), 4.43-4.31 (m, 1H), 3.96-3.88 (m, 1H), 3.70 (dd, 1H, J = 9.1, 5.3 Hz), 3.50 (dd, 1H, J = 9.1, 5.3 Hz), 3.53-3.40 (m, 1H), 2.25-2.01 (m, 2H), 1.98 (s, 3H). 13C NMR (CDCl3) δ 170.4, 138.1, 130.6, 128.8, 127.9, 124.3, 73.7, 72.2, 71.5, 50.8, 35.9, 25.4, 23.6. 6-O-Benzyl-4-O-mesyl-3-deoxy-3-N-(acetylamino)-5a-carba-D-gulal (+)-(3.21)
A solution of N-acetyl derivative (+)-3.20 (0.036 g, 0.130 mmol) in anhydrous pyridine (0.33 mL) was treated at 0°C with MsCl (0.02 mL, 0.260 mmol, 2.0 equiv) and the reaction mixture was stirred 12 h at the same temperature. Dilution with CH2Cl2 and evaporation of the washed (10%
aqueous HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl) organic solution afforded a
crude residue (0.525 g) consisting of trans N-(acetylamino)–O-mesyl derivative (+)-3.21 (1H NMR). Filtration on a silica gel-pad, by using a 9:1 AcOEt/acetone mixture as eluant, afforded
(+)-3.21 pure as a yellow liquid (0.034 g, 76% yield).
(+)-3.21: Rf = 0.44 (9:1 AcOEt/Acetone); [α]20D +56.4 (c 1.7, CHCl3). 1H NMR (CDCl3) δ 7.39-7.28 (m, 5H), 6.08-5.97 (m, 1H), 5.62-5.45 (m, 2H), 4.92-4.84 (m, 1H), 4.57 (d, 1H, J = 11.7 Hz), 4.65-4.54 (m, 1H), 4.44 (d, 1H, J = 11.7), 3.60 (dd, 1H, J = 8.9, 6.8 Hz), 3.54-3.40 (m, 1H), 3.25 (s, !" #!$ %&" '()*!"# !" #!$"$!% &'" ()*+!"#$ !"# $%&#&%'( )*# +,(-!"#$
3H), 2.30-2.03 (m, 3H), 1.98 (s, 3H). 13C NMR (CDCl
3) δ 170.4, 138.3, 128.6, 128.2, 127.9, 122.2
, 78.4, 73. 7, 70.5, 48.5, 38.4, 34.8, 24.2, 23.5.
(3S, 4R, 5S)-5-Benzyloxymethyl-3,4-(N-nosylazirido)-1-cyclohexene (-)-(1.18α-Ac)
A solution of trans N-(acetylamino)–O-mesyl derivative (+)-3.21 (0.069 g, 0.20 mmol) in anhydrous benzene (7.0 mL) was treated with t-BuOK (0.027 g, 0.24 mmol, 1.2 equiv) at room temperature, and the reaction mixture was stirred 3 h at the same temperature. After dilution with CH2Cl2, evaporation of the filtered organic solution afforded aziridine (-)-1.18α-Ac (0.048 g, 93%
yield) practically pure, as a pale yellow liquid.
(-)-1.18α-Ac: Rf = 0.44 (1:9 hexane/AcOEt); [α]20D -16.05 (c 1.03, CHCl3). 1H
NMR (CDCl3) δ 7.43-7.28 (m, 5H), 6.04-5.81 (m, 1H), 5.80-5.55 (m, 1H),
4.53-4.43 (s, 2H), 3.49-3.18 (m, 2H), 2.98 (dt, 1H, J = 6.0, 2.1 Hz), 2.82 (ddd, 1H, J = 6.0, 4.3, 1.2 Hz), 2.76-2.52 (m, 1H), 2.13 (s, 3H), 2.09-1.81 (m, 2H). 13C NMR
(CDCl3) δ 182.9, 138.3, 129.4, 128.6, 127.8, 122.8, 73.3, 70.8, 40.3, 32.6, 30.9, 23.9, 23.5.
Synthesis of aziridine (-)-1.18β-Ac
6-O-Benzyl-3-deoxy-3-azido-5a-carba-D-glucal (-)-(2.6)
Trans azido alcohol (-)-2.6 was prepared as previously described in Chapter 2 for
the corresponding racemic compound: [α]20D -80.5 (c 1.1, CHCl3).
6-O-Benzyl-3-deoxy-3-amino-5a-carba-D-glucal (+)-(2.7)
Trans amino alcohol (+)-2.7 was prepared as previously described in Chapter 2
for the corresponding racemic compound: [α]20
D +2.72 (c 1.0, CHCl3).
6-O-Benzyl-3-deoxy-3-N-(acetylamino)-5a-carba-D-glucal (+)-(3.22)
As previously described for trans amino alcohol (+)-2.3, a solution of trans amino alcohol (+)-2.6 (0.150 g, 0.64 mmol) in anhydrous CH2Cl2 (5.0 mL) was treated at 0°C with Et3N (0.098 mL,
0.768 mmol, 1.2 equiv) and AcCl (0.045 mL, 0.64 mmol, 1.0 equiv) and the reaction mixture was stirred 1 h at the same temperature. Dilution with CH2Cl2 and evaporation of the washed (saturated
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aqueous NaHCO3 and brine) organic solution afforded a crude residue consisting of N-aceyl
derivative (+)-3.22 (0.162 g, 92% yield), as a yellow solid, sufficiently pure to be directly used in the next step without any purification.
(+)-3.22: Rf = 0.50 (9:1 AcOEt/ meOH); [α]20 D +39.9 (c 1.7, CHCl3). m.p. 95-97 °C. 1H NMR (CDCl 3) δ 7.42-7.20 (m, 5H), 6.01-5.89 (bs, 1H), 5.82-5.68 (m, 1H), 5.35 (dd, 1H, J = 10.1, 2.1 Hz), 4.50 (s, 2H), 4.47-4.35 (m, 1H), 3.69-3.60 (m, 2H), 3.52 (dd, 1H, J = 10.2, 8.3 Hz), 2.27-2.15 (m, 1H), 2.14-2.0 (m, 2H), 1.98 (s, 3H). 13C NMR (CDCl 3) δ 172.4, 138.3, 129.3, 128.4, 127.7, 127.6, 125.9, 74.7, 73.3, 71.9, 55.2, 40.2, 28.2, 23.3. 6-O-Benzyl-4-O-mesyl-3-deoxy-3-N-(acetylamino)-5a-carba-D-gulal (+)-(3.23)
As previously described for N-acetyl derivative (+)-3.20, a solution of N-acetyl derivative (+)-3.22 (0.072 g, 0.260 mmol) anhydrous pyridine (0.7 mL) was treated at 0°C with MsCl (0.04 mL, 0.520 mmol, 2.0 equiv) and the reaction mixture was stirred 12 h at the same temperature. Dilution with CH2Cl2 and evaporation of the washed (10% aqueous HCl, saturated aqueous NaHCO3 and
saturated aqueous NaCl) organic solution afforded a crude residue (0.525 g) consisting of trans N-(acetylamino)–O-mesyl derivative (+)-3.23 (1H NMR). Filtration on a silica gel-pad, by using a 9:1
AcOEt/acetone mixture as eluant, gave trans N-(acetylamino)–O-mesyl derivative (+)-3.23, pure as a yellow liquid (0.065 g, 72% yield).
(+)-3.23: Rf = 0.45 (9:1 AcOEt/Acetone).;[α]20D +8.85 (c 1.0, CHCl3). 1H NMR (CDCl3) δ 7.40-7.28 (m, 5H), 5.92 (s, 1H), 5.76 (dd, 1H, J = 10.1, 2.7 Hz), 5.42 (dd, 1H, J = 10.1, 1.3 Hz), 4.85-4.71 (m, 2H), 4.56 (d, 1H, J = 11.6 Hz), 4.43 (d, 1H, J = 11.6 Hz), 3.66 (dd, 1H, J = 9.2, 4.1 Hz), 3.5 (dd, 1H, J = 9.2, 3.7 Hz), 3.0 (s, 3H), 2.44-2.20 (m, 3H), 1.99 (s, 3H). 13C NMR (CDCl 3) δ 170.7, 138.2, 132.7, 128.5, 128.0, 126.2, 81.1, 73.2, 69.4, 52.6, 51.6, 38.8, 38.6, 28.5, 23.6. (3R, 4S, 5S)-5-Benzyloxymethyl-3,4-(N-acetylazirido)-1-cyclohexene (-)-(1.18β-Ac)
As previously described for trans N-acetylamino–O-mesyl derivative (+)-3.21, a solution of trans
N-acetylamino–O-mesyl derivative (+)-3.23 (0.086 g, 0.24 mmol) in anhydrous benzene (8.6 mL)
was treated with t-BuOK (0.033 g, 0.19 mmol, 1.2 equiv) at room temperature, and the reaction mixture was stirred for 3 h at the same temperature. After dilution with CH2Cl2, evaporation of the
filtered organic solution afforded aziridine (0.058 g, 95% yield) (-)-1.18β-Ac practically pure, as a pale yellow liquid.
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(-)-1.18β-Ac: Rf = 0.44 (1:9 hexane/AcOEt); [α]20D -20.18 (c 0.85, CHCl3). 1H
NMR (CDCl3) δ 7.43-7.29 (m, 5H), 6.05-5.96 (m, 1H), 5.90-5.81 (m, 1H), 4.59 (s,
2H), 4.57-4.45 (m, 1H), 3.65-3.57 (m, 1H), 3.12-3.04 (m, 1H), 3.01-2.90 (m, 2H), 2.08 (s, 3H), 2.05-1.83 (m, 2H), 1.79-1.62 (m, 1H).
References
1. Plumet, J.; Gomez, A. M.; Lopez, J. C. Mini-Rev. Org. Chem. 2007, 4, 201. 2. Rao, J. P.; Rau, B. V. Tetrahedron: Asymmetry 2010, 21, 930.
3. Boyd, D. R.; Sharma, N. D.; Acaru, C. A.; Malone, J. F.; O’Dowd, C. R.; Allen, C. C. R.; Stevenson, P. J. Org. Lett. 2010, 12, 2206.
4. Arjona, O.; Gomez, A. M,.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919 and references therein.
5. Gomez, A. M.; Moreno, E.; Valverde, S.; Lopez, J. C. Synlett. 2002, 6, 891. 6. Sudha, A. V. R. L.; Nagarajan, M. Chem. Commun. 1998, 925.
7. Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M.; Crotti, P. Tetrahedron 2002, 58, 6069. 8. Di Bussolo, V.; Checchia, L.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2008, 10, 2493. 9. Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. J. Org. Chem. 1979, 44, 1438. 10. Frau, I.; Di Bussolo, V.; Favero, L.; Pineschi, M.; Crotti, P. Chirality, 2011, 23, 820.
11. a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. b) Boeckman, R. K. Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2004, 10, 696.
12. a) Kocienski, P. J. “Protecting Groups” in “Thieme Foundations of Organic Chemistry Series”, Enders, D.; Noyori, R.; Trost, B. M., Eds, Georg Thieme Verlag Stuttgart, 1994, p. 52. b) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
13. Chen, C-L.; Namba, K.; Kishi, Y. Org. Lett. 2009, 22, 409.
14. Lapitskaya, M.A.; Demin, P.M.; Zatonsky, G.V.; Pivnitsky, K.K. Russ. Chem. Bull. Int. Ed 2004, 2617.
15. Di Bussolo, V.; Frau, I.; Checchia, L.; Favero, L.; Pineschi, M.; Uccello-Barretta, G.; Balzano, F.; Roselli, G.; Renzi, G.; Crotti, P. Tetrahedron 2011, 67, 4696.
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