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Synlett 2015; 26(03): 367-374
DOI: 10.1055/s-0034-1379503
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© Georg Thieme Verlag Stuttgart · New York

Syntheses of Mono- and Divalent C-Aminoglycosides Using 1,2-Oxazine Chemistry and Olefin Metathesis

Maja Kandziora
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany   Email: hans.reissig@chemie.fu-berlin.de
,
Eike Mucha
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany   Email: hans.reissig@chemie.fu-berlin.de
,
Sina P. Zucker
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany   Email: hans.reissig@chemie.fu-berlin.de
,
Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany   Email: hans.reissig@chemie.fu-berlin.de
› Author Affiliations
Further Information

Publication History

Received: 15 October 2014

Accepted: 30 October 2014

Publication Date:
03 December 2014 (online)

 
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Abstract

An approach to mono- and divalent C-aminoglycosides starting from a new enantiopure 1,2-oxazine derivative is described. The introduction of a vinyl group into the 1,3-dioxolanyl substituent of a 1,2-oxazine allowed the Lewis acid promoted preparation of a vinyl-substituted bicyclic 1,2-oxazinone. After reduction of the carbonyl group, exhaustive hydrogenolysis provided branched C-aminoglycosides either with β-d-talose or β-d-idose configuration. The vinyl group of the protected rearrangement product 8 also allowed a self-metathesis with Grubbs II catalyst providing a ‘dimeric’ compound as an E/Z mixture. Its hydrogenolysis furnished the divalent C-aminoglycoside in good overall yield.


 

Key words

1,2-oxazine - pyran - C-glycoside - amino sugar - olefin meta­thesis - hydrogenation

Amino sugars and their derivatives have gained increasing interest due to their widespread biological activity and other properties.[1] Aminoglycosides belong to the most ­potent antibiotics known for more than five decades. However, the emergence and rapid spread of aminoglycoside-resistant pathogens limit their intensive clinical use.[2] As consequence of this trend, new methods for the synthesis of unnatural amino sugar derivatives with improved antibacterial properties are required.[3] One approach towards new unnatural C-2-branched 4-amino carbohydrate derivatives involves a de novo strategy employing enantiopure 1,3-dioxolanyl-substituted 1,2-oxazines A, B and C (Scheme [1]) that are easily accessible by [3+3] cyclizations of lithiated alkoxyallenes and carbohydrate-derived nitrones.[4] The Lewis acid induced rearrangements of these 1,2-oxazines lead to the corresponding bicyclic 1,2-oxazine intermediates D, E or F in a highly stereoselective fashion. After ­reduction of the carbonyl group and the crucial reductive N–O bond cleavage, 4-aminopyrans G, H, I or J are obtained. Compounds G [5] and H [6] can be regarded as C-glycosides of amino sugars. The two diastereomeric methoxy-substituted amino sugars I and J are accessible from F by stereodivergent routes. Compounds I and J are 4-amino d-idose and d-talose derivatives with branching at C-2.[7] All compounds are available with excellent diastereoselectivities and in both enantiomeric forms depending on the configuration of the enantiopure precursor nitrone.[8]

In this report we describe the successful synthesis of a new (2-vinyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine and its transformation into the corresponding C-glycosidic aminopyrans. In addition, we report the synthesis of a divalent C-aminoglycoside employing a cross-metathesis as crucial reaction.

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Scheme 1 Examples of C-2-branched 4-amino sugar derivatives G, H, I and J obtained by a de novo strategy employing 1,3-dioxolanyl-substituted 1,2-oxazines A, B and C

The preparation of (2-vinyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 2 started from diol 1 that is easily accessible by the mild cleavage of the corresponding acetonide employing indium trichloride and water.[9] With cerium ammonium nitrate as Lewis acid[10] and an excess of acrolein dimethyl acetal (high concentrations are advantageous) diol 1 was converted into the desired vinyl-substituted dioxolane derivative 2 in excellent 89% yield (dr 63:37; Scheme [2]). Unfortunately, these conditions were not suitable for the synthesis of (2-but-3′-enyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 3. We examined Lewis acids such as zinc triflate, ytterbium(III) triflate hydrate, scandium(III) triflate or boron trifluoride diethyl etherate to achieve the acetal formation of 1 and used either pent-4-enal or the corresponding dimethyl acetal. The best yield could be achieved with the aldehyde as precursor and Yb(OTf)3 hydrate as Lewis acid giving compound 3 in 65% yield (dr 80:20; Scheme [2]). Other weak acids like pyridine/hydrogen fluoride or Brønsted acids such as trifluoroacetic acid and p-toluenesulfonic acid led to an undesired side product.[11] The diastereomers of 2 and 3 could be separated by chromatography, but no configurational assignments were attempted. The subsequent Lewis acid mediated rearrangements are stereoconvergent processes via oxocarbenium ions and hence diastereomeric mixtures of 2 or 3, respectively, were used for these reactions (see Scheme [3]).

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Scheme 2 Preparations of (2-vinyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 2 and (2-but-3′-enyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 3

After some optimization, the Lewis acid induced rearrangement of 1,2-oxazine 2 with trimethylsilyl trifluoromethanesulfonate led to ketone 4 in 76% yield and with excellent stereoselectivity (Scheme [3]). Product 4 is not very stable and should rapidly be transformed in subsequent products. In addition, an interesting side product 5 was isolated in 2% yield. A mechanism for the formation of a structurally comparable tricyclic product has earlier been proposed by our group.[12]

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Scheme 3 Preparation of enantiopure bicyclic compounds 4 and 6 by Lewis acid mediated rearrangements of 1,2-oxazine 2

The tin tetrachloride mediated rearrangement and subsequent protection of the resulting primary hydroxyl group with tert-butyldimethylsilyl triflate under standard conditions provided the considerably more stable protected compound 6, but only moderate overall yields of up to 49% could be achieved. The mechanism of these Lewis acid induced rearrangements can be understood as an intramolecular aldol or Prins reaction type cyclization. The sterically less hindered oxygen atom of the dioxolane moiety of 1,2-oxazine 2 is coordinated by the Lewis acid which opens the dioxolane ring by forming an oxocarbenium ion that is additionally stabilized by the vinyl moiety. This electrophilic intermediate then attacks intramolecularly the enol ether C-5 carbon atom of the 1,2-oxazine ring.[5a] The resulting configuration of the product may be explained plausibly by a six-membered chair-like transition state with the vinyl group in the sterically more favorable equatorial position.

We also treated 1,2-oxazine derivative 3 with different Lewis acids in order to obtain a 3-butenyl-substituted bicyclic product. Unfortunately, the corresponding compound was obtained irreproducibly in low yields and selectivity under the formation of numerous unknown side-products. The reason for this disappointing result may be the lower stabilization of the intermediate oxocarbenium ion derived from 1,2-oxazine 3.

By consecutive Lewis acid promoted rearrangement of 1,2-oxazine derivative 2 and direct reduction of the unpurified ketone 4 we could considerably improve the overall efficacy of the reaction sequence. Its treatment with sodium borohydride under standard conditions furnished the dia­stereomers 7a and 7b in a ratio of 83:17 and in a satisfactory overall yield of 67% (Scheme [4]). Both isomers are fairly stable and after separation by column chromatography the major product 7a was bis-O-benzylated under standard conditions to obtain the compound 8 in 95% yield.

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Scheme 4 Consecutive Lewis acid promoted rearrangement of 1,2-oxazine 2 and immediate reduction providing diols 7a and 7b and bis-O-benzylation of 7a furnishing protected compound 8

In order to prepare unnatural 6-ethyl-substituted C-glycosidic amino sugars, bicyclic compounds 7a and 7b were exhaustively reduced with hydrogen in the presence of palladium on charcoal. After conversion of the vinyl into an ethyl group, the N–O bond was reductively cleaved and the compounds were finally debenzylated to obtain 3-aminopyrans 9a and 9b (Scheme [5]). Heterogenic hydrogenation is an important method in organic synthesis, but many catalysts are sensitive towards poisoning due to products such as amino alcohols.[13] We therefore applied a large amount of palladium on charcoal to achieve full conversion of 7a and 7b into 9a and 9b, compounds that are very polar and difficult to purify. Nevertheless, 1,2-oxazine 7a was converted into 3-aminopyran 9a by hydrogenolysis under standard conditions in methanol in a moderate yield of 35%. Methanol as solvent led to side products containing N,O-aminal subunits due to generation of formaldehyde and its subsequent reactions[14] (also see compounds 15 and 16 shown in Scheme [7]). After some optimization, we discovered that 2-propanol is a more feasible solvent. Under these improved conditions 1,2-oxazine 7b was converted into enantiopure 3-aminopyran 9b in a good yield of 69%. Compound 9a is a branched C-glycoside with β-d-talose configuration whereas isomer 9b correlates to β-d-idose. These new C-glycosidic amino sugar derivatives may have antibiotic activity[2a] but have so far not been tested.

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Scheme 5 Syntheses of ethyl-substituted C-glycosidic amino sugars 9a and 9b by exhaustive hydrogenolysis of compounds 7a and 7b

The vinyl moiety of bicyclic compounds such as 7a, 7b or 8 should allow several useful transformations like dihydroxylation, epoxidation and ozonolysis leading to new interesting intermediates. We were more interested in carbon–carbon bond-forming reaction and therefore examined the olefin metathesis[15] with our substrates. Bicyclic compound 8 turned out to be a challenging substrate for this process due to the steric hindrance next to the vinyl group. We first examined compound 8 in a cross-metathesis reaction with allyltrimethylsilane (Scheme [6]). After extensive optimization, for example using additives such as copper(I) chloride[16] or titanium(IV) isopropoxide,[17] we found that the desired product 10 could be isolated in 63% yield when 10 equivalents of allyltrimethylsilane were employed and when 10 mol% of the Grubbs II catalyst were added in three portions during a period of 24 hours; otherwise no full conversion of 8 was observed. The 1H NMR spectrum of the crude product showed signals of two dia­stereomers (ratio ca. 10:1), but only the major isomer was isolated after column chromatography. We then tried to prepare the 2-propenyl-substituted 11 by proto-desilylation of compound 10 by employing Brønsted or Lewis acids.[18] Whereas acids like trifluoroacetic acid or pyridine hydrofluoride did not induce any reaction boron trifluoride diethyl etherate led to the formation of 1,3-butadienyl-substituted pyran 12 in 47% yield (not optimized). The strong Lewis acid seems to coordinate predominantly at the pyran oxygen of 10 leading to a ring opening; the resulting allyl cation undergoes TMS displacement to deliver the 1,3-butadiene moiety of compound 12. Only the E-isomer of product 12 was detected. This new enantiopure building block may serve as a suitable precursor for further functionalizations and lead to interesting amino polyol compounds.[19]

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Scheme 6 Cross-metathesis reaction of bicyclic 1,2-oxazine 8 with allyltrimethylsilane leading to product 10 followed by BF3-mediated conversion into 1,3-butadiene derivative 12

Encouraged by this successful cross-metathesis with allyltrimethylsilane we attempted the self-metathesis of compound 8. Gratifyingly, this sterically very demanding reaction proceeded under similar conditions with excellent efficacy leading to ‘dimeric’ compound 13 in 97% yield with an E/Z ratio of 59:41 (Scheme [7]). In the subsequent palladium-catalyzed hydrogenolysis of compound (E)-13 we attempted to use 2-propanol as solvent (see reaction of 7b in Scheme [5]), but in this case the reaction was too slow and even after one week it did not go to completion. We therefore used methanol as solvent adding 10 equivalents of acetic acid[14] and then observed full conversion of 13 with the expected saturation of the alkene moiety, the cleavage of the N–O bonds and the required full O- and N-debenzylations. However, the resulting product mixture not only contained the desired product 14 but also side-products 15 and 16 (Scheme [7]). These undesired compounds were obviously formed by in situ generated formaldehyde (due to dehydrogenation of methanol)[14] [20] and subsequent N,O-aminal formation with aminopyran 14. Surprisingly, the N,O-aminal moieties of 15 and 16 could not be hydrolyzed with trifluoroacetic acid even at 60 °C, however, when the mixture of 14, 15 and 16 was treated with hydroxylamine hydrochloride[21] the N,O-aminals were smoothly cleaved and, after precipitation, the very polar product 14 was obtained in 60% overall yield as a pure solid.[22] This product may be regarded as divalent C-glycoside with β-d-talose configuration (pseudo disaccharide) that will be tested for its biological activities.

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Scheme 7 Synthesis of divalent C-aminoglycoside 14 by self-metathesis of compound 8 and subsequent hydrogenolysis of ‘dimer’ 13

In summary, in this communication we have described the synthesis of the two new 1,3-dioxolanyl-substituted 1,2-oxazine derivatives 2 and 3; however, only the vinyl-substituted derivative 2 could be transformed into the enantiopure bicyclic products 4 and 6 by the Lewis acid induced rearrangement. After the reduction of the carbonyl moiety and an N–O bond cleavage, two branched C-amino sugars with β-d-talose and β-d-idopyranose configuration could be prepared. Self-metathesis of the protected vinyl-substituted bicyclic compound 8 resulted in ‘dimeric’ compound 13. By the subsequent hydrogenolysis a new divalent C-aminoglycoside 14 was obtained in a satisfactory yield. Our study demonstrates that 2-alkenyl-1,3-dioxolan-4-yl-substituted 1,2-oxazines such as 2 are versatile building blocks for the de novo synthesis of unique C-aminoglycosides.

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Figure 1

 

Acknowledgment

This work was generously supported by the Deutsche Forschungsgemeinschaft (SFB 765) and by Bayer HealthCare. We acknowledge valuable discussions and help during preparation of the manuscript by Dr. Reinhold Zimmer.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1379503.
  • Supporting Information

  • References and Notes

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  • 22 Representative Experimental Procedures:(1R,5S,6S,8S,9R)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7a) and (1R,5S,6S,8S,9S)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7b): 1,2-Oxazine 2 (50 mg, 128 μmol) was dissolved in MeCN (2 mL) and cooled to 0 °C. Tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the solution was stirred for 3 h at 0 °C, then additional tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the reaction mixture was stirred for 18 h at r.t. H2O (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The combined organic layers were dried with Na2SO4, filtered and the solvent was removed in vacuo. The crude product was dissolved in EtOH (2 mL) and cooled to –30 °C. Sodium borohydride (10 mg, 256 μmol) was added and the suspension was stirred for 3 h at –30 °C. Then the solvent was removed in vacuo and the crude product was dissolved in CH2Cl2 (10 mL) and H2O (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The combined organic layers were dried with Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 1:4) to yield 7a (21 mg, 56%) and 7b(4 mg, 11%) as colorless solids.Data of 7a: mp 108–110 °C; [α]D 22 +47.9 (c = 1.04, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.96 (mc, 1 H, 5-H), 2.75 (br s, 1 H, OH), 3.11 (br s, 1 H, 1-H), 3.69, 3.73 (AB part of ABX system, J AX = 4.6 Hz, J BX = 6.6 Hz, J AB = 11.0 Hz, 2 H, 8-CH2), 3.70 (br s, 1 H, OH), 3.89 (br s, 1 H, 9-H), 3.99–4.03 (m, 1 H, 8-H), 4.09 (d, J = 14.1 Hz, 1 H, NCH2), 4.16–4.18 (m, 1 H, 4-H), 4.17 (s, 1 H, 6-H), 4.19 (ddd, J = 0.6, 5.8, 12.1 Hz, 1 H, 4-H), 4.23 (d, J = 14.1 Hz, 1 H, NCH2), 5.23 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.36 (br d, J = 17.4 Hz, 1 H, 2′-H), 5.84 (ddd, J = 4.7, 10.8, 17.4 Hz, 1 H, 1′-H), 7.27–7.34 (m, 5 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 39.1 (d, C-5), 62.1 (d, C-1), 62.2 (t, NCH2), 63.8 (t, 8-CH2), 65.1 (t, C-4), 70.4 (d, C-9), 78.7 (d, C-6), 79.3 (d, C-8), 116.6 (t, C-2′), 127.7, 128.6, 128.8 (3 × d, Ph), 135.9 (d, C-1′), 137.2 (s, Ph). IR (ATR): 3580–3180 (O–H), 3025–3005 (=C–H), 2930–2855 (C–H), 1595 (C=C), 1455 (C–H), 1230 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H22NO4: 292.1549; found: 292.1542; m/z [M + Na]+ calcd for C16H21NNaO4: 314.1368; found: 314.1366.Data of 7b: mp 55–58 °C; [α]D 22 +12.8 (c = 0.40, CHCl3). 1H NMR (700 MHz, CDCl3): δ = 1.79 (mc, 1 H, 5-H), 2.81 (mc, 1 H, 1-H), 3.79, 3.98 (AB part of ABX system, J AX = 4.0 Hz, J BX = 5.4 Hz, J AB = 11.6 Hz, 2 H, 8-CH2), 4.11 (dd, J = 2.0, 12.1 Hz, 1 H, 4-H), 4.12 (d, J = 13.4 Hz, 1 H, NCH2), 4.16–4.18 (m, 2 H, 4-H, 8-H), 4.27 (d, J = 13.4 Hz, 1 H, NCH2), 4.62 (t, J = 4.0 Hz, 1 H, 9-H), 4.74 (dd, J = 1.5, 3.5 Hz, 1 H, 6-H), 5.24 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.42 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.92 (ddd, J = 5.2, 10.8, 17.3 Hz, 1 H, 1′-H), 7.25–7.28, 7.31–7.34 (2 × m, 1 H, 4 H, Ph); signals for OH could not be detected. 13C NMR (175 MHz, CDCl3): δ = 39.9 (d, C-5), 57.8 (t, NCH2), 59.3 (d, C-1), 62.3 (d, C-9), 64.5 (t, C-4), 65.0 (t, 8-CH2), 72.26 (d, C-6), 72.32 (d, C-8), 116.5 (t, C-2′), 124.9, 127.8, 128.7 (3 × d, Ph), 136.8 (d, C-1′), 136.9 (s, Ph). IR (ATR): 3425 (O–H), 3055–3030 (=C–H), 2950–2825 (C–H), 1645 (C=C), 1445 (C–H), 1250 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H22NO4: 292.1549; found: 292.1537; m/z [M + Na]+ calcd for C16H21NNaO4: 314.1368; found: 314.1355. Anal. Calcd for C16H21NO4 (291.3): C, 65.96; H, 7.27; N, 4.81. Found: C, 65.99; H, 7.22; N, 4.86.(1R,5R,6S,8S,9R)-2-Benzyl-9-(benzyloxy)-8-(benzyloxy-methyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonane (8): To a suspension of sodium hydride in mineral oil (15 mg, 60% NaH) in THF (1 mL) a solution of compound 7a (20 mg, 67 μmol) in THF (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h at r.t. and then cooled to 0 °C. Benzyl bromide (26 μL, 37 mg, 215 μmol) was added and the suspension was stirred for 18 h at r.t. The reaction was quenched with MeOH (1 mL) and the solvent was removed in vacuo. H2O (5 mL) and EtOAc (10 mL) were added and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried with Na2SO4, filtered through a pad of Celite® and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 20:1) to yield 8 (30 mg, 95%) as a colorless solid; mp 45–47 °C; [α]D 22 +53.5 (c = 1.10, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.75 (mc, 1 H, 5-H), 2.98 (br s, 1 H, 1-H), 3.53 (br t, J = 2.8 Hz, 1 H, 9-H), 3.58 (br d, J = 11.7 Hz, 1 H, 4-H), 3.64, 3.70, 3.79 (ABX system, J BX = 5.2 Hz, J AX = 8.8 Hz, J AB = 11.8 Hz, 3 H, 8-CH2, 8-H), 4.15 (mc, 1 H, 6-H), 4.21 (d, J = 13.7 Hz, 1 H, NCH2Ph), 4.36, 4.42 (AB system, J AB = 11.8 Hz, 2 H, OCH2Ph), 4.43 (td, J = 1.9, 11.7 Hz, 1 H, 4-H), 4.50 (d, s, J = 13.7 Hz, 3 H, NCH2Ph, OCH2Ph), 5.10 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.26 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.81 (ddd, J = 5.1, 10.8, 17.3 Hz, 1 H, 1′-H), 7.04–7.07, 7.09–7.20, 7.21–7.28 (3 × m, 1 H, 10 H, 4 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 37.4 (d, C-5), 55.2 (d, C-1), 57.6 (t, C-4), 58.4 (t, NCH2Ph), 60.5 (t, OCH2Ph), 70.5, 70.6 (2 × t, OCH2Ph, 8-CH2), 73.7 (d, C-9), 78.3 (d, C-8), 79.0 (d, C-6), 116.6 (t, C-2′), 127.0, 127.4, 127.7, 127.9, 128.0, 128.2, 128.4, 128.7, 128.8 (9 × d, Ph), 136.2 (d, C-1′), 138.1, 138.3, 138.9 (3 × s, Ph). IR (ATR): 3060–3025 (=C–H), 2930–2870 (C–H), 1645 (C=C), 1450 (C–H), 1240 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C30H34NO4: 472.2488; found: 472.2524; (ESI–TOF): m/z [M + Na]+ calcd for C30H33NNaO4: 494.2307; found: 494.2345.(2S,3R,4S,5S,6S)-(3-Amino-6-ethyl-4-hydroxytetrahydro-2H-pyran-2,5-diyl)dimethanol (9b): A suspension of Pd/C (10% Pd, 70 mg) and i-PrOH (3 mL) was saturated with hydrogen for 15 min. To this suspension bicyclic compound 7b (70 mg, 240 μmol), dissolved in i-PrOH (1 mL), was added. The mixture was stirred for 18 h under hydrogen pressure (balloon). Then the mixture was filtrated through a pad of Celite®, the solvent was removed in vacuo and the crude material was purified by column chromatography (silica gel; CH2Cl2–MeOH, 10:1) to yield 9b (34 mg, 69%) as a colorless solid; mp 143–145 °C; [α]D 22 +63.1 (c = 1.02, MeOH). 1H NMR (700 MHz, CD3OD): δ = 0.77 (t, J = 7.4 Hz, 3 H, 2′-H), 1.39–1.45 (m, 1 H, 1′-H), 1.56–1.62 (m, 2 H, 5-H, 1′-H), 2.91 (br s, 1 H, 3-H), 3.15 (mc, 1 H, 6-H), 3.20 (br s, 1 H, 2-H), 3.37, 3.47 (AB part of ABX system, J AX = 5.6 Hz, J BX = 6.7 Hz, J AB = 11.5 Hz, 2 H, 2-CH2), 3.44 (dd, J = 2.9, 11.4 Hz, 1 H, 5-CH2), 3.60 (br d, J ≈ 11.4 Hz, 1 H, 5-CH2), 3.80 (br t, J = 5.2 Hz, 1 H, 4-H). 13C NMR (175 MHz, CD3OD): δ = 11.3 (q, C-2′), 26.3 (t, C-1′), 44.6 (d, C-5), 51.0 (d, C-3), 55.6 (t, 5-CH2), 62.9 (t, 2-CH2), 72.2 (d, C-4), 79.7 (d, C-2), 82.1 (d, C-6). IR (ATR): 3365–3300 (O–H, N–H), 2960–2845 (C–H), 1460 (C–H) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C9H20NO4: 206.1392; found: 206.1402; m/z [M + Na]+ calcd for C9H19NNaO4: 228.1212; found: 228.1212.(E,1R,5R,6S,8S,9R)-1,2-Bis[2-benzyl-9-(benzyloxy)-8-(benzyl­oxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]nonan-6-yl]ethene (13a) and (Z,1R,5R,6S,8S,9R)-1,2-Bis-[2-benzyl-9-(benzyl­oxy)-8-(benzyloxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]-nonan-6-yl]ethane (13b): Benzyl-protected bicyclic compound 8 (300 mg, 636 μmol) was dissolved in degassed CH2Cl2 (5 mL). Grubbs II catalyst (18 mg, 21 μmol) was added to this solution and the mixture was stirred for 3 h at 40 °C. Then a second portion of Grubbs II catalyst (18 mg, 21 μmol) was added and after another 3 h of stirring at 40 °C a third portion of the catalyst (18 mg, 21 μmol) was added. The reaction mixture was stirred for 18 h at 40 °C. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 4:1) to yield 13a and 13b (165 mg, 57%, E-isomer; 117 mg, 40%, Z-isomer) as colorless oils.Data of E-isomer 13a: [α]D 22 +66.1 (c = 1.04, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.95 (br s, 2 H, 5-H), 3.09 (br s, 2 H, 1-H), 3.66 (d, J = 1.9 Hz, 2 H, 9-H), 3.67 (d, J = 6.5 Hz, 2 H, 4-H), 3.77, 3.83, 3.90 (ABM part of ABMX system, J MX = 5.2 Hz, J BM = 6.4 Hz, J AM = 8.8 Hz, J AB = 11.6 Hz, 6 H, 8-H, 8-CH2), 4.34 (br s, 2 H, 6-H), 4.39 (d, J = 13.5 Hz, 2 H, NCH2Ph), 4.50, 4.56 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.53 (mc, 2 H, 4-H), 4.58 (d, J = 13.5 Hz, 2 H, NCH2Ph), 4.62, 4.65 (AB system, J AB = 12.0 Hz, 4 H, OCH2Ph), 5.96 (d, J = 1.5 Hz, 2 H, HC=CH), 7.20–7.36 (m, 20 H, Ph), 7.40–7.41 (m, 10 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 36.7 (d, C-5), 55.3 (d, C-1), 58.0 (t, C-4), 58.4 (t, NCH2Ph), 70.5 (t, OCH2Ph), 70.7 (t, 8-CH2), 73.7 (t, OCH2Ph), 76.1 (d, C-9), 77.9 (d, C-6), 78.3 (d, C-8), 127.1, 127.5, 127.7, 127.9, 128.2, 128.4, 128.7, 129.0 (8 × d, Ph), 129.3 (d, C=C), 138.1, 138.4, 138.8 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3060–3030 (=C–H), 2920–2860 (C–H), 1735, 1660 (C=C), 1495 (C–H), 1240 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C58H63N2O8: 915.4584; found: 915.4577; m/z [M + Na]+ calcd for C58H62N2NaO8: 937.4404; found: 937.4404. Anal. Calcd for C58H62N2O8 (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.85; H, 7.20; N, 3.06.Data of Z-isomer 13b: [α]D 22 +72.1 (c = 1.07, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 2.00 (mc, 2 H, 5-H), 2.49 (s, 2 H, 1-H), 3.49 (t, J = 2.6 Hz, 2 H, 9-H), 3.58 (d, J = 11.8 Hz, 2 H, 4-H), 3.61, 3.70, 3.76 (ABM part of ABMX system, J MX = 5.2 Hz, J AM = 6.5 Hz, J BM = 8.8 Hz, J AB = 11.7 Hz, 6 H, 8-H, 8-CH2), 4.23 (d, J = 13.7 Hz, 2 H, NCH2Ph), 4.33, 4.38 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.44, 4.52 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.45–4.48 (m, 2 H, 4-H), 4.50 (d, J = 13.7 Hz, 2 H, NCH2Ph), 4.54 (s, 2 H, 6-H), 5.65 (d, J = 3.6 Hz, 2 H, HC=CH), 7.05–7.27 (m, 30 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 36.9 (d, C-5), 55.4 (d, C-1), 57.7 (t, C-4), 58.4 (t, NCH2Ph), 70.4 (t, OCH2Ph), 70.8 (t, 8-CH2), 73.7 (t, OCH2Ph), 75.9 (d, C-9), 76.3 (d, C-6), 78.2 (d, C-8), 127.0, 127.4, 127.9, 128.0, 128.2, 128.5, 128.7, 128.8 (8 × d, Ph), 130.6 (d, C=C), 138.2, 138.3, 138.9 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3085–3030 (=C–H), 2965–2855 (C–H), 1735, 1655 (C=C), 1495 (C–H), 1230 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C58H63N2O8: 915.4584; found: 915.4585; m/z [M + Na]+ calcd for C58H62N2NaO8: 937.4404; found: 937.4407. Anal. Calcd for C58H62N2O8 (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.33; H, 7.42; N, 3.06.Divalent C-Aminoglycoside 14: A suspension of Pd/C (10% Pd, 330 mg), MeOH (35 mL) and acetic acid (108 mg, 103 μL, 1.80 mmol) was saturated with hydrogen for 15 min. The bicyclic compound 13a (165 mg, 180 µmol) was dissolved in MeOH (2 mL), and added to the suspension. The mixture was stirred for 3 d under hydrogen pressure (balloon). The mixture was filtered through a pad of Celite® and the solvent was removed in vacuo. The crude product was dissolved in MeOH (1 mL), hydroxylamine hydrochloride (55 mg, 791 μmol) was added and the reaction mixture was stirred for 30 min at 65 °C. The solvent was removed in vacuo, the crude product was dissolved in MeOH (0.5 mL) and EtOAc (0.5 mL) was added. The precipitated solid was filtered off, washed with EtOAc (3 × 1 mL) and dried in vacuo to yield 14 (41 mg, 60%; for numbering see Figure 1) as a brownish solid. Since the product is highly hygroscopic no melting point was determined.[α]D 22 –5.0 (c = 0.60, MeOH). 1H NMR (700 MHz, CD3OD): δ = 1.71–1.76 (m, 2 H, CH2), 1.98 (ddd, J = 1.6, 3.1, 5.9 Hz, 2 H, 5-H), 2.10–2.15 (m, 2 H, CH2), 3.52 (dd, J = 1.5, 4.4 Hz, 2 H, 3-H), 3.63, 3.80, 3.85 (ABX part of ABXY system, J XY = 1.5 Hz, J AX = J BX = 4.9 Hz, J AB = 11.8 Hz, 6 H, 2-H, 2-CH2), 3.69–3.70 (m, 2 H, 6-H), 3.88, 3.97 (AB part of ABX system, J AX = 1.6 Hz, J BX = 3.1 Hz, J AB = 11.5 Hz, 4 H, 5-CH2), 4.32 (dd, J = 4.4, 7.0 Hz, 2 H, 4-H). 13C NMR (175 MHz, CD3OD): δ = 29.8 (t, CH2), 44.0 (d, C-5), 52.3 (d, C-3), 55.2 (t, 5-CH2), 63.2 (t, 2-CH2), 68.9 (d, C-4), 77.0 (d, C-2), 80.3 (d, C-6). IR (ATR): 3310 (O–H, N–H), 2935 (C–H), 1235 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H33N2O8: 381.2237; found: 381.2235; m/z [M + Na]+ calcd for C16H32N2NaO8: 403.2056; found: 403.2041.

  • References and Notes

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  • 22 Representative Experimental Procedures:(1R,5S,6S,8S,9R)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7a) and (1R,5S,6S,8S,9S)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7b): 1,2-Oxazine 2 (50 mg, 128 μmol) was dissolved in MeCN (2 mL) and cooled to 0 °C. Tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the solution was stirred for 3 h at 0 °C, then additional tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the reaction mixture was stirred for 18 h at r.t. H2O (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The combined organic layers were dried with Na2SO4, filtered and the solvent was removed in vacuo. The crude product was dissolved in EtOH (2 mL) and cooled to –30 °C. Sodium borohydride (10 mg, 256 μmol) was added and the suspension was stirred for 3 h at –30 °C. Then the solvent was removed in vacuo and the crude product was dissolved in CH2Cl2 (10 mL) and H2O (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The combined organic layers were dried with Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 1:4) to yield 7a (21 mg, 56%) and 7b(4 mg, 11%) as colorless solids.Data of 7a: mp 108–110 °C; [α]D 22 +47.9 (c = 1.04, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.96 (mc, 1 H, 5-H), 2.75 (br s, 1 H, OH), 3.11 (br s, 1 H, 1-H), 3.69, 3.73 (AB part of ABX system, J AX = 4.6 Hz, J BX = 6.6 Hz, J AB = 11.0 Hz, 2 H, 8-CH2), 3.70 (br s, 1 H, OH), 3.89 (br s, 1 H, 9-H), 3.99–4.03 (m, 1 H, 8-H), 4.09 (d, J = 14.1 Hz, 1 H, NCH2), 4.16–4.18 (m, 1 H, 4-H), 4.17 (s, 1 H, 6-H), 4.19 (ddd, J = 0.6, 5.8, 12.1 Hz, 1 H, 4-H), 4.23 (d, J = 14.1 Hz, 1 H, NCH2), 5.23 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.36 (br d, J = 17.4 Hz, 1 H, 2′-H), 5.84 (ddd, J = 4.7, 10.8, 17.4 Hz, 1 H, 1′-H), 7.27–7.34 (m, 5 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 39.1 (d, C-5), 62.1 (d, C-1), 62.2 (t, NCH2), 63.8 (t, 8-CH2), 65.1 (t, C-4), 70.4 (d, C-9), 78.7 (d, C-6), 79.3 (d, C-8), 116.6 (t, C-2′), 127.7, 128.6, 128.8 (3 × d, Ph), 135.9 (d, C-1′), 137.2 (s, Ph). IR (ATR): 3580–3180 (O–H), 3025–3005 (=C–H), 2930–2855 (C–H), 1595 (C=C), 1455 (C–H), 1230 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H22NO4: 292.1549; found: 292.1542; m/z [M + Na]+ calcd for C16H21NNaO4: 314.1368; found: 314.1366.Data of 7b: mp 55–58 °C; [α]D 22 +12.8 (c = 0.40, CHCl3). 1H NMR (700 MHz, CDCl3): δ = 1.79 (mc, 1 H, 5-H), 2.81 (mc, 1 H, 1-H), 3.79, 3.98 (AB part of ABX system, J AX = 4.0 Hz, J BX = 5.4 Hz, J AB = 11.6 Hz, 2 H, 8-CH2), 4.11 (dd, J = 2.0, 12.1 Hz, 1 H, 4-H), 4.12 (d, J = 13.4 Hz, 1 H, NCH2), 4.16–4.18 (m, 2 H, 4-H, 8-H), 4.27 (d, J = 13.4 Hz, 1 H, NCH2), 4.62 (t, J = 4.0 Hz, 1 H, 9-H), 4.74 (dd, J = 1.5, 3.5 Hz, 1 H, 6-H), 5.24 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.42 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.92 (ddd, J = 5.2, 10.8, 17.3 Hz, 1 H, 1′-H), 7.25–7.28, 7.31–7.34 (2 × m, 1 H, 4 H, Ph); signals for OH could not be detected. 13C NMR (175 MHz, CDCl3): δ = 39.9 (d, C-5), 57.8 (t, NCH2), 59.3 (d, C-1), 62.3 (d, C-9), 64.5 (t, C-4), 65.0 (t, 8-CH2), 72.26 (d, C-6), 72.32 (d, C-8), 116.5 (t, C-2′), 124.9, 127.8, 128.7 (3 × d, Ph), 136.8 (d, C-1′), 136.9 (s, Ph). IR (ATR): 3425 (O–H), 3055–3030 (=C–H), 2950–2825 (C–H), 1645 (C=C), 1445 (C–H), 1250 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H22NO4: 292.1549; found: 292.1537; m/z [M + Na]+ calcd for C16H21NNaO4: 314.1368; found: 314.1355. Anal. Calcd for C16H21NO4 (291.3): C, 65.96; H, 7.27; N, 4.81. Found: C, 65.99; H, 7.22; N, 4.86.(1R,5R,6S,8S,9R)-2-Benzyl-9-(benzyloxy)-8-(benzyloxy-methyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonane (8): To a suspension of sodium hydride in mineral oil (15 mg, 60% NaH) in THF (1 mL) a solution of compound 7a (20 mg, 67 μmol) in THF (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h at r.t. and then cooled to 0 °C. Benzyl bromide (26 μL, 37 mg, 215 μmol) was added and the suspension was stirred for 18 h at r.t. The reaction was quenched with MeOH (1 mL) and the solvent was removed in vacuo. H2O (5 mL) and EtOAc (10 mL) were added and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried with Na2SO4, filtered through a pad of Celite® and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 20:1) to yield 8 (30 mg, 95%) as a colorless solid; mp 45–47 °C; [α]D 22 +53.5 (c = 1.10, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.75 (mc, 1 H, 5-H), 2.98 (br s, 1 H, 1-H), 3.53 (br t, J = 2.8 Hz, 1 H, 9-H), 3.58 (br d, J = 11.7 Hz, 1 H, 4-H), 3.64, 3.70, 3.79 (ABX system, J BX = 5.2 Hz, J AX = 8.8 Hz, J AB = 11.8 Hz, 3 H, 8-CH2, 8-H), 4.15 (mc, 1 H, 6-H), 4.21 (d, J = 13.7 Hz, 1 H, NCH2Ph), 4.36, 4.42 (AB system, J AB = 11.8 Hz, 2 H, OCH2Ph), 4.43 (td, J = 1.9, 11.7 Hz, 1 H, 4-H), 4.50 (d, s, J = 13.7 Hz, 3 H, NCH2Ph, OCH2Ph), 5.10 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.26 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.81 (ddd, J = 5.1, 10.8, 17.3 Hz, 1 H, 1′-H), 7.04–7.07, 7.09–7.20, 7.21–7.28 (3 × m, 1 H, 10 H, 4 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 37.4 (d, C-5), 55.2 (d, C-1), 57.6 (t, C-4), 58.4 (t, NCH2Ph), 60.5 (t, OCH2Ph), 70.5, 70.6 (2 × t, OCH2Ph, 8-CH2), 73.7 (d, C-9), 78.3 (d, C-8), 79.0 (d, C-6), 116.6 (t, C-2′), 127.0, 127.4, 127.7, 127.9, 128.0, 128.2, 128.4, 128.7, 128.8 (9 × d, Ph), 136.2 (d, C-1′), 138.1, 138.3, 138.9 (3 × s, Ph). IR (ATR): 3060–3025 (=C–H), 2930–2870 (C–H), 1645 (C=C), 1450 (C–H), 1240 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C30H34NO4: 472.2488; found: 472.2524; (ESI–TOF): m/z [M + Na]+ calcd for C30H33NNaO4: 494.2307; found: 494.2345.(2S,3R,4S,5S,6S)-(3-Amino-6-ethyl-4-hydroxytetrahydro-2H-pyran-2,5-diyl)dimethanol (9b): A suspension of Pd/C (10% Pd, 70 mg) and i-PrOH (3 mL) was saturated with hydrogen for 15 min. To this suspension bicyclic compound 7b (70 mg, 240 μmol), dissolved in i-PrOH (1 mL), was added. The mixture was stirred for 18 h under hydrogen pressure (balloon). Then the mixture was filtrated through a pad of Celite®, the solvent was removed in vacuo and the crude material was purified by column chromatography (silica gel; CH2Cl2–MeOH, 10:1) to yield 9b (34 mg, 69%) as a colorless solid; mp 143–145 °C; [α]D 22 +63.1 (c = 1.02, MeOH). 1H NMR (700 MHz, CD3OD): δ = 0.77 (t, J = 7.4 Hz, 3 H, 2′-H), 1.39–1.45 (m, 1 H, 1′-H), 1.56–1.62 (m, 2 H, 5-H, 1′-H), 2.91 (br s, 1 H, 3-H), 3.15 (mc, 1 H, 6-H), 3.20 (br s, 1 H, 2-H), 3.37, 3.47 (AB part of ABX system, J AX = 5.6 Hz, J BX = 6.7 Hz, J AB = 11.5 Hz, 2 H, 2-CH2), 3.44 (dd, J = 2.9, 11.4 Hz, 1 H, 5-CH2), 3.60 (br d, J ≈ 11.4 Hz, 1 H, 5-CH2), 3.80 (br t, J = 5.2 Hz, 1 H, 4-H). 13C NMR (175 MHz, CD3OD): δ = 11.3 (q, C-2′), 26.3 (t, C-1′), 44.6 (d, C-5), 51.0 (d, C-3), 55.6 (t, 5-CH2), 62.9 (t, 2-CH2), 72.2 (d, C-4), 79.7 (d, C-2), 82.1 (d, C-6). IR (ATR): 3365–3300 (O–H, N–H), 2960–2845 (C–H), 1460 (C–H) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C9H20NO4: 206.1392; found: 206.1402; m/z [M + Na]+ calcd for C9H19NNaO4: 228.1212; found: 228.1212.(E,1R,5R,6S,8S,9R)-1,2-Bis[2-benzyl-9-(benzyloxy)-8-(benzyl­oxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]nonan-6-yl]ethene (13a) and (Z,1R,5R,6S,8S,9R)-1,2-Bis-[2-benzyl-9-(benzyl­oxy)-8-(benzyloxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]-nonan-6-yl]ethane (13b): Benzyl-protected bicyclic compound 8 (300 mg, 636 μmol) was dissolved in degassed CH2Cl2 (5 mL). Grubbs II catalyst (18 mg, 21 μmol) was added to this solution and the mixture was stirred for 3 h at 40 °C. Then a second portion of Grubbs II catalyst (18 mg, 21 μmol) was added and after another 3 h of stirring at 40 °C a third portion of the catalyst (18 mg, 21 μmol) was added. The reaction mixture was stirred for 18 h at 40 °C. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 4:1) to yield 13a and 13b (165 mg, 57%, E-isomer; 117 mg, 40%, Z-isomer) as colorless oils.Data of E-isomer 13a: [α]D 22 +66.1 (c = 1.04, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.95 (br s, 2 H, 5-H), 3.09 (br s, 2 H, 1-H), 3.66 (d, J = 1.9 Hz, 2 H, 9-H), 3.67 (d, J = 6.5 Hz, 2 H, 4-H), 3.77, 3.83, 3.90 (ABM part of ABMX system, J MX = 5.2 Hz, J BM = 6.4 Hz, J AM = 8.8 Hz, J AB = 11.6 Hz, 6 H, 8-H, 8-CH2), 4.34 (br s, 2 H, 6-H), 4.39 (d, J = 13.5 Hz, 2 H, NCH2Ph), 4.50, 4.56 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.53 (mc, 2 H, 4-H), 4.58 (d, J = 13.5 Hz, 2 H, NCH2Ph), 4.62, 4.65 (AB system, J AB = 12.0 Hz, 4 H, OCH2Ph), 5.96 (d, J = 1.5 Hz, 2 H, HC=CH), 7.20–7.36 (m, 20 H, Ph), 7.40–7.41 (m, 10 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 36.7 (d, C-5), 55.3 (d, C-1), 58.0 (t, C-4), 58.4 (t, NCH2Ph), 70.5 (t, OCH2Ph), 70.7 (t, 8-CH2), 73.7 (t, OCH2Ph), 76.1 (d, C-9), 77.9 (d, C-6), 78.3 (d, C-8), 127.1, 127.5, 127.7, 127.9, 128.2, 128.4, 128.7, 129.0 (8 × d, Ph), 129.3 (d, C=C), 138.1, 138.4, 138.8 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3060–3030 (=C–H), 2920–2860 (C–H), 1735, 1660 (C=C), 1495 (C–H), 1240 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C58H63N2O8: 915.4584; found: 915.4577; m/z [M + Na]+ calcd for C58H62N2NaO8: 937.4404; found: 937.4404. Anal. Calcd for C58H62N2O8 (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.85; H, 7.20; N, 3.06.Data of Z-isomer 13b: [α]D 22 +72.1 (c = 1.07, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 2.00 (mc, 2 H, 5-H), 2.49 (s, 2 H, 1-H), 3.49 (t, J = 2.6 Hz, 2 H, 9-H), 3.58 (d, J = 11.8 Hz, 2 H, 4-H), 3.61, 3.70, 3.76 (ABM part of ABMX system, J MX = 5.2 Hz, J AM = 6.5 Hz, J BM = 8.8 Hz, J AB = 11.7 Hz, 6 H, 8-H, 8-CH2), 4.23 (d, J = 13.7 Hz, 2 H, NCH2Ph), 4.33, 4.38 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.44, 4.52 (AB system, J AB = 11.8 Hz, 4 H, OCH2Ph), 4.45–4.48 (m, 2 H, 4-H), 4.50 (d, J = 13.7 Hz, 2 H, NCH2Ph), 4.54 (s, 2 H, 6-H), 5.65 (d, J = 3.6 Hz, 2 H, HC=CH), 7.05–7.27 (m, 30 H, Ph). 13C NMR (125 MHz, CDCl3): δ = 36.9 (d, C-5), 55.4 (d, C-1), 57.7 (t, C-4), 58.4 (t, NCH2Ph), 70.4 (t, OCH2Ph), 70.8 (t, 8-CH2), 73.7 (t, OCH2Ph), 75.9 (d, C-9), 76.3 (d, C-6), 78.2 (d, C-8), 127.0, 127.4, 127.9, 128.0, 128.2, 128.5, 128.7, 128.8 (8 × d, Ph), 130.6 (d, C=C), 138.2, 138.3, 138.9 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3085–3030 (=C–H), 2965–2855 (C–H), 1735, 1655 (C=C), 1495 (C–H), 1230 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C58H63N2O8: 915.4584; found: 915.4585; m/z [M + Na]+ calcd for C58H62N2NaO8: 937.4404; found: 937.4407. Anal. Calcd for C58H62N2O8 (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.33; H, 7.42; N, 3.06.Divalent C-Aminoglycoside 14: A suspension of Pd/C (10% Pd, 330 mg), MeOH (35 mL) and acetic acid (108 mg, 103 μL, 1.80 mmol) was saturated with hydrogen for 15 min. The bicyclic compound 13a (165 mg, 180 µmol) was dissolved in MeOH (2 mL), and added to the suspension. The mixture was stirred for 3 d under hydrogen pressure (balloon). The mixture was filtered through a pad of Celite® and the solvent was removed in vacuo. The crude product was dissolved in MeOH (1 mL), hydroxylamine hydrochloride (55 mg, 791 μmol) was added and the reaction mixture was stirred for 30 min at 65 °C. The solvent was removed in vacuo, the crude product was dissolved in MeOH (0.5 mL) and EtOAc (0.5 mL) was added. The precipitated solid was filtered off, washed with EtOAc (3 × 1 mL) and dried in vacuo to yield 14 (41 mg, 60%; for numbering see Figure 1) as a brownish solid. Since the product is highly hygroscopic no melting point was determined.[α]D 22 –5.0 (c = 0.60, MeOH). 1H NMR (700 MHz, CD3OD): δ = 1.71–1.76 (m, 2 H, CH2), 1.98 (ddd, J = 1.6, 3.1, 5.9 Hz, 2 H, 5-H), 2.10–2.15 (m, 2 H, CH2), 3.52 (dd, J = 1.5, 4.4 Hz, 2 H, 3-H), 3.63, 3.80, 3.85 (ABX part of ABXY system, J XY = 1.5 Hz, J AX = J BX = 4.9 Hz, J AB = 11.8 Hz, 6 H, 2-H, 2-CH2), 3.69–3.70 (m, 2 H, 6-H), 3.88, 3.97 (AB part of ABX system, J AX = 1.6 Hz, J BX = 3.1 Hz, J AB = 11.5 Hz, 4 H, 5-CH2), 4.32 (dd, J = 4.4, 7.0 Hz, 2 H, 4-H). 13C NMR (175 MHz, CD3OD): δ = 29.8 (t, CH2), 44.0 (d, C-5), 52.3 (d, C-3), 55.2 (t, 5-CH2), 63.2 (t, 2-CH2), 68.9 (d, C-4), 77.0 (d, C-2), 80.3 (d, C-6). IR (ATR): 3310 (O–H, N–H), 2935 (C–H), 1235 (C–O) cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd for C16H33N2O8: 381.2237; found: 381.2235; m/z [M + Na]+ calcd for C16H32N2NaO8: 403.2056; found: 403.2041.

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Scheme 1 Examples of C-2-branched 4-amino sugar derivatives G, H, I and J obtained by a de novo strategy employing 1,3-dioxolanyl-substituted 1,2-oxazines A, B and C
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Scheme 2 Preparations of (2-vinyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 2 and (2-but-3′-enyl-1,3-dioxolan-4-yl)-substituted 1,2-oxazine 3
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Scheme 3 Preparation of enantiopure bicyclic compounds 4 and 6 by Lewis acid mediated rearrangements of 1,2-oxazine 2
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Scheme 4 Consecutive Lewis acid promoted rearrangement of 1,2-oxazine 2 and immediate reduction providing diols 7a and 7b and bis-O-benzylation of 7a furnishing protected compound 8
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Scheme 5 Syntheses of ethyl-substituted C-glycosidic amino sugars 9a and 9b by exhaustive hydrogenolysis of compounds 7a and 7b
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Scheme 6 Cross-metathesis reaction of bicyclic 1,2-oxazine 8 with allyltrimethylsilane leading to product 10 followed by BF3-mediated conversion into 1,3-butadiene derivative 12
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Scheme 7 Synthesis of divalent C-aminoglycoside 14 by self-metathesis of compound 8 and subsequent hydrogenolysis of ‘dimer’ 13
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Figure 1