Double asymmetric induction in organocatalyzed aldol reactions: Total synthesis of (+)-2-epi-hyacinthacine A2 and (-)-3-epi-hyacinthacine A1

Article abstract of DOI:10.1002/ejoc.201300716

The stereodivergent synthesis of two hyacinthacine analogues, which relies on an organocatalyzed aldol addition, is described. The aldol addition of dioxanone to an α-N-carbobenzyloxy-substituted chiral aldehyde, promoted by both (R)- and (S)-proline, pro

Full text of DOI:10.1002/ejoc.201300716

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300716
Double Asymmetric Induction in Organocatalyzed Aldol Reactions: Total
Synthesis of (+)-2-epi-Hyacinthacine A2 and (–)-3-epi-Hyacinthacine A1
Jasna Marjanovic,[a] Vladimir Divjakovic,[b] Radomir Matovic,[c] Zorana Ferjancic,*[a] and
Radomir N. Saicic*[a]
Keywords: Asymmetric synthesis / Azasugars / Natural products / Organocatalysis / Aldol reactions
The stereodivergent synthesis of two hyacinthacine ana-
logues, which relies on an organocatalyzed aldol addition, is
described. The aldol addition of dioxanone to an α-N-carbo-
benzyloxy-substituted chiral aldehyde, promoted by both
ceptable diastereomeric ratios. The success of the reaction
may be due to the use of an acyclic aldehyde acceptor, which
allows reagent control of the stereochemical outcome of the
key aldolization step in both the matched and mismatched
(R)- and (S)-proline, proceeds in reasonable yields with ac- cases.
ues.[7] Proline-catalyzed aldolization reactions of dioxanone
Introduction
were also applied in the synthesis of azasugars by using α-
azidoaldehydes as acceptors. In all of the reported exam-
ples, matched cases afforded the desired products in high
yields with high selectivities. However, only one mismatched
combination produced the aldol product in reasonable yield
with acceptable (5:1) diastereoselectivity, whereas the other
mismatched reactions were sluggish.[8] These results were
also rationalized by calculations.[9]
Reactions of chiral reagents with chiral substrates create
the phenomenon of double asymmetric synthesis,[1] in
which the stereochemical preferences of the substrate and
the reagent can mutually reinforce (matched selectivity) or
weaken (mismatched selectivity) each other. In principle, it
is desirable that the stereochemical outcome of such reac-
tions is determined by the reagent, for reasons of predict-
ability and generality. The aldol reaction is among the most
important methods for the formation of carbon–carbon
bonds,[2] and powerful reagents have been developed that
allow the stereochemical outcome of the reaction to be con-
trolled even in cases of mismatched selectivity with stereo-
chemically highly biased substrates.[3] However, in the
rapidly developing field of organocatalysis,[4] the phenome-
non of double asymmetric synthesis has not been systemati-
cally investigated. Examples are known in which chiral al-
dehydes are used as acceptors in aldolization reactions pro-
moted by chiral organocatalysts.[5] Thus, the (S)-proline-
catalyzed aldol addition of dioxanone to (S)-configured α-
branched aldehydes offers efficient entry to a range of
carbohydrate derivatives; however, in mismatched cases, the
(R)-proline-catalyzed reaction afforded aldol products with
yields lower than 40%.[6] In another study, both combina-
tions gave the desired products in good yields with high
diastereomeric excess (de) and enantiomeric excess (ee) val-
Results and Discussion
We set out to further investigate stereodivergent routes
to azasugars on the basis of organocatalysis. Our synthetic
targets were analogues of hyacinthacine, which are a class
of azasugars that has attracted considerable attention from
the chemical community as a result of their strong inhibi-
tory activity exerted upon enzymes involved in carbo-
hydrate processing.[10] The synthetic challenge of these com-
pounds is the installation of four contiguous stereocenters
into a bicyclic core.[11–14] According to our retrosynthetic
analysis, represented in Scheme 1, the stereogenic center at
C-3 should be introduced in the reductive amination step,
C-1 and C-2 should be created in the aldol reaction,
whereas C-7a should be imported from the chiral precursor,
glutamic acid.
Carbobenzyloxy (Cbz)-protected aldehyde 1 was pre-
pared according to the procedure previously described for
the N-tert-butoxycarbonyl (Boc) analogue.[15] The (S)-pro-
line-catalyzed aldol addition of dioxanone to aldehyde 1
produced aldol adduct 2 as the major product, along with
a minor amount of diastereoisomeric aldol 7 (70%; dia-
stereoisomeric ratio (dr) = 6:1 for 2/7 and the diastereo-
isomers were separable by column chromatography;
Scheme 2). Interestingly, a peak corresponding to a carb-
[a] Faculty of Chemistry, University of Belgrade,
Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
E-mail: rsaicic@chem.bg.ac.rs
Homepage: http://www.chem.bg.ac.rs
[b] Faculty of Sciences, University of Novi Sad,
Trg Dositeja Obradovica 3, 21000 Novi Sad, Serbia
[c] IHTM Center for Chemistry,
Njegoseva 12, 11000 Belgrade, Serbia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300716.
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Z. Ferjancic, R. N. Saicic et al.
SHORT COMMUNICATION
Figure 1. Aldol 2 in its hemiaminal form.
Scheme 1. Retrosynthetic analysis of hyacinthacines on the basis of
organocatalyzed aldol addition.
Next, we started a synthetic sequence leading to ent-3-
epi-hyacinthacine A1 (Scheme 3). The reaction of diox-
anone with aldehyde 1 catalyzed by (R)-proline afforded
aldol adduct 7 in 77% yield with 10:1dr; the higher yield
and stereoselectivity indicate that this is the matched case.
Major aldol product 7 did not tautomerize into the hemi-
aminal form. Reductive amination with aldol 7 proceeded
as before to afford pyrrolidine derivative 8 in 63% yield;
however, this latter compound was reluctant to undergo
lactamization and instead underwent ester hydrolysis.
Attempts to facilitate lactamization by inverting the order
of events, that is, by effecting the deprotection first, were
not fruitful, as compound 9 underwent lactonization to 10
preferentially to lactamization. Protection of the C-1 hy-
droxy group in 8 with tert-butyldimethylsilyl triflate
(TBDMSOTf) brought about spontaneous lactamization
onyl group (in the major diastereoisomer) could not be ob-
served in 13C NMR spectrum, whereas a peak at δ =
86.6 ppm was present; this indicated that the product as-
sumed the cyclic, hemiaminal form, as confirmed by single-
crystal X-ray diffraction analysis (Figure 1).[16] Reductive
dehydroxylation of 2 proceeded without event and afforded
desired pyrrolidine derivative 3 as a single isomer in 77%
yield. Upon exposure to ethanolic potassium carbonate, 3
was converted into tricyclic lactam 4 (92%), and its stereo-
chemical integrity was confirmed by X-ray analysis (for the
crystal structure of 4, see the Supporting Information). Re-
duction of lactam 4 with lithium aluminum hydride (85%)
followed by acidic deprotection (98%) gave desired ent-2-
epi-hyacinthacine A2 (6), and its spectral and physical data
were consistent with those previously reported {[α]D20
=
+32.0 (c = 0.65, MeOH), ref.[14b] [α]D20 = +32.0 (c = 0.2,
MeOH); m.p. 165–167 °C, corrected;[17] ref.[14b] m.p. 169–
171 °C}.
Scheme 2. Synthesis of ent-2-epi-hyacinthacine A2 (6).
Scheme 3. Synthesis of ent-3-epi-hyacinthacine A1 (14).
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Double Asymmetric Induction in Organocatalyzed Aldol Reactions
product by dry-flash chromatography (SiO2; petroleum ether/ethyl
acetate, 6:4) afforded title aminal 2 (575.0 mg, 59%) followed by
diastereoisomeric aldol 7 (97.4 mg, 10%). Data for 2: White crys-
(75%); to the best of our knowledge, silyl triflate promoted
cyclization of amino esters is without literature precedent.
The absolute configuration of lactam 12 was confirmed by
X-ray analysis (for the crystal structure of 12, see the Sup-
porting Information). Reduction of lactam 12 with lithium
aluminum hydride gave tricyclic amino alcohol 13, which
upon treatment with aqueous HCl was converted into the
target molecule, ent-3-epi-hyacinthacine A1 (14), as con-
firmed by its spectroscopic data, which are fully consistent
1
tals, m.p. 99–101 °C. H NMR (500 MHz, [D6]DMSO, 65 °C): δ =
7.41–7.29 (m, 5 H), 5.85 (s, 1 H), 5.10 (dd, J = 12.5, 8.0 Hz, 2 H),
4.61 (br. d, J = 7.5 Hz, 1 H), 4.35–4.15 (m, 1 H), 4.11–4.04 (m, 1
H), 4.05 (q, J = 7.0 Hz, 2 H), 3.78 (d, J = 4.5 Hz, 1 H), 3.76 (d, J
= 12.0 Hz, 1 H), 3.63 (td, J = 7.7, 2.7 Hz, 1 H), 2.37–2.22 (m, 2
H), 2.20–2.09 (m, 1 H), 2.04–1.96 (m, 1 H), 1.38 (s, 3 H), 1.27 (s,
3 H), 1.18 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz, [D6]-
with the previously described data. However, there is a dis- DMSO, 65 °C): δ = 172.4 (C), 153.3 (C), 136.4 (C), 127.9 (CH),
127.4 (CH), 127.4 (CH), 98.4 (C), 86.6 (C), 75.5 (CH2), 71.0 (CH),
65.7 (CH2), 64.9 (CH), 61.6 (CH), 59.3 (CH2), 28.7 (CH2), 26.1
crepancy between the literature values for the optical rota-
tion of 14; our results are more consistent with those given
in ref.[12a] {[α]D20 = –6.8 (c = 0.32, H2O), ref.[12a,18] [α]D20
=
(CH ), 25.9 (CH ), 20.9 (CH ), 13.7 (CH ) ppm. IR (ATR): ν =
˜
2
3
3
3
3435, 2928, 1730, 1702, 1453, 1413, 1378, 1337, 1220, 1078 cm–1.
HRMS (ESI): calcd. for C21H29NO8 [M + Na]+ 446.1785; found
446.1783. C21H29NO8 (423.46): calcd. C 59.56, H 6.90, N 3.31;
found C 59.35, H 6.96, N 3.19. [α]2D0 = +5.4 (c = 1.00, CHCl3).
+3.4 (c = 0.32, H2O), ref.[13g] [α]2D0 = –1.0 (c = 0.6, MeOH)}.
Conclusions
Reductive Dehydroxylation of 2 to Afford Ethyl 3-[(4aS,6S,7S,7aR)-
7-Hydroxy-2,2-dimethylhexahydro[1,3]dioxino[5,4-b]pyrrol-6-yl]-
propanoate (3): A mixture of aldol 2 (240.0 mg, 0.57 mmol) and
Pd/C (10%, 75.0 mg, 0.07 mmol) in ethanol (48.0 mL) was stirred
overnight under a hydrogen atmosphere (5 atm). The mixture was
filtered and concentrated under reduced pressure. Purification of
the residue by dry-flash chromatography (SiO2; dichloromethane/
methanol, 8:2) afforded 3 (119.3 mg, 77%) as a colorless viscous
To summarize, the stereodivergent synthesis of two epi-
hyacinthacine analogues was achieved on the basis of aldol-
ization reactions of dioxanone with a chiral aldehyde cata-
lyzed by both enantiomers of proline. Both matched and
mismatched combinations of reagents gave good results in
terms of yield and stereoselectivity. Thus, it appears that in
organocatalyzed double asymmetric aldol addition reac-
tions, the use of acyclic aldehyde acceptors offers better
chances for reagent control to be achieved.[19]
1
oil. H NMR (500 MHz, CDCl3): δ = 4.17 (br. t, J = 4.0 Hz, 1 H),
4.12 (q, J = 7.1 Hz, 2 H), 4.00 (dd, J = 12.4, 4.2 Hz, 1 H), 3.76
(dd, J = 8.0, 4.4 Hz, 1 H), 3.64 (dd, J = 12.4, 3.7 Hz, 1 H), 3.16–
3.09 (m, 2 H), 2.73 (br. s, 2 H), 2.47 (ddd, J = 8.1, 6.8, 5.4 Hz, 2
H), 2.03–1.96 (m, 1 H), 1.79–1.72 (m, 1 H), 1.43 (s, 3 H), 1.39 (s,
3 H), 1.24 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 173.6 (C), 98.3 (C), 79.9 (CH), 70.9 (CH), 62.3 (CH), 60.8
(CH2), 60.3 (CH2), 52.9 (CH), 31.6 (CH2), 29.6 (CH2), 28.1 (CH3),
Experimental Section
General: All chromatographic separations were performed on silica
gel, 10–18, 60 Å (dry-flash), 100–200 60 Å (column chromatog-
raphy), ICN Biomedicals, and ion-exchange column chromatog-
raphy (acidic resin DOWEX 50WX8-100). Standard techniques
were used for the purification of the reagents and solvents. Petro-
leum ether (PE) refers to the fraction boiling at 70–72 °C. NMR
spectra were recorded with a Bruker Avance III 500 (1H NMR at
500 MHz, 13C NMR at 125 MHz). Chemical shifts are expressed
in ppm (δ) using tetramethylsilane as the internal standard. IR
spectra were recorded with a Nicolet 6700 FT instrument. Mass
spectra were obtained with an Agilent Technologies 6210 TOF LC–
MS instrument (LC: series 1200) and LTQ Orbitrap XL hybrid
FTMS (Thermo Scientific). Microanalyses were performed by
using a Vario EL III instrument CHNOS Elementar Analyzer, Ele-
mentar Analysensysteme GmbH, Hanau, Germany. Melting points
were determined with a Kofler hot-stage and Electrothermal appa-
ratus and are uncorrected, unless otherwise stated. Optical rotation
was determined with a Rudolph Research Analytical AUTOPOL
IV Automatic Polarimeter. Diffraction data were collected with an
Oxford Diffraction KM4 four-circle goniometer equipped with a
Sapphire CCD detector.
20.1 (CH ), 14.2 (CH ) ppm. IR (film): ν 3333, 2987, 2934, 1731,
˜
3
3
1446, 1377, 1343, 1271, 1226, 1197, 1168, 1136, 1059, 949 cm–1.
HRMS (ESI): calcd. for C13H23NO5 [M + H]+ 274.1649; found
274.1645. [α]2D0 = –39.3 (c = 1.03, CHCl3).
(4aS,8aS,9S,9aR)-9-Hydroxy-2,2-dimethylhexahydro[1,3]dioxino-
[4,5-b]pyrrolizin-6(7H)-one (4): A mixture of amine 3 (108.8 mg,
0.40 mmol), K2CO3 (249.0 mg, 1.80 mmol), and ethanol (4.5 mL)
was stirred overnight at room temperature. The solvent was re-
moved under reduced pressure, and the crude product was purified
by dry-flash chromatography (SiO2; dichloromethane/methanol,
95:5) to give 4 (83.4 mg, 92%) as white crystals, m.p. 116–117 °C.
1H NMR (500 MHz, CDCl3): δ = 4.45 (t, J = 4.2 Hz, 1 H), 4.09–
4.03 (m, 2 H), 3.88–3.83 (m, 2 H), 3.71–3.65 (m, 1 H), 2.78–2.70
(m, 1 H), 2.56 (br. d, J = 11.1 Hz, 1 H), 2.46–2.38 (m, 2 H), 1.99–
1.90 (m, 1 H), 1.46 (s, 3 H), 1.42 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 176.5 (C), 98.7 (C), 78.0 (CH), 72.1 (CH),
64.3 (CH), 60.3 (CH2), 50.8 (CH), 34.0 (CH2), 27.3 (CH3), 24.7
(CH ), 20.7 (CH ) ppm. IR (ATR): ν = 3411, 2990, 2939, 2889,
˜
2
3
1677, 1457, 1403, 1381, 1334, 1278, 1238, 1202, 1170, 1141, 1108,
1080, 1046, 960, 903 cm–1. HRMS (ESI): calcd. for C11H17NO4
[2M + H]+ 455.2388; found 455.2376. C11H17NO4 (227.26): calcd.
Aldol Addition Catalyzed by (S)-Proline to Afford (4aR,6S,7S,7aS)-
Benzyl 6-(3-Ethoxy-3-oxopropyl)-4a,7-dihydroxy-2,2-dimethyltetra-
hydro[1,3]dioxino[5,4-b]pyrrole-5(6H)-carboxylate (2): A solution of
C 58.14, H 7.54, N 6.16; found C 57.77, H 7.46, N 5.89. [α]2D0
+105.7 (c = 1.53, CHCl3).
=
dioxanone (436.0 mg, 3.35 mmol), aldehyde
1
(674.6 mg,
2.30 mmol), and (S)-proline (49.6 mg, 0.43 mmol) in DMF was
stirred overnight at room temperature. The reaction mixture was
diluted with water and extracted with EtOAc. The combined or-
ganic extract was washed with water, dried with anhydrous MgSO4,
and concentrated under reduced pressure. Purification of the crude
(4aS,8aS,9S,9aR)-2,2-Dimethyloctahydro[1,3]dioxino[4,5-b]pyrroliz-
in-9-ol (5): To a solution of amide 4 (83.0 mg, 0.40 mmol) in freshly
distilled, cold (0 °C) THF (10.0 mL) was added lithium aluminum
hydride (40.0 mg, 0.90 mmol) in portions over 5 min. The reaction
mixture was stirred for 5 min at 0 °C and then heated at 70 °C for
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Z. Ferjancic, R. N. Saicic et al.
SHORT COMMUNICATION
1 h. The reaction mixture was then cooled (0 °C) and quenched by
the subsequent addition of water (80 μL), 10% aq. NaOH (80 μL),
and water (240 μL). The resulting mixture was filtered, and the
precipitate was washed with EtOAc. The combined organic extract
was dried with anhydrous MgSO4 and concentrated under reduced
pressure. Purification of the residue by dry-flash chromatography
(SiO2; dichloromethane/methanol, 8:2) afforded 5 (66.3 mg, 85%)
Reductive Amination of 7 to Afford Ethyl 3-[(4aR,6S,7R,7aS)-7-
Hydroxy-2,2-dimethylhexahydro[1,3]dioxino[5,4-b]pyrrol-6-yl]prop-
anoate (8): A mixture of aldol 7 (240.0 mg, 0.57 mmol) and Pd/C
(10%, 82.0 mg, 0.08 mmol) in ethanol (46.0 mL) was stirred over-
night under a hydrogen atmosphere (5 atm). The mixture was fil-
tered and concentrated under reduced pressure. Purification of the
residue by dry-flash chromatography (SiO2; dichloromethane/meth-
anol, 8:2) afforded 8 (97.6 mg, 63%) as a yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 4.33–4.28 (m, 2 H), 4.18–4.10 (m, 3 H),
3.81 (dd, J = 12.5, 3.5 Hz, 1 H), 3.72–3.45 (m, 2 H), 3.17 (dt, J =
8.6, 6.1 Hz, 1 H), 3.03 (dd, J = 7.3, 3.8, Hz, 1 H), 2.60–2.48 (m, 2
1
as a colorless viscous oil. H NMR (500 MHz, CD3OD): δ = 4.32
(t, J = 3.5 Hz, 1 H), 4.06 (dd, J = 12.6, 2.6 Hz, 1 H), 3.74–3.68 (m,
2 H), 3.48 (td, J = 8.5, 3.0 Hz, 1 H), 2.87 (dt, J = 11.0, 6.9 Hz, 1
H), 2.66–2.58 (m, 2 H), 1.99–1.89 (m, 1 H), 1.82–1.75 (m, 3 H),
1.46 (s, 3 H), 1.42 (s, 3 H) ppm. 13C NMR (126 MHz, CD3OD): δ H), 2.11–2.03 (m, 1 H), 1.93–1.85 (m, 1 H), 1.47 (s, 3 H), 1.43 (s,
= 99.1 (C), 79.8 (CH), 74.2 (CH), 69.7 (CH), 62.7 (CH2), 62.3 3 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
(CH), 55.3 (CH2), 31.3 (CH2), 29.6 (CH3), 25.8 (CH2), 19.5 (CH3)
δ = 174.0 (C), 99.0 (C), 73.7 (CH), 70.6 (CH), 61.2 (CH), 60.6
ppm. IR (ATR): ν = 3071, 2994, 2946, 2912, 2872, 2830, 1582,
(CH2), 60.1 (CH2), 53.9 (CH), 31.9 (CH2), 28.2 (CH3), 24.7 (CH2),
˜
1452, 1376, 1331, 1272, 1231, 1199, 1175, 1141, 1087, 1025, 955,
869 cm–1. HRMS (ESI): calcd. for C11H19NO3 [M + H]+ 214.1438;
found 214.1428. [α]2D0 = +15.7 (c = 0.81, MeOH).
20.1 (CH ), 14.2 (CH ) ppm. IR (film): ν = 3502, 2988, 2937, 1732,
˜
3 3
1650, 1452, 1377, 1226, 1170, 1137, 1095, 1067, 946 cm–1. HRMS
(ESI): calcd. for C13H23NO5 [M + H]+ 274.1649; found 274.1635.
[α]2D0 = +10.9 (c = 1.16, CHCl3).
ent-2-epi-Hyacinthacine A2 (6): A solution of amine 5 (39.5 mg,
0.18 mmol) in methanol/3 m HCl (4.6 mL, v/v = 2:1) was stirred
and heated to reflux for 2 h. After the volatiles were removed under
reduced pressure, the residue was purified by ion-exchange column
chromatography (acidic resin DOWEX 50WX8–100) to give 6
(31.3 mg, 98%) as white crystals, which were recrystallized from 2-
propanol, m.p. 165–167 °C, corrected[17] (ref.[14b] m.p. 169–171 °C).
1H NMR (500 MHz, D2O): δ = 4.26 (t, J = 3.6 Hz, 1 H), 3.91 (dd,
J = 8.6, 4.0 Hz, 1 H), 3.85 (dd, J = 11.0, 7.7 Hz, 1 H), 3.67 (dd, J
= 11.0, 6.0 Hz, 1 H), 3.38 (td, J = 8.2, 3.7 Hz, 1 H), 2.94 (ddd, J
= 7.7, 6.0, 3.3 Hz, 1 H), 2.88–2.83 (m, 1 H), 2.74–2.68 (m, 1 H),
1.98–1.73 (m, 4 H) ppm. 13C NMR (126 MHz, D2O): δ = 79.7
(CH), 76.2 (CH), 71.6 (CH), 69.6 (CH), 62.9 (CH2), 57.0 (CH2),
(2R,3S,3aR,7aS)-3-Hydroxy-2-(hydroxymethyl)hexahydropyrano-
[3,2-b]pyrrol-5(6H)-one (10): A solution of amine 8 (29.5 mg,
0.11 mmol) in ethanol/1.5 m HCl (6.0 mL, v/v = 2:1) was stirred for
2 h at room temperature. The solvent and the volatiles were re-
moved under reduced pressure to give crude 9 (29.0 mg) as a pale
yellow viscous oil, which was used further without purification.
A mixture of crude 9 (29.0 mg, 0.12 mmol) and K2CO3 (64.0 mg,
0.46 mmol) in ethanol (1.2 mL) was heated to 66 °C for 2 h. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (SiO2; dichloromethane/meth-
anol, 8:2), to give 10 (14.4 mg, 71%) as white crystals, m.p. 148–
1
152 °C. H NMR (500 MHz, CD3OD): δ = 4.49 (d, J = 4.0 Hz, 1
H), 4.06 (dd, J = 11.5, 2.5 Hz, 1 H), 3.86 (ddd, J = 9.6, 6.5, 3.0 Hz,
1 H), 3.73 (br. t, J = 3.5 Hz, 1 H), 3.71–3.67 (m, 1 H), 3.59 (dd, J
= 11.6, 4.0 Hz, 1 H), 2.61–2.50 (m, 1 H), 2.31 (ddd, J = 16.5, 9.3,
0.9 Hz, 1 H), 2.14 (tt, J = 12.0, 9.5 Hz, 1 H), 1.92–1.83 (m, 1 H)
ppm. 13C NMR (126 MHz, CD3OD): δ = 177.0 (C), 76.7 (CH),
70.3 (CH), 65.3 (CH), 59.6 (CH), 57.9 (CH2), 35.6 (CH2), 21.1
31.9 (CH ), 27.2 (CH ) ppm. IR (ATR): ν = 3399, 2966, 2923,
˜
2
2
2872, 2709, 1739, 1573, 1460, 1361, 1320, 1260, 1205, 1159, 1123,
1085, 1048, 1011, 983, 916, 814 cm–1. HRMS (ESI): calcd. for
C8H15NO3 [M + H]+ 174.1125; found 174.1126. [α]2D0 = +32.0 (c =
0.65, MeOH) {ref.[14b] [α]2D0 = +32.0 (c = 0.20, MeOH)}.
(CH ) ppm. IR (ATR): ν = 3248, 2953, 2894, 1656, 1446, 1373,
˜
2
Aldol Addition Catalyzed by (R)-Proline to Afford (4S,5R)-Ethyl 4-
(Benzyloxycarbonylamino)-5-[(R)-2,2-dimethyl-5-oxo-1,3-dioxan-4-
yl]-5-hydroxypentanoate (7): A solution of dioxanone (0.8 g,
6.15 mmol), aldehyde 1 (1.1 g, 3.72 mmol), and (R)-proline
(82.0 mg, 0.71 mmol) in DMF (8.4 mL) was stirred overnight at
room temperature. The reaction mixture was diluted with water
and extracted with EtOAc. The combined organic extract was
washed with water, dried with anhydrous MgSO4, and concentrated
under reduced pressure. Purification of the crude product by dry-
flash chromatography (SiO2; petroleum ether/ethyl acetate, 6:4) af-
forded title aldol 7 (1.1 g, 70%) as a yellow oil followed by diaste-
reoisomeric aldol 2 (110.0 mg, 7 %). Data for 7: 1H NMR
(500 MHz, [D6]DMSO): δ = 7.40–7.27 (m, 5 H), 6.64 (d, J =
9.5 Hz, 1 H), 5.04 (d, J = 6.5 Hz, 1 H), 5.00 (dd, J = 23.5, 12.5 Hz,
1343, 1306, 1239, 1197, 1145, 1022, 981 cm–1. HRMS (ESI): calcd.
for C8H13NO4 [M + H]+ 188.0917; found 188.0913. [α]2D0 = +18.5
(c = 0.93, MeOH).
(4aR,8aS,9R,9aS)-9-(tert-Butyldimethylsilyloxy)-2,2-dimethylhexa-
hydro[1,3]dioxino[4,5-b]pyrrolizin-6(7H)-one (11): To a solution of
amine 8 (200.0 mg, 0.73 mmol) in cold (0 °C) dichloromethane
(1.2 mL) was added 2,6-lutidine (644.0 mg, 6.01 mmol) and
TBDMSOTf (805.0 mg, 3.04 mmol) under an argon atmosphere.
The reaction mixture was stirred for 30 min at room temperature,
then diluted with dichloromethane, washed with aqueous saturated
NaHCO3, dried with anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (SiO2; dichloromethane/methanol, 95:5), to give 11 (46.4 mg,
2 H) 4.27 (dd, J = 17.2, 1.1 Hz, 1 H), 4.17 (dd, J = 6.5, 1.0 Hz, 1 65 %) as white crystals, m.p. 70–72 °C. 1H NMR (500 MHz,
H), 4.05–3.99 (m, 3 H), 3.80–3.68 (m, 2 H), 2.26 (br. t, J = 7.7 Hz, CDCl3): δ = 4.47 (dd, J = 10.5, 5.2 Hz, 1 H), 4.33 (dd, J = 7.5,
2 H), 1.70 (dd, J = 14.8, 7.3 Hz, 2 H), 1.31 (s, 3 H), 1.26 (s, 3 H), 4.4 Hz, 1 H), 4.12 (dd, J = 4.3, 3.5 Hz, 1 H), 3.88 (t, J = 10.4 Hz,
1.16 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz, [D6]DMSO):
δ = 208.3 (C), 172.6 (C), 156.0 (C), 137.2 (C), 128.3 (CH), 127.7
(CH), 127.6 (CH), 100.5 (C), 74.5 (CH), 69.5 (CH), 66.4 (CH2),
1 H), 3.81 (td, J = 7.3, 3.3 Hz, 1 H), 3.67–3.59 (m, 1 H), 2.60–2.50
(m, 1 H), 2.45 (ddd, J = 16.8, 10.1, 3.0 Hz, 1 H), 2.24 (dtd, J =
12.5, 9.9, 7.2 Hz, 1 H), 1.93 (dddd, J = 12.5, 9.4, 7.6, 3.1 Hz, 1 H),
65.2 (CH2), 59.7 (CH2), 50.8 (CH), 30.4 (CH2), 27.1 (CH2), 23.9 1.38 (s, 3 H), 1.37 (s, 3 H), 0.92 (s, 9 H), 0.12 (s, 3 H), 0.08 (s, 3
(CH ), 22.9 (CH ), 14.1 (CH ) ppm. IR (film): ν = 3500, 3439,
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.8 (C), 99.4 (C),
74.4 (CH), 71.2 (CH), 63.6 (CH), 59.2 (CH2), 51.8 (CH), 34.4
(CH2), 27.6 (CH3), 25.8 (CH3), 24.9 (CH3), 18.8 (CH2), 18.4 (C),
˜
3
3
3
3377, 3089, 3064, 3034, 2986, 2939, 2904, 1730, 1713, 1519, 1451,
1417, 1380, 1332, 1257, 1179, 1092, 1044, 949, 863 cm–1. HRMS
(ESI): calcd. for C21H29NO8 [M + H]+ 424.1966; found 424.1961.
[α]2D0 = +87.0 (c = 1.27, CHCl3).
–4.3 (CH ), –5.2 (CH ) ppm. IR (film): ν = 3503, 2987, 2954, 2932,
˜
3
3
2891, 2857, 1688, 1466, 1418, 1375, 1297, 1253, 1219, 1140, 1051,
5558
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5555–5560

Double Asymmetric Induction in Organocatalyzed Aldol Reactions
1027, 1010, 972 cm–1. HRMS (ESI): calcd. for C17H31NO4Si [M +
H]+ 342.2095; found 342.2095. [α]2D0 = +25.1 (c = 0.71, CHCl3).
[1]
[2]
S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem.
1985, 97, 1–31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1–30.
a) R. Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH,
Weinheim, Germany, 2004, vols. 1 and 2; for review articles,
see: b) C. Heathcock, in: Comprehensive Organic Synthesis
(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, UK, 1991,
vol. 2, p. 133–179; c) C. Heathcock, in: Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford,
UK, 1991, vol. 2, p. 181–238; d) B. M. Kim, S. F. Williams, S.
Masamune, in: Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, UK, 1991, vol. 2, p.
239–275; for a review article on catalytic enantioselective aldol
reactions, see: e) E. M. Carreira, A. Fettes, C. Marti, Org. Re-
act. 2006, 67, 2–216.
For representative examples, see: a) D. A. Evans, J. Bartoli,
T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127–2129; b) D. A.
Evans, J. Bartoli, Tetrahedron Lett. 1982, 23, 807–810; c) S.
Masamune, M. Hirama, S. Mori, Sk. A. Ali, D. S. Garvey, J.
Am. Chem. Soc. 1981, 103, 1568–1571; d) for a tabular survey
of aldol reactions of boron enolates with double asymmetric
induction, see: C. J. Cowden, I. Paterson, Org. React. 1997, 51,
3–200.
Books on organocatalysis: a) P. I. Dalko, Enantioselective Or-
ganocatalysis: Reactions and Experimental Procedures, Wiley-
VCH, Weinheim, Germany, 2007; b) A. Berkessel, H. Gröger,
Asymmetric Organocatalysis – From Biomimetic Concepts to
Applications, in: Asymmetric Synthesis Wiley-VCH, Weinheim,
Germany, 2005; review articles: c) S. Bertelsen, K. A.
Jørgensen, Chem. Soc. Rev. 2009, 38, 2178–2189; d) D. W. C.
MacMillan, Nature 2008, 455, 304–308; e) A. Dondoni, A.
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Ed. 2008, 47, 4638–4660; f) H. Pellissier, Tetrahedron 2007, 63,
9267–9331; g) B. List, J. W. Yang, Science 2006, 313, 1584–
1586; h) J. Seagad, B. List, Org. Biomol. Chem. 2005, 3, 719–
724; i) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–
5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175; j) a thematic
issue of Chem. Rev. 2007, 107, No. 12 is dedicated to organoca-
talysis k) a thematic issue of Acc. Chem. Res. 2004, 37 (No. 8)
is dedicated to organocatalysis.
(4aR,8aS,9R,9aS)-9-Hydroxy-2,2-dimethylhexahydro[1,3]dioxino-
[4,5-b]pyrrolizin-6(7H)-one (12): A solution of lactam 11 (46.4 mg,
0.14 mmol) and tetrabutylammonium fluoride (TBAF; 50.0 mg,
0.19 mmol) in freshly distilled THF (11.3 mL) was stirred for 1 h
at room temperature. The solvent was removed under reduced pres-
sure, and the crude product was purified by column chromatog-
raphy (SiO2; dichloromethane/methanol, 95:5) to give 12 (22.3 mg,
75 %) as white crystals, m.p. 110–112 °C. 1H NMR (500 MHz,
CDCl3): δ = 4.50 (dd, J = 11.3, 5.8 Hz, 1 H), 4.43 (dd, J = 7.1,
4.9 Hz, 1 H), 4.16–4.09 (m, 1 H), 3.92–3.79 (m, 2 H), 3.71–3.62 (m,
1 H), 3.00 (br. d, J = 1.2 Hz, 1 H), 2.64–2.44 (m, 2 H), 2.37 (dtd,
J = 12.6, 9.8, 7.3 Hz, 1 H), 2.04–1.97 (m, 1 H), 1.42 (s, 3 H), 1.41
(s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.9 (C), 100.1
(C), 73.6 (CH), 69.0 (CH), 63.7 (CH), 58.9 (CH2), 52.1 (CH), 34.5
[3]
[4]
(CH ), 26.2 (CH ), 24.4 (CH ), 18.2 (CH ) ppm. IR (film): ν =
˜
2
3
3
2
3498, 2986, 2954, 2913, 1675, 1447, 1370, 1338, 1301, 1218, 1184,
1149, 1119, 1054, 1024, 876 cm–1. HRMS (ESI): calcd. for
C11H17NO4 [M + H]+ 228.1230; found 228.1227. [α]2D0 = +9.8 (c =
0.83, CHCl3).
ent-3-epi-Hyacinthacine A1 (14): To a cold (0 °C) solution of amide
12 (22.3 mg, 0.09 mmol) in freshly distilled THF (3.0 mL) was
added lithium aluminum hydride (10.2 mg, 0.30 mmol) in portions
over 5 min. The reaction mixture was stirred for 5 min at 0 °C and
then heated to 70 °C for 1 h. After cooling to 0 °C, the reaction
mixture was quenched by the sequential addition of water (20 μL),
10% NaOH (20 μL), and water (60 μL). The resulting mixture was
filtered and concentrated under reduced pressure to give crude 13
(20.7 mg) as a pale yellow viscous oil, which was used further with-
out purification. A solution of crude amine 13 (20.7 mg,
0.09 mmol) in methanol/1 m HCl (4.0 mL, v/v = 2:1) was heated to
reflux for 2 h. After the volatiles were removed under reduced pres-
sure, the residue was purified by ion-exchange column chromatog-
raphy (acidic resin DOWEX 50WX8-100) to give 14 (16.8 mg,
1
95%) as a pale yellow viscous oil. H NMR (500 MHz, CD3OD):
[5]
Review article on enantioselective organocatalyzed aldol reac-
tions: V. Bisai, A. Bisai, V. K. Singh, Tetrahedron 2012, 68,
4541–4580; however, no examples of double asymmetric reac-
tions are provided.
D. Enders, C. Grondal, Angew. Chem. 2005, 117, 1235–1238;
Angew. Chem. Int. Ed. 2005, 44, 1210–1212.
I. Ibrahem, W. Zou, Y. Xu, A. Cordova, Adv. Synth. Catal.
2006, 348, 211–222.
F. Calderón, E. G. Doyagüez, A. F. Fernández-Mayoralas, J.
δ = 4.24–4.15 (m, 2 H), 3.95 (dd, J = 12.0, 5.5 Hz, 2 H), 3.91 (dd,
J = 12.0, 7.0 Hz, 1 H), 3.73 (dd, J = 15.5, 7.6 Hz, 1 H), 3.33–3.29
(m, 2 H), 3.14–3.05 (m, 1 H), 2.22–2.10 (m, 1 H), 2.09–2.01 (m, 1
H), 1.85–1.74 (m, 2 H) ppm. 13C NMR (126 MHz, CD3OD): δ =
74.7 (CH), 72.1 (CH), 68.6 (CH), 65.6 (CH), 58.2 (CH2), 50.3
[6]
[7]
[8]
[9]
[10]
(CH ), 27.5 (CH ), 26.1 (CH ) ppm. IR (ATR): ν = 3358, 2924,
˜
2
2
2
1651, 1504, 1457, 1340, 1139, 1038, 979, 729 cm–1. HRMS (ESI):
calcd. for C8H15NO3 [M + H]+ 174.1125; found 174.1122. [α]2D0
=
Org. Chem. 2006, 71, 6258–6261.
–6.8 (c = 0.32, H2O) {ref.[12a,18] [α]2D0 = +3.4 (c = 0.32, H2O), ref.[13g]
[α]2D0 = –1.0 (c = 0.6, MeOH)}.
F. Calderón, E. G. Doyagüez, P. H.-Y. Cheong, A. Fernández-
Mayoralas, K. N. Houk, J. Org. Chem. 2008, 73, 7916–7920.
For selected review articles on iminosugars and their biological
properties, see: a) B. G. Winchester, Tetrahedron: Asymmetry
2009, 20, 645–651; b) N. Asano, R. J. Nash, R. J. Molyneux,
G. W. Fleet, Tetrahedron: Asymmetry 2000, 11, 1645–1680; c)
A. A. Watson, G. W. J. Fleet, N. Asano, R. J. Molyneux, R. J.
Nash, Phytochemistry 2001, 56, 265–295; d) J. R. Lidell, Nat.
Prod. Rep. 2000, 17, 455–462.
Review articles on the synthesis of iminosugars and bicyclic
polyhydroxylated alkaloids: a) B. L. Stocker, E. M. Dan-
gerfield, A. L. Win-Mason, G. W. Haslett, M. S. M. Timmer,
Eur. J. Org. Chem. 2010, 1615–1637; b) M. D. Lopez, J. Cobo,
M. Nogueras, Curr. Org. Chem. 2008, 12, 718–750.
Total syntheses of hyacinthacine A1: a) L. Chabaud, Y. Land-
ais, P. Renaud, Org. Lett. 2005, 7, 2587–2590; b) T. J. Donohoe,
H. O. Sintim, J. Hollinshead, J. Org. Chem. 2005, 70, 7297–
7304; c) I. Izquierdo, M.-T. Plaza, J. A. Tamayo, F. Sanchez-
Cantalejo, Eur. J. Org. Chem. 2007, 6078–6083; d) S. Chandra-
sekhar, B. B. Parida, C. Rambabu, J. Org. Chem. 2008, 73,
CCDC-935825 (for 2), -935822 (for 4), and -935850 (for 12) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedure and spectroscopic data for aldehyde
1
[11]
[12]
1; ORTEP diagrams of compounds 2, 4, and 12; copies of the H
NMR and 13C NMR spectra for all compounds.
Acknowledgments
This work was supported by the Serbian Ministry of Education,
Science and Technological Development (project number 172027).
The authors gratefully acknowledge the support by the European
Community’s FP7 programme through the RegPot Project FCUB
ERA GA number 256716 and by the Municipality of Stari Grad.
Eur. J. Org. Chem. 2013, 5555–5560
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5559

Z. Ferjancic, R. N. Saicic et al.
SHORT COMMUNICATION
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[16] A similar conformational phenomenon was earlier observed in
the case of γ-mercaptoaldols, which spontaneously cyclized
into hemithioacetals: J. Fanton, F. Camps, J. A. Castillo, C.
Guerard-Helaine, M. Lemaire, F. Charmanttray, L. Hecquet,
Eur. J. Org. Chem. 2012, 203–210.
[17] The melting point of 6 was also determined with a WRS-1B
Digital melting-point apparatus and it was found to be 166 °C,
uncorrected.
[18] Note that the enantiomer was synthetized; therefore, the sign
of the optical rotation is opposite.
[19] While this work was in progress, a similar approach to hya-
cinthacine analogues by using prolinal as the aldehyde acceptor
was disclosed: K. A. Delawarally, M.S. Thesis, University of
Saskatchewan, Saskatoon, Canada, 2011; whereas in the
matched case the result was comparable, the mismatched com-
bination was not synthetically useful. Apparently, this supports
our presumption that acyclic aldehydes would be a better
choice as reaction partners.
[14] Syntheses of hyacinthacine analogues: a) A. Rajender, J. P. Rao,
B. V. Rao, Eur. J. Org. Chem. 2013, 1749–1757; b) J. Rehak, L.
Fisera, J. Kozisek, L. Bellovicova, Tetrahedron 2011, 67, 5762–
5769; c) E. A. Brock, S. G. Davies, J. A. Lee, P. M. Roberts,
J. E. Thomson, Org. Lett. 2011, 13, 1594–1597; d) X. Garra-
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Received: May 16, 2013
Published Online: July 18, 2013
5560
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5555–5560