Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis

Article Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

pubs.acs.org/jnp

Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis Anthony W. Carroll,† Anthony C. Willis,‡ Masako Hoshino,§ Atsushi Kato,§ and Stephen G. Pyne*,† †

School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia § Department of Hospital Pharmacy, University of Toyama, Sugitani, Toyama 2630, Japan ‡

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S Supporting Information *

ABSTRACT: Hyacinthacines C1 and C4 are natural products that were isolated from Hyacinthoides non-scripta and Scilla socialis in 1999 and 2007, respectively. Despite their different 1H NMR and 13C NMR spectroscopic data, these compounds have been assigned the same structures, including absolute configurations. This work details the total synthesis of natural (+)-hyacinthacine C1, whose structure is confirmed as being the C-6 epimer of that reported. The synthetic strategy focused on inverting the configuration at C-1 of the final hyacinthacines via operating the inversion at the corresponding carbon atom in three previously synthesized intermediates. To do this, the advanced intermediates were subjected to Swern oxidation, followed by a stereoselective reduction with L-Selectride. This approach led to the synthesis of (+)-5-epi-hyacinthacine C1 (15), the corrected structure for (+)-hyacinthacine C1 (19), (+)-6,7-di-epi-hyacinthacine C1 (23), and (+)-7-epi-hyacinthacine C1 (29). Glycosidase inhibition assays revealed that (+)-hyacinthacine C1 (19) proved the most active, with IC50 values of 33.7, 55.5, and 78.2 μM, against the α-glucosidase of rice, human lysosome, and rat intestinal maltase, respectively.

T

hyacinthacine A, B, or C type (Figure 1), depending on the number of hydroxy groups (3, 4, and 5, respectively).10−12 The hyacinthacine alkaloids display a range of glycosidase inhibitory activities, leading to a number of reports detailing their total synthesis.13−34 Structurally, the hyacinthacine Ctype subclass of these alkaloids is the most diverse subclass of hyacinthacine and has recently generated synthetic interest.20,23,24,35−40 They can contain up to seven possible stereogenic centers, which means that there are 128 unique possible stereoisomers containing a 3-hydroxymethyl-5-methylpyrrolizidine-1,2,6,7-tetraol core that can be potentially synthesized. Their high degree of oxidation and analogous structure to glucose make this class a particularly enticing but challenging target for synthetic chemists interested in the preparation of therapeutic iminosugars. For a number of years, our research group has been interested in synthesizing naturally occurring, biologically active iminosugars and compounds with structurally analogous motifs.21,22,41−49 The hyacinthacine C-type alkaloids caught

he hyacinthacine alkaloids form a recently discovered subclass of hydroxylated 3-hydroxymethylpyrrolizidine natural products that have demonstrated potential antiviral, anticancer, antidiabetic, and antiobesity drug-like properties as a result of their inherent glycosidase inhibitory activities.1−6 Although analogous to biologically active iminosugars including casuarine, alexine, and australine, these structurally complex sugar mimetics have been labeled according to their natural source, hyacinthaceae, a subfamily within the Asparagaceae plant family (Figure 1). The genus of this plant has been of interest since the late 1960s, when a report by Thursby-Pelham detailed the toxicological effects on livestock after consuming the leaves of Hyacinthoides nonscripta.7,8 From an economic point of view, this prompted a 1999 study by Asano et al., who investigated the aqueous extracts of the immature fruits and stalks of H. non-scripta and the related Scilla campanulata and isolated three novel biologically active iminosugars, which they labeled as hyacinthacines C1, B1, and B2.9 Since then, another 16 hyacinthacine-type alkaloids have been isolated from related Hyacinthaceae species, Muscari armeniacum, Scilla sibirica, and Scilla socialis, and these can be subdivided structurally into © XXXX American Chemical Society and American Society of Pharmacognosy

Received: October 21, 2018

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DOI: 10.1021/acs.jnatprod.8b00879 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Article

furnished via either an Appel cyclization52 or O-mesylation, then through a N-cyclization process. To generate the anti-6,7diol in the final hyacinthacine C-type compounds, the cyclic sulfates 7A, 8A, and 9B were successfully synthesized and subsequently ring-opened via nucleophilic substitution from in situ formed CsOBz. Upon closer analysis of this reaction pathway, we hypothesized that the configuration at C-8 in compounds 7−9 could be selectively inverted to obtain access to the C1/C4-type hyacinthacine alkaloids and potentially resolve the current issues that accompany their structures (Scheme 1). We herein report the true structure and synthesis of hyacinthacine C1. In addition to this, the synthetic pathway also accessed three additional diastereomers of hyacinthacine C1/C4. All final products were assessed as glycosidase inhibitors.

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Figure 1. Selected examples of the structures assigned to the naturally occurring hyacinthacines A1-, B1-, and C-type alkaloids containing 3, 4, or 5 hydroxy substituents, respectively.

RESULTS AND DISCUSSION To elucidate the synthetic pathway toward hyacinthacine C1/ C4-type alkaloids, we focused on the advanced pyrrolizidine 9 that was obtained in an earlier report.49 It was envisaged that if the unprotected secondary alcohol at C-8 in pyrrolizidine 9 was oxidized to the corresponding ketone, 53 then a diastereoselective reduction with L-Selectride54 would occur at the less hindered convex face (β-face), resulting in an inversion of configuration.22 Thus, the unprotected hydroxy group was subjected to Swern oxidation conditions53 to give ketone 11 in 83% yield [Scheme 2(a)]. Ketone 11 was then subjected to a reduction with L-Selectride, which was suspected to give exclusively alcohol 12 based on the substantial 1H NMR differences between alcohol 12 and the starting alcohol 9. To confirm this, the alcohol was converted to its benzyl ether, which returned a clearly resolved 1H NMR spectrum of 13, which was subsequently subjected to extensive 1D-NOE difference analysis (Supporting Information, S7). The proposed configuration of 13 was confirmed on the basis of positive NOE enhancements observed between H-3a−H-8b, H-3a−H3-1″, H-8−H-7, H-8−H-8a, H-7−H-8a, H-8a−H-8b, and H-4−H-6 (Figure 2). Similar to our previous work, a global deprotection of 12, first deprotecting the acetonide moiety under acidic conditions to give 14 [Scheme 2(b)], then using PdCl2/H2 followed by purification via ion-exchange chromatography, afforded (+)-5-epi-hyacinthacine C1 (15) {[α]D25 −14 (c 0.9, H2O)}. Compound 15 and related

our attention particularly because these highly functionalized structures have led to several structural misassignments that warrant correcting. The most obvious example of this can be seen through the structures of hyacinthacine C1 and C4 (3). Although reported eight years apart, both natural isolates were assigned identical structures despite prominent differences in their NMR spectroscopic data.9,12 In addition to this, previous synthetic work found the structures of hyacinthacine C3 (5)19 and hyacinthacine C5 (6)23,24,40 to be incorrect, with the latter only being recently corrected by synthetic work from our research group.49 It is well established that utilizing the one-pot, multicomponent Petasis borono-Mannich reaction is a useful strategy to access chiral 1,2-amino alcohols, an also common structural feature of many bioactive alkaloids.50 Recognizing this, we have demonstrated that hydroxylated iminosugars containing this motif can be synthesized from a suitably prepared borono-Mannich (Petasis) product.21,22,41,43,50,51 The most recent example of this detailed the Petasis boronoMannich reaction used to prepare exclusively aminotetraol A; we demonstrated that this precursor could be used to synthesize the correct structure of hyacinthacine C5 (10) (Scheme 1) as well as pyrrolizidine 6, which was previously proposed as the structure for the natural alkaloid.49 During this synthesis, the pyrrolizidine core for both products was

Scheme 1. Established Stereodivergent Syntheses of Hyacinthacine C-Type Alkaloids 6 and 1049

B



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Scheme 2. Synthesis of 13 and (+)-5-epi-Hyacinthacine C1 (15)

Scheme 3. Synthesis of (+)-Hyacinthacine C1 (19)

Figure 3. Experimental NOE correlations projected onto a DFTminimized molecular model [B3LYP/6-31G(d)] of 17 (Bn groups not shown).

H-8, and H-7−H-1′ (Figure 3), confirming formation of the intended product. Acid hydrolysis of the acetonide moiety in 17, then O-debenzylation using PdCl2/H2, followed by purification via ion-exchange chromatography, afforded (+)-hyacinthacine C1 (19) {[α]25 D +13 (c 0.1, H2O)}. After comparative NMR analysis of synthetic 19 against the spectroscopic data reported for the original isolates labeled hyacinthacine C1 {[α]D +15 (c 0.3, H2O)}9 and hyacinthacine C4 {[α]D −38 (c 0.4, H2O)},12 the 1H NMR multiplicities and chemical shifts of the natural isolate labeled hyacinthacine C1 were found to be a close match with synthetic compound 19 (Table 1). Additionally, a consistent 0.4−0.6 ppm difference


Table 1. Comparison of Literature 1H NMR Data of Natural (+)-Hyacinthacine C412 (500 ΜΗz, D2O), Natural (+)-Hyacinthacine C19 (400 ΜΗz, D2O), and Synthetic 19 (500 MHz, D2O)

analogues in this paper are named based on the corrected structure of hyacinthacine C1 (19) (Scheme 3). Having established the utility of the Swern oxidation and the diastereoselective reduction, the next objective was to determine if this method could be successfully applied to pyrrolizidine alcohols 7 and 8. Owing to its availability, pyrrolizidine alcohol 8 was initially subjected to the established Swern oxidation conditions to afford the oxopyrrolizidine 16 (Scheme 3) in 80% yield. Next, a diastereoselective reduction using L-Selectride gave exclusively the pyrrolizidine alcohol 17 in 66% yield. In addition to the prominent 1H NMR spectroscopic differences between 17 and the parent C-8 epimer 8, an extensive 2D NOESY analysis was performed to confirm the inversion at C-8 in 17 (Supporting Information, S16). Key positive correlations were observed between H-4− H-3a, H-4−H-8a, H3-1″−H-6, H-8a−H-8b, H-7−H-8, H-8a−

position 1 2 3 5 6 7 7a 8 9 C

(+)-hyacinthacine C412


4.18, 4.00, 3.38, 2.96, 3.90, 4.15, 3.57, 3.65, 1.29,

4.15, 4.00, 3.44, 3.29, 3.89, 4.50, 3.66, 3.66, 1.27,

t (4.0) dd (4.0, 8.7) dt (4.6, 8.7) dq (6.9, 9.2) dd (8.2, 9.2) t (8.2) dd (3.7, 8.2) d (4.6) d (6.9)

t (3.9) dd (3.9, 9.0) dt (4.4, 9.0) dt (3.9, 7.0) dd (3.9, 4.6) dd (4.6, 8.6) dd (3.9, 8.6) m d (7.0)

19 4.18, 4.02, 3.47, 3.31, 3.92, 4.53, 3.68, 3.68, 1.29,

t (3.8) dd (3.7, 9.2) dt (9.2, 4.6) dq (3.9, 7.1) t (4.4) dd (4.7, 8.6) m m d (7.2)



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Table 2. Comparison of Literature 13C NMR Data of Natural (+)-Hyacinthacine C412 (125 ΜΗz, D2O), Natural (+)-Hyacinthacine C19 (100 ΜΗz, D2O), and Synthetic 19 (125 MHz, D2O) position



19

ΔδC

1 2 3 5 6 7 7a 8 9

75.2 77.3 65.1 62.0 82.9 80.0 67.3 66.4 16.0

74.6 77.7 64.7 60.4 77.1 75.7 68.3 65.9 12.8

74.1 77.3 64.1 59.9 76.6 75.1 67.8 65.4 12.4

0.5 0.4 0.6 0.5 0.5 0.6 0.5 0.5 0.4


Scheme 4. Synthesis of (+)-6,7-Di-epi-hyacinthacine C1 (23)

for the 13C NMR chemical shifts (Table 2) was observed. The 1 H NMR spectrum of 19 was referenced to the D2O solvent residual peak at 4.79 ppm, while the 13C NMR spectrum in D2O was referenced to internal methanol. Comparatively, the 1 H and 13C NMR chemical shifts of the natural (+)-hyacinthacine C1 are expressed in reference to the internal standard sodium 3-(trimethylsilyl)propionate (TPS) in D2O.9 This may explain the slight NMR spectroscopic differences observed between synthetic 19 and the natural product. Regardless, the specific rotation of our synthetic 19 is a close match to the isolated hyacinthacine C1.9 In conjunction with the fact that the natural isolates hyacinthacine C4 and C1 cannot be the same structure, we convincingly showed that the true structure for hyacinthacine C1 is, in fact, the C-6 epimer 19. The next focus was to synthesize (+)-6,7-di-epi-hyacinthacine C1 (23) from pyrrolizidine alcohol 7. In the initial report, pyrrolizidine alcohol 7 was described as a pale yellow oil.49 Dissolving the oil in EtOH and allowing slow evaporation of the solvent over 48 h resulted in large crystals, which were consequently subjected to X-ray crystallographic studies and unambiguously confirmed the initially proposed stereochemical assignment.49,55 The crystalline alcohol 7 was treated under the established Swern oxidation conditions. Unlike the previous synthetic strategies, the intended ketone 20 proved difficult to purify and seemed prone to degradation on silica medium. Thus, the crude ketone product was instead reduced with L-Selectride, which successfully afforded the target alcohol 21 in 65% yield over two steps. Similarly, comparative analysis of the 1H NMR spectroscopic data between 21 and the parent alcohol 7 suggested a successful inversion at C-8. To confirm this, alcohol 21 was subjected to extensive 1D NOE difference experiments, which confirmed the relative configuration of the newly inverted C-8 stereocenter (Supporting Information, S23). More specifically, key positive NOE enhancements were observed between H-8b−H-3a, H-3a− H3-1″, H-8−H-7, H-8−H-8a, H-7−H-8a, H-7−H-1′, and H31″−H-6 (Figure 4). Alcohol 21 was then globally deprotected to give (+)-6,7-di-epi-hyacinthacine C1 (23) {[α]25 D +14 (c 0.2, H2O)}. Having identified the true structure for natural hyacinthacine C1, we next attempted to synthesize hyacinthacine C4 from 21; this was unsuccessful. Instead, the synthetic attempts led to the unprecedented synthesis of the hyacinthacine C1/C4-related analogue (+)-7-epi-hyacinthacine C1 (29), which was still an

important contribution to the glycosidase inhibition studies. To obtain this product, the secondary hydroxy group of 21 was converted to its benzyl ether to afford compound 24 in 52% yield (Scheme 5). With the previous success in establishing anti-6,7-diol chemistry49 it was decided to subject 24 to an acid Scheme 5. Synthesis of (+)-7-epi-Hyacinthacine C1 (29)

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hydrolysis of the acetonide moiety to afford the syn-diol 25, which was subsequently converted to the cyclic sulfate 26.56 Prone to degradation, the cyclic sulfate was immediately treated with Cs2CO3 and benzoic acid, which led to subsequent ring opening with in situ formed CsOBz to give the major benzoate regioisomer 27 in 42% yield. The benzoate 27 was subjected to a comprehensive 2DNOESY analysis, which showed key correlations between H9−H-7, H3-9−H-3, H-5−H-6, H-1−H-7a, H-1−H-2, H-7a− H-2, and H-8−H-2, suggesting the proposed configuration of structure 27 to be correct (Figure 5). Interestingly, this result

results were compared to the glycosidase inhibitory values obtained from the previous study.49 Collectively, the observed glycosidase activities can be explained by considering the C-1, C-2, and C-3 stereocenters, which are originally sourced from the starting sugar L-xylose.49 Inverting the configuration at C-1, as operated here, leads to another related carbohydrate, namely, L-lyxose. Both L-xylose and L-lyxose are non-natural sugars. In this study, the A-ring of compounds 19, 15, 23, and 29 contains a configurational similarity to that of L-lyxose, where compound 19 was comparatively the most efficient (but still weak) toward inhibiting glucosidases. Since glucosidases are functionally deputed to recognize glucose, we therefore generalize that iminosugars containing any configurational deviations from glucose (such as L-xylose and L-lyxose) reduce the glucose-like structure of the iminosugar and thus will diminish glucosidase inhibition activity. In comparison with the previous study, the potency and selectivity of compounds 19, 15, 23, and 29 were relatively less notable. Therefore, inverting the C-1 stereocenter decreases the potency and selectivity of the iminosugar as a glycosidase inhibitor. This trend can be best explained through comparison of results from our previous study as well as this study, with the structurally analogous casuarine (one of the most powerful glucosidase inhibitors). More specifically, it has been proven by crystal structure determination and computational methods that casuarine perfectly mimics the stereochemical arrangement of glucose, with the A-ring overlapping the C-3 to C-6 portion of glucose.57,58 In the earlier study, all synthesized hyacinthacine C-type compounds contained identical configurations with that of casuarine at C-7a, C-1, C-2, and C-3.49 In this study, the relatively diminished glycosidase activity observed can be ascribed to a worse mimicry of casuarine (and ultimately glucose), since only configurations at C-7a, C2, and C-3 were preserved. This is no surprise since inverting C-1 of casuarine gives rise to an allose-related configuration and is responsible for its diminished glycosidase inhibition activity. When compared with casuarine from the previous work, it was observed that hyacinthacine C-type alkaloids containing a methyl substituent at C-5 resulted in a decrease in glycosidase inhibition properties.49 This behavior appears to be general. For example, a comparison of 7-deoxycasuarine58 and its 5methyl-substituted homologue59 shows a one order magnitude loss of activity toward the amyloglucosidase of A. niger (IC50 values of 4.5 and 39 μM, respectively). In another example, australine60 and its 5-methyl-substituted homologue, hyacinthacine B4,11 display a similar loss of activity toward the amyloglucosidase of A. niger (IC50 values of 5.8 and 89 μM, respectively). It is therefore reasonable to suggest that, in general, this moiety sterically prevents the pyrrolizidine from effectively binding to the glycosidase active site. In summary, we have demonstrated the utility of the previous synthetic approach through the synthesis of four novel hyacinthacine C1/C4-related analogues, 15, 19, 23, and 29. More specifically, access to these diastereomers was obtained after strategically employing both the Swern oxidation and a stereoselective reduction with L-Selectride on their parent pyrrolizidine structures 9, 8, and 7 to afford inversion at C-8 (C-1 in the final products). Both the 1H NMR and 13C NMR spectroscopic data of compound 19 match the spectroscopic data of the natural isolate labeled hyacinthacine C1,9 which we therefore conclude to be the same product. With the new finding that hyacinthacine C1 is actually the C-6

Figure 5. Experimental NOE NMR correlations projected onto a DFT-minimized molecular model [B3LYP/6-31G(d)] of 27 (Bn groups not shown).

was consistent with the regioselectivity observed in a previous related study and results from a 1,2-diaxial-like ring-opening pathway with attack of the benzoate at C-3. Attack at C-8b requires a different reactive conformation in which the C-4 methyl group is pseudoaxial and sterically blocks substitution at C-8b. A referee has suggested that the observed regioselectivity could be the result of hyperconjugative stabilization of the participating carbon, C-3a, by the C-4 methyl group (anti to the leaving group). Both these steric and stereoelectronic effects could be clearly valid; however, determining their relative contributions will require further study. It is suspected that the C-8b benzoate regioisomer was also formed but could not be obtained due to the insufficient amount of starting material in combination with the generally low yield for this reaction. Regardless of this outcome, a basemediated hydrolysis of the benzoate 27 afforded diol 28 in good yield. Debenzylation of 28 under hydrogenolysis conditions (PdCl2/H2) gave (+)-7-epi-hyacinthacine C1 (29) {[α]25 D +7 (c 0.1, H2O)} in 75% yield. The NMR spectroscopic data of 23 and 29 were different from those reported for natural hyacinthacine C4. Glycosidase Inhibition Analysis. Synthesized hyacinthacine C1 (19) and the synthesized diastereomers 15, 23, and 29 were assessed for their inhibitory potential against a panel of glycosidases (Table S1). Compounds 15 and 29 remained relatively inactive against all glycosidases tested. Comparatively, 19 proved the most potent of all analogues tested in this study. More specifically, 19 displayed selective and weak to moderate inhibition for the α-glucosidase of rice, rat intestinal maltase, and human lysosome (IC50 values of 33.7, 78.2, and 55 μM, respectively). Analogue 23 was found to be selective for the amyloglucosidase of Aspergillus niger and displayed a weak inhibition with an IC50 value of 95.5 μM. To gain a better understanding of the structure−activity relationship, these E



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11 as an opaque yellow oil (24 mg, 83%): Rf 0.25 (3:7 EtOAc/ hexanes); [α]25 D +23 (c 1.6, CHCl3); IR νmax 3030, 2910, 2875, 1716, 1451, 1380, 1227, 1095, 691 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.37−7.24 (10H, m, ArH), 5.04−4.95 (2H, m, OCH2Ph, H8b), 4.69 (1H, d, J = 11.8 Hz, OCH2Ph), 4.56−4.46 (3H, m, OCH2Ph, H3a), 3.94 (1H, dd, J = 9.3, 1.3 Hz, H7), 3.89−3.83 (2H, m, H8a, H6), 3.79 (1H, q, J = 7.3 Hz, H4), 3.63 (1H, dd, J = 10.2, 2.7 Hz, H1′), 3.45 (1H, dd, J = 10.3, 4.9 Hz, H1′), 1.46 (3H, s, C2-CH3), 1.25 (3H, s, C2-CH3), 1.07 (3H, d, J = 7.3 Hz, H1″); 13C NMR (CDCl3, 125 MHz) δ 211.0 (C8), 138.1 (ArC), 137.8 (ArC), 128.4 (ArCH), 128.3 (ArCH), 128.1 (ArCH), 127.78 (ArCH), 127.76 (ArCH), 127.68 (ArCH), 112.66 (C2), 88.4 (C3a), 84.1 (C8b), 80.3 (C7), 73.3 (OCH2Ph), 72.6 (OCH2Ph), 70.4 (C1′), 70.2 (C8a), 63.9 (C4), 63.8 (C6), 26.3 (C2-CH3), 23.0 (C2-CH3), 19.3 (C1″); HREIMS m/z 438.2275 [M + H+] (calcd for C26H32NO5 438.2280). General Method for the Reduction of a Ketone to a Secondary Alcohol with L-Selectride. (3aS,4S,6R,7R,8S,8aS,8bR)-7-Benzyloxy-6-[(benzyloxy)methyl]-2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizin-8-ol (12). To a cooled (−78 °C) solution of ketone 11 (52 mg, 0.119 mmol) in tetrahydrofuran (THF) (5 mL) was added a solution of L-Selectride (1.0 M solution in THF, 476 μL, 0.476 mmol). The reaction mixture was stirred for 1 h at −78 °C, allowed to warm to room temperature, and stirred for 2 h. By this time, TLC analysis confirmed full consumption of the starting material. The reaction mixture was quenched with NH4Cl solution (1.0 M, 7 mL). The product was extracted with EtOAc (3 × 10 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by FCC (3:97 MeOH/CH2Cl2) afforded the title product 12 as an orange oil (50 mg, 96%): Rf 0.45 (3:97 MeOH/CH2Cl2); [α]25 D +25 (c 0.5, CHCl3); IR νmax 3398, 3133, 2982, 1620, 1503, 1062, 864, 698 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.37−7.23 (10H, m, ArH), 4.86 (1H, t, J = 6.0 Hz, H8b), 4.73 (1H, d, J = 11.7 Hz, OCH2Ph), 4.58−4.52 (2H, m, OCH2Ph, H8), 4.50−4.45 (2H, m, OCH2Ph), 4.39 (1H, dd, J = 6.2, 4.9 Hz, H3a), 4.26 (1H, d, J = 4.8 Hz, OH), 3.89 (1H, dd, J = 7.5, 5.2 Hz, H7), 3.62 (1H, t, J = 5.2 Hz, H8a), 3.54−3.49 (1H, m, H1′), 3.49− 3.42 (2H, m, H1′, H6), 3.34 (1H, dd, J = 6.9, 5.2 Hz, H4), 1.53 (3H, s, C2-CH3), 1.31 (3H, s, C2-CH3), 1.13 (3H, d, J = 6.7 Hz, H1″); 13C NMR (CDCl3, 125 MHz) δ 138.4 (ArC), 138.3 (ArC), 128.3 (ArCH), 128.3 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 127.5 (ArCH), 113.5 (C2), 88.6 (C3a), 82.2 (C8b), 81.9 (C7), 73.2 (OCH2Ph), 72.4 (OCH2Ph), 71.8 (C1′), 71.2 (C8), 67.1 (C6), 66.3 (C4), 66.3 (C8a), 26.9 (C2-CH3), 24.4 (C2-CH3), 19.1 (C1″); HREIMS m/z 440.2430 [M + H+] (calcd for C26H34NO5, 440.2437). General Method for O-Benzylation. (3aS,4S,6R,7R,8S,8aS,8bR)-7,8-Bisbenzyloxy-6-[(benzyloxy)methyl]-2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine (13). To a solution of compound 12 (46 mg, 0.105 mmol) in THF (5 mL) at 0 °C was slowly added NaH (6.3 mg, 0.158 mmol 60% dispersion in mineral oil). The reaction mixture was heated at reflux under a nitrogen atmosphere for 5 min and cooled to rt. Benzyl bromide (15 μL, 0.126 mmol) and TBAI (5.8 mg, 0.0158 mmol) were added, and the mixture was heated at reflux for 15 min. By this time, TLC analysis had confirmed full consumption of the starting material. The reaction mixture was cooled to 0 °C and quenched by the dropwise addition of H2O (10 mL). The mixture was extracted with Et2O (3 × 10 mL), and the combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The resultant brown oil was purified by FCC (2:3 EtOAc/hexanes) to afford product 13 as a yellow oil (30 mg, 54%): Rf 0.55 (5:95 MeOH/CH2Cl2); [α]25 D +48 (c 1.5, CHCl3); IR νmax 2328, 1645, 1320, 962, 664 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.45−7.12 (15H, m, ArH), 4.80−4.72 (2H, m, OCH2Ph, H8b), 4.71−4.64 (1H, m, OCH2Ph), 4.55−4.50 (2H, m, OCH2Ph), 4.46 (1H, d, J = 12.2 Hz, OCH2Ph), 4.39 (1H, d, J = 12.0 Hz, OCH2Ph), 4.33 (1H dd, J = 6.4, 4.4 Hz, H3a), 4.13 (1H, t, J = 5.2 Hz, H8), 3.87 (1H, dd, J = 7.4, 5.5 Hz, H7), 3.50 (1H, t, J = 5.2 Hz, H8a), 3.48− 3.42 (2H, m, H6, H1′), 3.42−3.37 (1H, m, H1′), 3.30 (1H, qd, J = 6.7, 4.3 Hz, H4), 1.43 (3H, s, C2-CH3), 1.30 (3H, s, C2-CH3), 1.10 (3H, d, J = 6.7 Hz, H1″); 13C NMR (CDCl3, 125 MHz) δ 139.0

epimer of the originally assigned structure and also in addition to the other diastereomers synthesized in this study, there is a strong possibility that the structure for hyacinthacine C4 proposed in 200712 is correct. Glycosidase inhibition studies revealed that the inverted stereocenter at C-1 generally diminished the potency and selectivity of the hydroxylated pyrrolizidine. This stereocenter was originally translated from the starting sugar L-xylose, and so we conclude that manipulating this decreases the carbohydrate nature of the resultant iminosugars and thus makes them less recognizable for the glycosidase active site. We therefore propose that the original carbohydrate nature (similar to casuarine) should be conserved for future analogues in order to improve their glycosidase inhibitory potential. Overall, the synthesis of hyacinthacine C4 is required to confirm our proposal that the natural isolate is the correct structure. In combination with these results, this would also greatly aid the understanding of the hydroxylated pyrrolizidine structure−activity relationships as glycosidase inhibitors. This would be therapeutically beneficial toward finding treatments for type II diabetes and managing the obesity epidemic, as results obtained would help influence the future design of potent biologically active iminosugars.

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EXPERIMENTAL SECTION

General Experimental Procedures. Flash column chromatography (FCC) was performed over silica gel 60 (230−400 mesh). LRESIMS data were acquired on a single quadrupole (MeOH as solvent) mass spectrometer. HRESIMS were determined on a quadrupole time-of-flight mass spectrometer. FTIR data were determined on neat samples. Optical rotations were measured using a 2 mL cell at room temperature. The average of 40 measurements was used to calculate specific rotations. 1H (500 MHz) and 13C NMR (125 MHz) spectra were recorded in CDCl3, D2O, or methanol-d4 solutions. All signals obtained in CDCl3 were relative to the tetramethylsilane (TMS) signal for 1H NMR and the CDCl3 signal for 13C NMR, referenced at 0.00 and 77.16 ppm, respectively. All signals obtained in methanol-d4 were relative to the CD2HOD signal for 1H NMR and the methanol-d4 signal for 13C NMR, referenced at 3.31 and 49.00 ppm, respectively. All signals obtained in D2O were relative to the D2O signal for 1H NMR, referenced at 4.79. For 13C NMR the referencing of peaks is relative to internal MeOH (δ 49.50). NMR assignments were based upon gCOSY, APT, gHSQC, and NOESY or ROESY experiments. In some cases, 13C NMR signals that were absent in the standard 13C NMR spectrum were identified using gHSQC experiments. Pyrrolizidine compounds are named using systematic nomenclature. The NMR assignments of those compounds are based on the numbering system of the hyacinthacine alkaloids and not the systematic name. The 3D structures generated were prepared with ChemDraw 16.0 and Avogadro, an open-source molecular builder and visualization tool, version 1.2.0.61 The density functional theory (DFT) used to minimize the three-dimensional structures was calculated with B3LYP/6-31G(d)62−64 using the Gaussian 09 basis set.65 General Method for Swern Oxidation. (3aS,4S,6R,7R,8aR,8bR)-7-Benzyloxy-6-[(benzyloxy)methyl]-2,2,4-trimethylhexahydro-8H-[1,3]dioxolo[4,5-a]pyrrolizin-8-one (11). To a cooled (−78 °C), stirred solution of DMSO (93 μL, 1.30 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (56.0 μL, 0.653 mmol). After stirring for 5 min, a solution of 9 (29 mg, 0.0653 mmol) in CH2Cl2 (2 mL) was added to the mixture followed by the addition of Et3N (364 μL, 2.61 mmol). After stirring at −78 °C for 1 h, thin-layer chromatography (TLC) analysis confirmed full consumption of the starting material. The reaction was quenched with H2O (5 mL), and the mixture extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by FCC (3:7 EtOAc/hexanes) afforded the ketone F



Article

3.5, 2.1 Hz, H6), 3.69 (1H, dd, J = 5.2, 1.5 Hz, H8a), 3.65 (1H, dd, J = 10.4, 3.5 Hz, H1′), 3.43 (1H, dd, J = 10.5, 2.1 Hz, H1′), 3.30 (1H, qd, J = 7.2, 4.0 Hz, H4), 1.47−1.41 (6H, m, C2-CH3, H1″), 1.26 (3H, s, C2-CH3); 13C NMR (CDCl3, 125 MHz) δ 211.8 (C8), 138.0 (ArC), 137.9 (ArC), 128.4 (ArCH), 128.2 (ArCH), 128.12 (ArCH), 128.11, 127.8 (ArCH), 127.7 (ArCH), 112.5 (C2), 84.4 (C3a), 83.5 (C8b), 80.9 (C7), 73.4 (OCH2Ph), 73.0 (OCH2Ph), 72.4 (C8a), 69.0 (C1′), 61.01 (C6), 60.97 (C4), 26.2 (C2-CH3), 22.9 (C2-CH3), 12.0 (C1″); HREIMS m/z 438.2300 [M + H+] (calcd for C26H32NO5, 438.2280). (3aS,4R,6R,7R,8S,8aS,8bR)-7-Benzyloxy-6-[(benzyloxy)methyl]2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizin-8-ol (17). Compound 17 was synthesized from the tricyclic ketone 16 (28 mg, 0.0640 mmol) by using the general method for the reduction of a ketone to a secondary alcohol with L-Selectride. The product was purified by FCC (5:95 MeOH/CH2Cl2) to give the target compound as an orange oil (18.5 mg, 66%): Rf 0.25 (5:95 MeOH/CH2Cl2); [α]25 D +52 (c 0.9, CHCl3); IR νmax 3290, 2989, 2926, 2873, 1585, 1484, 1095, 694 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.37−7.20 (10H, m, ArH), 4.75−4.61 (3H, m, OCH2Ph, H8b, H8), 4.54 (1H, dd, J = 6.0, 4.4 Hz, H3a), 4.52−4.46 (3H, m, OCH2Ph), 3.99 (1H, dd, J = 8.1, 4.7 Hz, H7), 3.76−3.69 (2H, m, OH, H6), 3.49 (1H, dd, J = 7.3, 4.6 Hz, H8a), 3.42 (1H, dd, J = 9.8, 3.4 Hz, H1′), 3.30 (1H, dd, J = 9.8, 6.3 Hz, H1′), 3.12 (1H, qd, J = 7.0, 4.2 Hz, H4), 1.43 (3H, s, C2-CH3), 1.33 (3H, d, J = 7.1 Hz, H1″), 1.26 (3H, s, C2-CH3); 13C NMR (CDCl3, 125 MHz) δ 138.7 (ArC), 138.2 (ArC), 128.3 (ArCH), 128.1 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 127.3 (ArCH), 111.8 (C2), 85.4 (C3a), 82.6 (C7), 82.4 (C8), 73.3 (OCH2Ph), 72.8 (OCH2Ph), 72.4 (C1′), 71.3 (C8a), 70.4 (C8b), 63.2 (C6), 58.9 (C4), 25.7 (C2-CH3), 23.3 (C2-CH3), 11.9 (C1″); HREIMS m/z 440.2430 [M + H+] (calcd for C26H34NO5, 440.2437). (1R,2S,3R,5R,6R,7S,7aR)-6-Benzyloxy-5-[(benzyloxy)methyl]-3methylhexahydro-1H-pyrrolizine-1,2,7-triol (18). Compound 18 was synthesized from 17 (18.5 mg, 0.0421 mmol) using the general method for hydrolysis of an acetonide. The product was purified by FCC (8:92 MeOH/CH2Cl2) to give a yellow oil (15 mg, 87%): Rf 0.25 (8:92 MeOH/CH2Cl2); [α]25 D +12 (c 0.7, CHCl3); IR νmax 3340, 3119, 2926, 2893, 1568, 1478, 1058, 634 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.39−7.22 (10H, m, ArH), 4.60 (1H, d, J = 12.2 Hz, OCH2Ph), 4.53−4.45 (3H, m, OCH2Ph), 4.44 (1H, dd, J = 8.2, 5.0 Hz, H7), 4.18 (1H, t, J = 3.8 Hz, H1), 4.02 (1H, dd, J = 8.0, 3.4 Hz, H2), 3.81 (1H, t, J = 4.5 Hz, H6), 3.72 (1H, dd, J = 8.2, 3.4 Hz, H7a), 3.61 (1H, dt, J = 8.1, 4.0 Hz, H3), 3.47 (2H, dd, J = 3.9, 1.6 Hz, H8), 3.42−3.34 (1H, m, H5), 1.24 (3H, d, J = 7.1 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 138.3 (ArC), 137.1 (ArC), 128.7 (ArCH), 128.4 (ArCH), 128.3 (ArCH), 128.0 (ArCH), 127.8 (ArCH), 127.6 (ArCH), 82.3 (C2), 74.9 (C6), 74.4 (C7), 73.4 (OCH2Ph), 73.1 (OCH2Ph), 71.3 (C8), 70.8 (C1), 66.8 (C7a), 60.4 (C3), 57.9 (C5), 10.9 (C9); HREIMS m/z 400.2133 [M + H+] (calcd for C23H30NO5, 400.2124). (1S,2R,3R,5R,6S,7R,7aR)-3-Hydroxymethyl-5-methylhexahydro1H-pyrrolizine-1,2,6,7-tetraol [(corrected structure for (+)-hyacinthacine C1)] (19). Compound 19 was synthesized by the general method for O-benzyl deprotection from 18 (10 mg, 0.0250 mmol). The crude product was filtered through a pad of Celite and washed with additional MeOH (6 mL). The combined filtrates were concentrated in vacuo to afford a clear film. The compound was isolated through basic ion-exchange chromatography followed by concentration in vacuo, providing the title compound as a colorless film (3 mg, 52%): [α]25 D +13 (c 0.1, H2O); IR νmax 3349, 2925, 1598, 1420, 1071, 967, 651 cm−1; 1H NMR (D2O, 500 MHz) δ 4.53 (1H, dd, J = 8.6, 4.7 Hz, H7), 4.18 (1H, t, J = 3.8 Hz, H1), 4.02 (1H, dd, J = 9.2, 3.7 Hz, H2), 3.92 (1H, t, J = 4.4 Hz, H6), 3.68 (3H, m, H8, H7a), 3.47 (1H, dt, J = 9.2, 4.6 Hz, H3), 3.31 (1H, dq, J = 7.1, 3.9 Hz, H5), 1.29 (3H, d, J = 7.2 Hz, H9); 13C NMR (D2O, 125 MHz) δ 77.3 (C2), 76.6 (C6), 75.1 (C7), 74.1 (C1), 67.8 (C7a), 65.4 (C8), 64.1 (C3), 59.9 (C5), 12.4 (C9); HREIMS m/z 220.1183 [M + H+] (calcd for C9H17NO5, 220.1185).

(ArC), 138.50 (ArC), 138.46 (ArC), 128.24 (ArCH), 128.18 (ArCH), 128.1 (ArCH), 127.82 (ArCH), 127.77 (ArCH), 127.69 (ArCH), 127.44 (ArCH), 127.41 (ArCH), 127.3 (ArCH), 113.3 (C2), 88.7 (C3a), 81.6 (C7), 80.7 (C8b), 76.9 (C8), 73.4 (OCH2Ph), 73.2 (OCH2Ph), 72.5 (OCH2Ph), 71.9 (C1′), 67.6 (C6), 66.7 (C8a), 65.8 (C4), 26.7 (C2-CH3), 24.3 (C2-CH3), 19.4 (C1″); HREIMS m/z 530.2919 [M + H+] (calcd for C33H40NO5, 530.2906). General Method for Hydrolysis of an Acetonide. (1R,2S,3S,5R,6R,7S,7aR)-6-Benzyloxy-5-[(benzyloxy)methyl]-3methylhexahydro-1H-pyrrolizine-1,2,7-triol (14). To a solution of 12 (50 mg, 0.114 mmol) in EtOH/H2O (1:9, 5 mL) was added 5 N HCl (0.5 mL). The mixture was stirred at room temperature for 4 h, by which time TLC analysis confirmed the consumption of starting material. The mixture was neutralized by the addition of a saturated solution of NaHCO3 to a pH of 7. The solution was evaporated to 5 mL under reduced pressure and extracted with EtOAc (3 × 15 mL), and the combined extracts were washed with saturated NaCl (15 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a brown oil. Purification by FCC (5:95 MeOH/CH2Cl2) gave the title compound 14 as a pale yellow oil (36 mg, 79%): Rf 0.15 (5:95 MeOH/CH2Cl2); [α]25 D −67 (c 0.4, CHCl3); IR νmax 3334, 3063, 2925, 2868, 1679, 1512, 1082, 656 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.38−7.20 (10H, m, ArH), 4.59−4.46 (4H, m, OCH2Ph), 4.34 (1H, t, J = 4.3 Hz, H7), 4.31 (1H, t, J = 5.5 Hz, H1), 4.03 (1H, dd, J = 7.4, 4.0 Hz, H6), 3.70−3.58 (2H, m, H2, H7a), 3.49 (2H, d, J = 4.5 Hz, H8), 3.13 (1H, dt, J = 8.0, 4.5 Hz, H3), 2.86 (1H, quint, J = 6.3 Hz, H5), 1.19 (3H, d, J = 6.2 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 138.2 (ArC), 136.9 (ArC), 128.7 (ArCH), 128.4 (ArCH), 128.4 (ArCH), 128.1 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 82.6 (C7), 79.4 (C1), 73.4 (C6), 73.1 (C7a), 72.7 (OCH2Ph), 72.2 (OCH2Ph), 71.0 (C8), 67.4 (C2), 66.7 (C5), 65.7 (C3), 19.4 (C9); HREIMS m/z 400.2118 [M + H+] (calcd for C23H30NO5, 400.2124). General Method for O-Benzyl Deprotection. (1S,2R,3R,5S,6S,7R,7aR)-3-Hydroxymethyl-5-methylhexahydro-1Hpyrrolizine-1,2,6,7-tetraol [(+)-5-epi-hyacinthacine C1] (15). To a nitrogen-purged solution of compound 14 (34 mg, 0.0852 mmol) in MeOH (3 mL) was added PdCl2 (30 mg, 0.170 mmol). A balloon of H2 was attached to the system, and the mixture was stirred at rt for 3 h. After LRESIMS analysis confirmed full consumption of the starting material, the mixture was filtered through a pad of Celite and washed with additional MeOH (6 mL). The combined filtrates were concentrated in vacuo to give a yellow film. An Amberlyst A-26 resin (1.70 g) basic ion-exchange chromatography column was prepared by mixing the resin with a 15% aqueous ammonia solution (v/v) and allowing it to stand for 15 min followed by washing the column with distilled H2O until a pH close to 7 was achieved. The compound was dissolved in distilled H2O (2 mL) and held on the column for 15 min before its elution with H2O (3 × 5 mL). Concentration in vacuo provided 15 (15 mg, 80%) as a colorless film: [α]25 D −14 (c 0.9, H2O); IR νmax 3331, 2956, 1590, 1578, 1439, 1067, 812, 732, 643 cm−1; 1H NMR (D2O, 500 MHz) δ 4.41 (1H, t, J = 4.9 Hz, H1), 4.37 (1H, t, J = 5.0 Hz, H7), 3.97 (1H, dd, J = 7.3, 4.4 Hz, H2), 3.72−3.60 (3H, m, H6, H8), 3.58 (1H, t, J = 5.4 Hz, H7a), 3.08−3.01 (2H, m, H3, H5), 1.21 (3H, d, J = 6.4 Hz, H9); 13C NMR (D2O, 125 MHz) δ 78.4 (C6), 74.5 (C2), 72.6 (C1), 72.0 (C7), 70.6 (C3), 65.1 (C5), 64.3 (C7a), 62.5 (C8), 17.5 (C9); HREIMS m/z 220.1177 [M + H+] (calcd for C9H17NO5, 220.1185). (3aS,4R,6R,7R,8aR,8bR)-7-Benzyloxy-6-[(benzyloxy)methyl]2,2,4-trimethylhexahydro-8H-[1,3]dioxolo[4,5-a]pyrrolizin-8-one (16). Compound 16 was synthesized from the tricyclic alcohol 8 (35 mg, 0.0796 mmol) by using the general method for the Swern oxidation. The product was purified by FCC (2:3 EtOAc/hexanes) to give the target compound as an opaque yellow oil (28 mg, 80%): Rf 0.25 (2:3 EtOAc/hexanes); [α]25 D +95 (c 1.4, CHCl3); IR νmax 3379, 2980, 2849, 1612, 1452, 1363, 1212, 1002, 678 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.36−7.21 (10H, m, ArH), 5.03 (1H, d, J = 11.6 Hz, OCH2Ph), 4.89 (1H, t, J = 5.5 Hz, H8b), 4.59 (1H, d, J = 11.6 Hz, OCH2Ph), 4.54 (1H, dd, J = 5.8, 4.1 Hz, H3a), 4.46 (2H, s, OCH2Ph), 4.16 (1H, dd, J = 8.5, 1.5 Hz, H7), 3.96 (1H, ddd, J = 8.6, G



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(3aR,4R,6R,7R,8R,8aS,8bS)-7-Benzyloxy-6-[(benzyloxy)methyl]2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizin-8-ol (7). To a solution of the amino-diol49 (80 mg, 0.175 mmol) in dry CH2Cl2 (10 mL) at 0 °C were added Et3N (37 μL, 0.263 mmol), PPh3 (69 mg, 0.263 mmol), and CBr4 (87 mg, 0.263 mmol). The mixture was stirred at 0 °C for 5 min, then allowed to warm to room temperature for 30 min, by which time TLC analysis confirmed full consumption of the starting material. The mixture was poured into H2O (15 mL) and subsequently extracted with CH2Cl2 (3 × 15 mL). The combined extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo to give a yellow oil. The residue was purified by FCC (3:5 EtOAc/hexanes) to give 7 as a pale yellow oil (248 mg, 87%). The oil was dissolved in EtOH and was subjected to slow evaporation at room temperature over 48 h, resulting in the formation of large colorless crystals of 7: mp 92−94 °C; Rf 0.25 (5:95 MeOH/ CH2Cl2); IR νmax 3397, 2983, 1520, 1493, 1120, 1066, 866 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.44−7.16 (10H, m, ArH), 4.68 (1H, d, J = 12.0 Hz, OCH2Ph), 4.63 (1H, dd, J = 6.8, 3.5 Hz, H8b), 4.58 (1H, d, J = 11.9 Hz, OCH2Ph), 4.49 (1H, d, J = 11.9 Hz, OCH2Ph), 4.45 (1H, d, J = 12.0 Hz, OCH2Ph), 4.28 (1H, s, H8), 4.17 (1H, t, J = 7.3 Hz, H3a), 3.83 (1H, s, H7), 3.63 (1H, d, J = 3.4 Hz, H8a), 3.45 (1H, dd, J = 9.2, 2.8 Hz, H1′), 3.35 (1H, dd, J = 9.2, 4.0 Hz, H1′), 3.31− 3.25 (2H, m, H4, H6), 1.49 (3H, s, C2-CH3), 1.28 (6H, s, C2-CH3, H1″); 13C NMR (CDCl3, 125 MHz) δ 137.7 (ArC), 137.2 (ArC), 128.5 (ArCH), 128.0 (ArCH), 128.0 (ArCH), 127.8 (ArCH), 127.4 (ArCH), 114.1 (C2), 88.4 (C7), 85.7 (C3a), 83.8 (C8b), 78.3 (C8a), 76.3 (C8), 73.8 (OCH2Ph), 73.1 (C1′), 71.5 (OCH2Ph), 63.7 (C4 or C6), 63.5 (C4 or C6), 27.8 (C2-CH3), 25.6 (C2-CH3), 14.9 (C1″); HREIMS m/z 440.2445 [M + H+] (calcd for C26H34NO6, 440.2437). (3aR,4R,6R,7R,8aR,8bS)-7-Benzyloxy-6-[(benzyloxy)methyl]2,2,4-trimethylhexahydro-8H-[1,3]dioxolo[4,5-a]pyrrolizin-8-one (20). Compound 20 was synthesized from the tricyclic alcohol 7 (71 mg, 0.162 mmol) by using the general method for the Swern oxidation. The resultant yellow oil (71 mg) was used for the next step without further purification. LRESIMS m/z 438 (100%) [M + H+]. (3aR,6R,7R,8S,8aS,8bS)-7-Benzyloxy-6-[(benzyloxy)methyl]2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizin-8-ol (21). Compound 21 was synthesized from the crude tricyclic ketone 20 (71 mg, 0.162 mmol) by using the general method for the reduction of a ketone to a secondary alcohol with L-Selectride. The product was purified by FCC (5:95 MeOH/CH2Cl2) to give the target compound as an orange oil (46 mg, 65%): Rf 0.45 (5:95 MeOH/CH2Cl2); [α]25 D −72 (c 0.4, CHCl3); IR νmax 3340, 2967, 2872, 1516, 1496, 1140, 1066, 866, 635 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.39−7.19 (10H, m, ArH), 4.86 (1H, dd, J = 6.3, 3.2 Hz, H8b), 4.58 (1H, d, J = 11.7 Hz, OCH2Ph), 4.55−4.47 (3H, m, OCH2Ph), 4.23 (1H, t, J = 5.7 Hz, H3a), 4.19 (1H, d, J = 4.7 Hz, H8), 3.87 (1H, t, J = 4.3 Hz, H7), 3.61 (1H, t, J = 4.1 Hz, H8a), 3.47−3.36 (2H, m, H1′, H4), 3.36−3.26 (2H, m, H1′, H6), 1.50 (3H, s, C2-CH3), 1.32 (3H, s, C2-CH3), 1.21 (3H, d, J = 7.0 Hz, H″); 13C NMR (CDCl3, 125 MHz) δ 138.4 (ArC), 137.5 (ArC), 128.6 (ArCH), 128.4 (ArCH), 128.1 (ArCH), 127.9 (ArCH), 127.59 (ArCH), 127.56 (ArCH), 112.7 (C2), 87.3 (C3a), 83.4 (C7), 79.0 (C8b), 73.3 (OCH2Ph), 72.8 (C8a), 72.7 (C1′), 72.3 (OCH2Ph), 69.2 (C8), 62.0 (C4), 60.1 (C6), 27.8 (C2-CH3), 25.7 (C2-CH3), 14.9 (C1″); HREIMS m/z 440.2446 [M + H+] (calcd for C26H34NO5, 440.2437). (1S,2R,3R,5R,6R,7S,7aR)-6-Benzyloxy-5-[(benzyloxy)methyl]-3methylhexahydro-1H-pyrrolizine-1,2,7-triol (22). Compound 22 was synthesized from alcohol 21 (40 mg, 0.0911 mmol) using the general method for hydrolysis of an acetonide. The product was purified by FCC (8:92 MeOH/CH2Cl2) to give the target product as a brown oil (20 mg, 55%): Rf 0.30 (5:95 MeOH/CH2Cl2); [α]25 D +68 (c 0.9, CHCl3); IR νmax 3387, 3100, 2878, 1657, 1520, 1467, 1075, 696 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.39−7.21 (10H, m, ArH), 4.54−4.45 (4H, m, OCH2Ph), 4.39 (1H, t, J = 5.1 Hz, H7), 4.13 (1H, t, J = 3.9 Hz, H1), 3.88 (1H, dd, J = 7.9, 3.8 Hz, H2), 3.80 (1H, t, J = 4.4 Hz, H6), 3.53−3.43 (3H, m, H8, H7a), 3.40−3.30 (2H, m, H5, H3), 1.10 (3H, d, J = 7.0 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 138.3 (ArC), 137.3 (ArC), 128.6 (ArCH), 128.4 (ArCH), 128.2

(ArCH), 128.0 (ArCH), 127.6 (ArCH), 127.5 (ArCH), 83.5 (C2), 79.0 (C6), 73.3 (OCH2Ph), 72.7 (OCH2Ph), 71.9 (C8), 71.5 (C7a), 69.1 (C7), 67.5 (C1), 60.7 (C5), 58.8 (C3), 14.3 (C9); HREIMS m/ z 400.2127 [M + H+] (calcd for C23H30NO5, 400.2124). (1S,2R,3R,5R,6R,7S,7aR)-3-Hydroxymethyl-5-methylhexahydro1H-pyrrolizine-1,2,6,7-tetraol [(+)-6,7-di-epi-hyacinthacine C1] (23). Compound 23 was synthesized by the general method for Obenzyl deprotection from 22 (18 mg, 0.0451 mmol). The crude product was filtered through a pad of Celite and washed with additional MeOH (6 mL). The combined filtrates were concentrated in vacuo, returning a yellow film. The compound was isolated through basic ion-exchange chromatography followed by concentration in vacuo, providing the title compound as a colorless film (6 mg, 61%): [α]25 D +13 (c 0.2, H2O); IR νmax 3302, 2967, 1620, 1578, 1439, 1190, 1056, 687 cm−1; 1H NMR (D2O, 500 MHz) δ 4.33 (1H, t, J = 4.7 Hz, H7), 4.17 (1H, t, J = 4.3 Hz, H1), 3.99 (1H, dd, J = 8.1, 4.1 Hz, H2), 3.86 (1H, t, J = 5.4 Hz, H6), 3.66−3.57 (2H, m, H8), 3.40 (1H, t, J = 4.6 Hz, H7a), 3.21 (1H, quint, J = 6.7 Hz, H5), 3.14 (1H, dt, J = 8.0, 4.9 Hz, H3), 1.17 (3H, d, J = 7.0 Hz, H9); 13C NMR (D2O, 125 MHz) δ 77.5 (C6), 74.8 (C2), 70.2 (C6), 69.7 (C1), 69.1 (C7), 62.7 (C8), 60.9 (C3), 59.0 (C5), 13.2 (C9); HREIMS m/z 220.1197 [M + H+] (calcd for C9H17NO5, 220.1185). (3aR,4R,6R,7R,8S,8aS,8bS)-7,8-Bisbenzyloxy-6-[(benzyloxy)methyl]-2,2,4-trimethylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine (24). Compound 24 was synthesized from 21 (62 mg, 0.141 mmol) by the general method for O-benzylation. The product was purified by FCC (1:4 EtOAc/hexanes) to give the target compound as a yellow oil (39 mg, 52%): Rf 0.30 (2:3 EtOAc/ hexanes); [α]25 D −13 (c 0.4, CHCl3); IR νmax 2978, 1612, 1514, 1254, 1042, 678 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.39−7.20 (15H, m, ArH), 5.10 (1H, dd, J = 6.6, 3.0 Hz, H8b), 4.64−4.60 (3H, m, OCH2Ph), 4.56 (1H, d, J = 12.1 Hz, OCH2Ph), 4.47 (2H, s, OCH2Ph), 4.21 (1H, t, J = 6.8 Hz, H3a), 4.13 (1H, dd, J = 6.3, 4.3 Hz, H8), 3.84 (1H, dd, J = 4.4, 2.2 Hz, H7), 3.71 (1H, dd, J = 6.5, 3.0 Hz, H8a), 3.37−3.23 (3H, m, H6, H4, H1′), 3.12 (1H, dd, J = 9.5, 7.6 Hz, H1′), 1.49 (3H, s, C2-CH3), 1.31 (3H, s, C2-CH3), 1.23 (3H, d, J = 7.0 Hz, H1″); 13C NMR (CDCl3, 125 MHz) δ 138.4 (ArC), 138.3 (ArC), 138.2 (ArC), 128.4 (ArCH), 128.36 (ArCH), 128.35 (ArCH), 127.71 (ArCH), 127.65 (ArCH), 127.6 (ArCH), 113.5 (C2), 86.1 (C3a), 81.0 (C8b), 80.5 (C7), 77.4 (C8), 73.2 (OCH2Ph), 73.1 (C1′), 72.4 (OCH2Ph), 71.8 (OCH2Ph), 71.1 (C8a), 63.2 (C6), 61.2 (C4), 27.8 (C2-CH3), 25.7 (C2-CH3), 14.2 (C1″); HREIMS m/z 530.2925 [M + H+] (calcd for C33H40NO5, 530.2906). (1S,2R,3R,5R,6R,7S,7aR)-6,7-Bisbenzyloxy-5-[(benzyloxy)methyl]3-methylhexahydro-1H-pyrrolizine-1,2-diol (25). Compound 25 was synthesized from 24 (38 mg, 0.0717 mmol) using the general method for hydrolysis of an acetonide. The product was purified by FCC (5:95 MeOH/CH2Cl2) to give the target product as a brown oil (30 mg, 85%): Rf 0.15 (5:95 MeOH/CH2Cl2); [α]25 D +18 (c 1.5, CHCl3); IR νmax 3327, 3099, 2912, 2843, 1589, 1075, 678 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.41−7.20 (15H, m, ArH), 4.74 (1H, d, J = 11.6 Hz, OCH2Ph), 4.63 (1H, d, J = 11.7 Hz, OCH2Ph), 4.59−4.39 (5H, m, OCH2Ph, H7), 4.10 (1H, t, J = 4.2 Hz, H1), 3.94−3.86 (1H, m, H2), 3.83 (1H, t, J = 4.8 Hz, H6), 3.68 (1H, t, J = 5.1 Hz, H7a), 3.60−3.40 (4H, m, H5, H3, H8), 1.96 (1H, s, OH), 1.16 (3H, d, J = 6.9 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 138.1 (ArC), 138.0 (ArC), 137.6 (ArC), 128.45 (ArCH), 128.35 (ArCH), 127.9 (ArCH), 127.8 (ArCH), 127.60 (ArCH), 127.58 (ArCH), 82.0 (C2), 78.1 (C6), 75.0 (C1), 73.4 (OCH2Ph), 73.3 (OCH2Ph), 72.6 (OCH2Ph), 71.3 (C7a), 71.1 (C8), 69.7 (C7), 61.8 (C5), 59.6 (C3), 14.1 (C9); HREIMS m/z 490.2612 [M + H+] (calcd for C30H36NO5, 490.2593). (3aR,4R,6R,7R,8S,8aS,8bS)-7,8-Bisbenzyloxy-6-[(benzyloxy)methyl]-4-methylhexahydro-4H-[1,3,2]dioxathiolo[4,5-a]pyrrolizine 2,2-dioxide (26). To a solution of the diol 25 (25 mg, 0.0511 mmol) in anhydrous CH2Cl2 (5 mL) under a nitrogen atmosphere was added at 0 °C Et3N (18 μL, 0.128 mmol), then SOCl2 (1.0 M solution in CH2Cl2, 0.0766 μL, 0.0766 mmol) dropwise. After stirring at 0 °C for 1 h, TLC analysis confirmed the consumption of starting material. The reaction was quenched with H2O (10 mL), and the mixture was extracted with CH2Cl2 (3 × 15 H



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mL). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 26 as a brown oil (28 mg), which was used for the next step without further purification. LRESIMS m/z 586 (100%) [M + Cl−]. (1S,2S,3R,5R,6R,7S,7aR)-6,7-Bisbenzyloxy-5-[(benzyloxy)methyl]1-hydroxy-3-methylhexahydro-1H-pyrrolizin-2-yl benzoate (27). To a solution of sulfate 26 (28 mg, 0.0511 mmol) in dry DMSO (1 mL) was added benzoic acid (31 mg, 0.256 mmol) and Cs2CO3 (83 mg, 0.256 mmol). The mixture was stirred under a nitrogen atmosphere at 50 °C for 20 h. After LRESIMS confirmed the consumption of starting material, a mixture of THF (2 mL), distilled H2O (0.75 mL), and concentrated H2SO4 (0.25 mL) was added to the reaction and stirred at 60 °C for 20 h. The reaction mixture was neutralized with saturated NaHCO3 to pH 7, followed by extraction with CH2Cl2 (3 × 15 mL). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a brown oil. Purification by FCC (3:2 EtOAc/hexanes) gave 27 (13 mg, 42%): Rf 0.25 (3:2 EtOAc/hexane); [α]25 D +9 (c 0.7, CHCl3); IR νmax 3380, 3093, 1710, 1576, 1104, 1011, 608 cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.00 (2H, d, J = 7.7 Hz, o-Bz), 7.54 (1H, t, J = 7.2, 6.8 Hz, pBz), 7.39 (2H, t, J = 7.8 Hz, m-Bz), 7.36−7.17 (15H, m, ArH), 5.30 (1H, t, J = 5.8 Hz, H6), 4.77 (1H, dd, J = 6.9, 5.5 Hz, H7), 4.71 (1H, d, J = 12.0 Hz, OCH2Ph), 4.67 (1H, d, J = 12.0 Hz, OCH2Ph), 4.57− 4.47 (3H, m, OCH2Ph), 4.42 (1H, d, J = 12.0 Hz, OCH2Ph), 4.13 (1H, t, J = 4.5 Hz, H1), 3.93−3.86 (2H, m, H5, H2), 3.69 (1H, q, J = 5.7 Hz, H3), 3.59 (1H, t, J = 5.9 Hz, H7a), 3.44 (2H, d, J = 5.3 Hz, H8), 1.25 (3H, d, J = 8.8 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 167.2 (CO), 138.4 (ArC), 138.3 (ArC), 137.9 (ArC), 133.2 (ArCH), 129.8 (ArCH), 128.40 (ArCH), 128.37 (ArCH), 128.33 (ArCH), 128.26 (ArCH), 127.7 (ArCH), 127.63 (ArCH), 127.58 (ArCH), 127.5 (ArCH), 84.6 (C6), 81.8 (C2), 75.4 (C1), 74.3 (C7), 73.4 (OCH2Ph), 72.9 (OCH2Ph), 72.3 (OCH2Ph), 72.2 (C8), 70.8 (C7a), 60.3 (C3), 57.2 (C5), 11.8 (C9); HREIMS m/z 594.2843 [M + H+] (calcd for C37H40NO6, 594.2856). (1S,2S,3R,5R,6R,7S,7aR)-6,7-Bisbenzyloxy-5-[(benzyloxy)methyl]3-methylhexahydro-1H-pyrrolizine-1,2-diol (28). To a solution of 27 (10 mg, 0.0168 mmol) in MeOH (5 mL) was added solid K2CO3 (4 mg, 0.0253 mmol). After stirring at 40 °C for 2 h, all volatiles were evaporated and the residue was dissolved in EtOAc. The solution was washed with H2O (3 × 5 mL) and brine (5 mL), then dried (MgSO4), filtered, and concentrated in vacuo to give a brown oil. The crude product was then purified by FCC (5:95 MeOH/CH2Cl2) to give 28 as a brown film (7 mg, 87%): Rf 0.20 (5:95 MeOH/CH2Cl2); [α]25 D +30 (c 0.4, CHCl3); IR νmax 3362, 3101, 2967, 1542, 1489 1027, 872, 696 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.39−7.22 (15H, m, ArH), 4.83 (1H, d, J = 11.2 Hz, OCH2Ph), 4.68−4.51 (5H, m, OCH2Ph), 4.40 (1H, t, J = 2.2 Hz, H7), 4.22 (1H, t, J = 4.5 Hz, H1), 4.12 (1H, dd, J = 8.2, 3.7 Hz, H2), 4.09−4.01 (1H, m, H7a), 4.01− 3.92 (2H, m, H5, H6), 3.76 (1H, dt, J = 8.5, 4.5 Hz, H3), 3.67 (1H, dd, J = 10.4, 5.0 Hz, H8), 3.61 (1H, dd, J = 10.4, 3.9 Hz, H8), 1.31 (3H, d, J = 6.7 Hz, H9); 13C NMR (CDCl3, 125 MHz) δ 137.8 (ArC), 136.9 (ArC), 136.6 (ArC), 128.8 (ArCH), 128.6 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 128.34 (ArCH), 128.30 (ArCH), 128.1 (ArCH), 127.9 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 81.1 (C6), 80.9 (C2), 75.8 (C1), 75.4 (C7), 74.3 (OCH2Ph), 73.7 (OCH2Ph), 73.5 (OCH2Ph), 73.3 (C7a), 68.7 (C8), 61.0 (C5), 60.6 (C3), 10.2 (C9); HREIMS m/z 490.2597 [M + H+] (calcd for C30H36NO5, 490.2593). (1S,2R,3R,5R,6S,7S,7aR)-3-Hydroxymethyl-5-methylhexahydro1H-pyrrolizine-1,2,6,7-tetraol [(+)-7-epi-hyacinthacine C1] (29). Compound 29 was synthesized by the general method of O-benzyl deprotection from 28 (6 mg, 0.0123 mmol). The crude product was filtered through a pad of Celite and washed with additional MeOH (6 mL). The combined filtrates were concentrated in vacuo, affording a yellow film. The title compound was isolated through basic ionexchange chromatography followed by concentration in vacuo, as a colorless film (2 mg, 75%): [α]25 D +7 (c 0.1, H2O); IR νmax 3303, 2981, 1702, 1570, 1412, 1087, 1078, 656 cm−1; 1H NMR (D2O, 500 MHz) δ 4.29 (1H, d, J = 5.8 Hz, H7), 4.15 (1H, t, J = 3.9 Hz, H1), 4.11 (1H, dd, J = 7.4, 6.0 Hz, H6), 3.97 (1H, dd, J = 9.1, 3.9 Hz, H2), 3.74 (1H,

dd, J = 11.6, 4.3 Hz, H8), 3.61 (1H, dd, J = 11.7, 6.4 Hz, H8), 3.46 (1H, quint, J = 6.8 Hz, H5), 3.33−3.26 (2H, m, H7a, H3), 1.12 (3H, d, J = 7.0 Hz, H9); 13C NMR (D2O, 125 MHz) δ 78.4 (C6), 74.9 (C2), 71.4 (C7), 69.3 (C1), 68.8 (C7a), 63.0 (C8), 60.6 (C3), 57.0 (C5), 10.3 (C9); HREIMS m/z 220.1181 [M + H+] (calcd for C9H17NO5, 220.1185).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00879.

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NMR spectra (1H, 13C, gCOSY, gHSQC, NOESY, and ROESY) and ORTEP single-crystal X-ray crystallographic data (PDF) X-ray crystallographic data (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: + 61 2 42213511. ORCID

Stephen G. Pyne: 0000-0003-0462-0277 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Australia Research Council and the University of Wollongong for financial support. We also thank the Australian Government for an Australian Postgraduate Award scholarship for A.W.C. We also thank Dr. H. Yu for his assistance with molecular modeling. We also wish to acknowledge that this research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government. This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japanese Society for the Promotion of Science (JSPS KAKENHI Grant Number JP17K08362) (AK).

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REFERENCES

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Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis

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