A concise synthesis of carbasugars isolated from Streptomyces lincolnensis

Article abstract of DOI:10.1016/j.tet.2020.131346

(?)-Quinic acid was used as a starting material in the hemisynthesis of two epimeric carbasugars isolated from Streptomyces lincolnensis. Previous 10–12 steps syntheses for the carbasugars have been herein shortened to 4–6 steps by using quinic acid as a

Full text of DOI:10.1016/j.tet.2020.131346

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise synthesis of carbasugars isolated from Streptomyces
lincolnensis
,
, b, *
Suvi Holmstedt a **, Nuno R. Candeias a
a Faculty of Engineering and Natural Sciences, Tampere University, 33101, Tampere, Finland
b LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
(ꢀ)-Quinic acid was used as a starting material in the hemisynthesis of two epimeric carbasugars isolated
from Streptomyces lincolnensis. Previous 10e12 steps syntheses for the carbasugars have been herein
shortened to 4e6 steps by using quinic acid as a chiron, based on a regioselective reduction step, with
stereoinversion of a tertiary center. Both C-5 epimers of (1R, 2R, 3R)-5-(hydroxymethyl)cyclohexane-
1,2,3-triol were obtained in up to 76% overall yield.
Received 10 April 2020
Received in revised form
12 June 2020
Accepted 13 June 2020
Available online xxx
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Carbasugar
Chiron
Cyclitol
Hemisynthesis
Quinic acid
1. Introduction
cyclitols like valienol and gabosine I [8]. The first total synthesis of
these carbasugars has been reported by Nanda et al. three years
Natural product-driven drug discovery combined with hemi-
synthesis brings together nature’s maximum potential to create
new biologically active molecules and the development of their
structural analogs. Carbasugars are a group of organic small mol-
ecules that are abundant in nature and have wide biological po-
tency due to the ability to mimic carbohydrates in biological
processes [1,2]. It is noteworthy that the first synthesis of a natural
carbasugar by McCasland [3] preceded its isolation in 7 years [4],
followed by extensive studies and raising the interest of many
research groups. Simpler cyclitols often are side chains and sub-
units of larger natural products owning versatile biological activity
(e.g. massonianoside B [5], nicotiflorin [6], and verbascoside [7] are
after their isolation from natural sources [9]. Such de novo syn-
thesis relied on the kinetic enzymatic resolution and the use of
(hydroxymethyl)cycloalkenone scaffold as a key intermediate.
Subsequent oxidations into several epimers provided natural and
unnatural carbasugars. Overall, final carbasugars 1 and 2 were
obtained in 10e12 steps, through formation of the above-
mentioned key intermediate in 8 steps. In 1986, before the isola-
tion and the first total synthesis of carbasugars 1 and 2, a protected
analog of 1 has been prepared and used as a synthetic intermediate
by Trost et al. in the stereoselective synthesis of isoquinuclidines
from quinic acid [10].
In the present work, we redesigned the hemisynthesis strategy
aiming at a more concise and simple synthesis for these natural
carbasugars from a common synthetic intermediate. Quinic acid, a
secondary metabolite of the shikimate pathway [11], has been
explored in many natural product syntheses as chiral pool element
[12,13] and the quest for new compounds with biological activity
[14e16]. The three-dimensional arrangement of the secondary
hydroxy groups and methylene unit serves as a great overlap of the
functional groups to be adapted for the chiron strategy in total
synthesis [17e19]. Indeed this plain strategy is a powerful tool to
synthesize natural products with similar scaffolds such as the ones
carba-L-rhamnose derivatives).
In 2004 Sedmera et al. isolated two structurally new carbasugars
1 and 2 from Streptomyces lincolnensis, which is known to produce
many antibiotics such as antibacterial lincomycin as well as C7
* Corresponding author. LAQV-REQUIMTE, Department of Chemistry, University
of Aveiro, 3810-193, Aveiro, Portugal.
** Corresponding author. Faculty of Engineering and Natural Sciences, Tampere
University, 33101, Tampere, Finland.
E-mail addresses: suvi.holmstedt@tuni.fi (S. Holmstedt), ncandeias@ua.pt
(N.R. Candeias).
shown in Fig. 1. Structurally, carbasugar
1 corresponds to
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S. Holmstedt, N.R. Candeias / Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of reduction conditions.
Entrya
Hydride (equiv.)
Conditions
5 Yield %
1
2
3
4
LiAlH4 (2)
DIBAL-H (2)
NaBH4 (2)
NaBH4 (2)
NaBH4 (10)
NaBH4 (10)
NaBH4 (3)
THF, 0 ꢁC
tracesc
n.d.c
3
39
42
THF, 0 ꢁC to reflux
DMSO, 0 ꢁCe80 ꢁC
EtOH, 0 ꢁC to RT
MeOH, 0 ꢁC to RT
THF/MeOH 16:1, 0 ꢁC
THF/MeOH 16:1, ꢀ5 ꢁC
5
6b
7b
55
84
a
Lactone 4 was dissolved in the specified solvent and the mixture cooled to 0 ꢁ
C
or maintained at room temperature. The reducing agent was added, and the mixture
was allowed to stir 3e18 h. The starting temperature was raised if no reaction was
observed.
b
Lactone 4 in THF was added to a stirred suspension of NaBH4 in THF/MeOH.
Complex mixture of multiple products, no product isolation.
c
Fig. 1. Selected natural products structurally related to carbasugars 1 and 2.
cleavage of primary, secondary, and tertiary alkyl halides and
tosylates [26], we set to increase the selectivity towards formation
of 5. As sodium borohydride reductions are known to be solvent
dependent [27,28], we decided to test different solvents. Replacing
DMSO by protic ethanol resulted in the formation of 5 in a mod-
erate 39% yield (Table 1, entry 4). The complete consumption of
starting material was achieved by increasing the amount of hydride
to 10 equivalents in methanol (Table 1, entry 5). Ketal 5 was ob-
tained in similar 42% yield as when using 2 equivalents of hydride
source (entry 4), together with plenty of uncharacterized side
products. The addition of methanol to THF has been demonstrated
to improve selectivity in the reduction of esters and lactones with
NaBH4 [29]. Upon testing similar conditions and inverting the
addition order, we were glad to obtain 5 in improved 55% yield
(Table 1, entry 6). Generally, the portion-wise addition of the dis-
solved lactone to a suspension of NaBH4 provided better yields than
the standard portion-wise addition of powder reducing agent to
the solution of the lactone. We believe this can be due to the high
reactivity of the product towards the reducing agent. Ultimately,
the best conditions obtained for the reduction of the lactone and
removal of the tertiary hydroxy group derivative relied on using
low temperatures to slow down the reactivity during the
exothermic addition of the lactone to an excess of NaBH4 (3
equivalents). The desired synthetic intermediate 5 was obtained in
84% yield (Table 1, entry 7).
Regioselectivities on epoxide opening have been reported to
depend on the electrophilicity of hydride reagents [30]. Namely,
BH3 allows the opening of epoxides from the most substituted
carbon [31]. With this in mind, different possibilities to justify the
unexpected stereochemistry of the product obtained have been
considered (Scheme 2a). After the reduction of the lactone moiety
and putative formation of unidentified borane hydride species, the
reactive primary alkoxide 4a can undergo two different paths. The
direct displacement of the methanesulfonate group by the hydride
may provide the observed compound 5 if, a somewhat concerted
hydride delivery on the stereochemically hindered tertiary carbon
occurs. Alternatively, 4a may undergo O, O-methanesulfonyl
migration to form primary mesylate 4b [32e34]. The obtained
stereocenter inversion may occur upon hydride delivery on the
more substituted carbon of the epoxide intermediate 4c, formed by
the attack of tertiary alkoxide. Notably, the more immediate for-
mation of epoxide 4d (Scheme 2b), upon the attack of the primary
alkoxide to the tertiary vicinal carbon in 4a, could lead to epimer 7,
which we have not been able to identify in our mixtures.
(ꢀ)-dihydroshikimic acid with only one oxidation state difference
and is an analog to many carba- -rhamnose side chains derivatives.
Additionally, carbasugar 2 is a structural analog to (ꢀ)-gabosine B
[20] and (þ)-palitantin [21]. We herein present an efficient total
synthesis of natural carbasugars 1 and further modification to its
epimer 2, both isolated from S. lincolnensis.
L
2. Results and discussion
2.1. Synthesis of (1R,2R,3R,5S)-5-(hydroxymethyl)cyclohexane-
1,2,3-triol (1)
The synthesis of 1 started with the simultaneous protection of
quinic acid’s (3) carboxyl and secondary hydroxy functionalities
yielding acetal protected lactone 4 as previously described (Scheme
1) [22]. We envisioned that preparation of diol 5 (or its C-5 epimer),
previously prepared by Trost [10], could be shortened by in situ
formation of an epoxide during the reduction of the lactone, fol-
lowed by its regioselective reduction [23e25]. While not certain
about the stereo- and regioselectivity of the epoxide opening, the
reduction of mesylated 4 was carefully optimized with common
hydride sources (Table 1).
Despite the complete consumption of lactone 4, reduction at-
tempts with lithium aluminum hydride provided only traces of the
desired product 5, while no product was observed with less reac-
tive DIBAL-H (Table 1, entries 1 and 2). When changing the reducing
agent to NaBH4 in DMSO, 5 was isolated in 3% yield (Table 1, entry 3)
from a complex mixture of non-characterized products (as judged
by TLC). Motivated by the previous use of this reductant in the
After deoxygenation, the acetal deprotection with HCl/MeOH
yielded natural carbasugar 1 (Scheme 1) with a 76% overall yield
from (ꢀ)-quinic acid. The spectral comparison with the original
reports on the isolation of this natural product [8] confirmed the
Scheme 1. Synthesis of carbasugar 1 from (ꢀ)-quinic acid.
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S. Holmstedt, N.R. Candeias / Tetrahedron xxx (xxxx) xxx
3
Scheme 2. Proposed reaction mechanism for the formation of 5.
Scheme 3. Synthesis of carbasugar 2 from protected carbasugar 5.
removal of the tertiary hydroxy group and the stereo-inversion of
the C-5 carbon.
Table 2
The unexpected stereoinversion at C-5 upon hydride delivery in
4 / 5 was further confirmed by a careful comparison of the re-
ported [8] chemical shifts and J-couplings of natural product 1. The
two hydroxymethyl protons show very similar chemicals shifts
(3.301 and 3.265 ppm) in the form of a multiplet that deconvolves
to two sets of doublet of doublets with 11.3 and 6.6 Hz coupling
constants (vs 11.0 and 6.3 Hz) [8]. The hydrogen at C-5 has a
chemical shift of 1.715 ppm appearing as a multiplet due to the
multiple couplings with the vicinal protons (at C-4, C-6 and C-7),
also matching closely with the original report (1.714 ppm). Notably,
all 13C NMR chemical shifts of the final product differ from the
paper on isolation of 1 in less than 0.06 ppm. Secondary C-7 and
tertiary C-5 resonate at 66.55 and 32.71 ppm, respectively, in close
agreement with Sedmera’s report (66.55 and 32.71 ppm) [8].
Optimization of oxidation conditions.
Entry Oxidation conditions
Yield %
1a
2a
3a
4b
DMP (1 equiv.), CH2Cl2, RT, 1 h
PCC (1.2 equiv.), CH2Cl2, RT, 20 h
TEMPO (20 mol%), PhI(OAc)2, (2 equiv.), CH2Cl2, RT, 4 h
TEMPO (10 mol%), TBAB (10 mol%), NCS (2 equiv.), CH2Cl2/buffer, 77
RT, 45 min
15
13
34
a
Alcohol 5 was dissolved in CH2Cl2 (0.1 M) and the specified oxidizing agent was
added at RT. Mixture was stirred at for specified time, quenched and purified using
flash column chromatography.
b
Procedure described in experimental section.
The a-carbonyl position of the aldehyde 6 was epimerized using
1 equivalent of K2CO3 as base (Scheme 3) in methanol. While
testing epimerization conditions, the TLC analysis from reaction
mixtures showed the aldehyde 6 being a minor product and the
equilibrium largely favoring epimer 6’. The simple evaporation of
the reaction solvent or quenching by adjusting to pH 7 (using
aqueous HCl) followed by column chromatography purification
resulted in equilibration to starting material 6. The difficult isola-
tion of 6’ was circumvented by in situ reduction to alcohol 7 with
sodium borohydride, thus allowing the isolation of the diol in 77%
yield. Finally, the acetal deprotection gave the natural carbasugar 2,
also with NMR spectral characterization in close agreement with
the values reported by Sedmera [8]. Comparison of chemical shifts
of 1 and 2 show little changes in positions 1, 3 and 7, contrarily to
the remaining cyclohexyl positions. A significant change in the
chemical shift of C-2 between 1 (71.71 ppm) and 2 (76.30 ppm)
could be explained by the establishment of an intramolecular
hydrogen bond with C-1 in 1.
2.2. Synthesis of (1R,2R,3R,5R)-5-(hydroxymethyl)cyclohexane-
1,2,3-triol (2)
Considering the synthesis of the epimer 2, we envisioned that
this second natural product could be achieved by epimerization of
the a-carbonyl position of the corresponding aldehyde (Scheme 3).
The putative establishment of an intramolecular hydrogen bond
between the hydroxy and the carbonyl groups on the same face of
the six-membered ring should drive the epimerization towards the
desired product. Bearing this in mind, conditions to target the se-
lective oxidation of the primary alcohol were investigated and the
results are presented in Table 2. The reaction suffered a lack of
regioselectivity and the yields were poor for the exclusive oxidation
of primary alcohol despite the use of parsimonious oxidizing agents
(Table 2, entries 1 and 2). Better regioselectivity was observed
when oxidizing with catalytic TEMPO in combination with (diac-
etoxyiodo)benzene, although the isolated yield remained poor
(Table 2, entry 3). Changing the oxidizing agent from iodobenzene
based oxidizing agents to N-chlorosuccinimide, resulted in an
increased formation of 6 in 77% yield after 45 min (Table 2, entry 4).
Precise control of the reaction time was required, as extended re-
action times resulted in increased amounts of side products whilst
shorter reaction times were not sufficient for complete consump-
tion of the starting material.
2.3. Computational study
In order to verify our assumption on the stabilization of epimer
6′ due to the establishment of an intramolecular hydrogen bond,
we have performed the conformational analysis of both C-5 epi-
mers using DFT [35] (Scheme 4). The conformational analysis of 6
resulted in the identification of the two chair conformers 6A and 6B
as the most stable conformations. A somewhat distorted chair
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S. Holmstedt, N.R. Candeias / Tetrahedron xxx (xxxx) xxx
acetone (d d
1H 2.03 ppm, 13C 30.50 ppm). The following abbrevi-
ations were used to describe peak splitting patterns: s ¼ singlet,
d ¼ doublet, t ¼ triplet, m ¼ multiplet. Coupling constants J were
reported in Hertz (Hz). High-resolution mass spectra were recorded
on a Waters ESI-TOF MS spectrometer.
4.2. (3aR,4R,7S,8aR)-2,2-dimethyl-6-oxotetrahydro-4,7-methano
[1,3]dioxolo[4,5-c]oxepin-7(6H)-yl methanesulfonate (4)
i) Quinic acid 3 (3.0 g, 15.6 mmol) was weighed into round
bottomed flask equipped with stirring bar. Acetonitrile (200 mL)
was added, followed by addition of Amberlyst 15 (3.5 g), and the
mixture was refluxed for 2 days. The mixture was cooled to
room temperature and 2,2-dimethoxypropane (3.8 mL, 3.25 g,
31.2 mmol, 2 equiv.) was added and refluxed for 3 h. The reac-
tion mixture was filtrated through Celite plug and the solvent
was evaporated to give pure (3aR,4R,7S,8aR)-7-hydroxy-2,2-
dimethyltetrahydro-4,7-methano[1,3]dioxolo[4,5-c]oxepin-
6(4H)-one as a beige solid (3.28 g, 98%). 1H NMR (500 MHz,
Scheme 4. Simplified conformational analysis of epimers 6 and 6’. Energy values relate
to 6A as the zero value and are given as electronic energies, optimized at PBE1PBE/6-
31G** level of theory.
conformation can be detected in the case of 6A, due to an intra-
molecular hydrogen bond between the secondary hydroxy group
and the vicinal oxygen from the acetonide. Notwithstanding a
similar effect observed for the most stable chair conformation of
epimer 6′, i.e. 6′A, the placement of the carbonyl group in the more
CDCl3):
d
4.71 (dd, J ¼ 6.1, 2.5 Hz, 1H-1), 4.51e4.47 (m, 1H-3),
4.29 (ddd, J ¼ 6.7, 2.4, 1.5 Hz, 1H-2), 3.16 (s, 1HeOH), 2.63 (d,
J ¼ 11.7 Hz, 1H-6), 2.36 (ddd, J ¼ 14.7, 7.6, 2.3 Hz, 1H-4),
2.33e2.27 (m, 1H-6), 2.17 (dd, J ¼ 14.6, 2.9 Hz, 1H-4), 1.51 (s,
favorable equatorial position has
a clear stabilizing effect
3HeCH3), 1.31 (s, 3HeCH3); 13C NMR (125 MHz, CDCl3):
d 179.08
(ꢀ2.1 kcal/mol) when compared with epimer 6. As envisioned, a
more stable conformation for epimer 6′ could be found, namely
twist-boat conformation 6′C (ꢀ2.9 kcal/mol) where an intra-
molecular hydrogen bond is established between the aldehyde
oxygen and the hydroxy group (2.027 Å).
(C]O), 109.90 (Cisop.), 75.97 (C1), 72.19 (C5), 71.66 (C2), 71.60
(C3), 38.23 (C4), 34.37 (C6), 27.08 (CH3), 24.41 (CH3); HRMS
calculated for [M]þ 214.0841, found 214.0913. The spectral data
of the compound is consistent with the literature data [10].
ii) Lactone ((3aR,4R,7S,8aR)-7-hydroxy-2,2-dimethyltetrahydro-
4,7-methano[1,3]dioxolo[4,5-c]oxepin-6(4H)-one) synthesized
in section 4.2 i) (3.28 g, 15.3 mmol) was dissolved in Et2O
(100 mL) at 0 ꢁC. Et3N (4.3 mL, 3.1 g, 30.6 mmol, 2 equiv.) was
added followed by slow addition of MsCl (1.8 mL, 2.6 g, 23 mmol,
1 equiv.). The ice bath was removed after 5 min and the mixture
was left stirring for 2 h at room temperature forming a thick
solution. The mixture was diluted with EtOAc (100 mL) and
quenched with H2O (100 mL). Layers were separated and the
aqueous phase was extracted with CH2Cl2 (3 ꢂ 50 mL). The
organic phases were combined, dried with anhydrous MgSO4,
filtered through silica pad (3 cm) and the solvents were evap-
orated to give pure 4 as a beige solid (4.24 g, 95%). 1H NMR
3. Conclusion
In summary, we herein report the shortest and the highest
yielding synthesis of the two natural 3,4,5-trihydroxycyclohexyl
cyclitols isolated from Streptomyces lincolnensis. Both C-5 epimers
of (1R, 2R, 3R)-5-(hydroxymethyl)cyclohexane-1,2,3-triol were
obtained in 4e6 steps in 76% or 44% overall yields from (ꢀ)-quinic
acid. The regioselective reduction of a quinic acid-derived lactone
was used as a key step in the installation of the hydroxymethyl
substituent, upon stereoselective hydride delivery to a tertiary
carbon. The unprecedented conversion of the less stable epimer of
the corresponding aldehyde into the more stable C-5 epimer
allowed the preparation of both natural carbasugars by the inser-
tion of an oxidation-epimerization-reduction sequence.
(500 MHz, CDCl3):
d
4.80 (dd, J ¼ 6.4, 2.5 Hz, 1H-1), 4.57e4.45
(m, 1H-3), 4.31 (ddd, J ¼ 6.2, 2.1, 0.9 Hz, 1H-2), 3.28 (s, 3H -OMs-
CH3), 3.12e3.05 (m, 1H-6), 2.83 (d, J ¼ 11.8 Hz, 1H-4), 2.54 (ddd,
J ¼ 14.4, 7.7, 2.4 Hz,1H-6), 2.39 (dd, J ¼ 14.5, 3.0 Hz,1H-4),1.52 (s,
4. Experimental section
3HeCH3), 1.32 (s, 3HeCH3). 13C NMR (125 MHz, CDCl3):
d 172.91
(C]O), 110.41 (Cisop.), 82.27 (C5), 75.82 (C1), 72.01 (C2), 71.17
(C3), 41.34 (OMs-CH3), 36.60 (C4), 33.24 (C6), 27.06 (CH3), 24.45
(CH3); HRMS calculated for [MþNa]þ 315.0515, found 315.0479.
The spectral data of the compound is consistent with the liter-
ature data [36].
4.1. General remarks
All syntheses were carried out in oven-dried glassware under
inert atmosphere. Anhydrous diethyl ether and triethylamine were
obtained using PureSolv Micro multi-unit purification system.
Acetonitrile was left standing over 3 Å molecular sieves and used
without further purification. All other reagents were purchased
from Sigma Aldrich or TCI and used without purification. Reactions
were monitored through thin-layer chromatography (TLC) with
commercial silica gel plates (Merck silica gel, 60 F254). Plates were
visualized by staining upon heating with vanillin stain. Flash col-
4.3. (3aS,4R,6R,7aR)-6-(hydroxymethyl)-2,2-
dimethylhexahydrobenzo[d][1,3]dioxol-4-ol (5)
Methanol (0.2 mL) was added to a ꢀ5 ꢁC suspension of NaBH4
(78 mg, 2.1 mmol, 3 equiv.) in THF (1 mL) and the mixture was
stirred until little bubbling was visible. A solution of lactone 4
(200 mg, 0.68 mmol) in THF (2.2 mL) was added dropwise and the
reaction mixture was allowed to warm up to room temperature and
was left stirring overnight. The reaction was quenched with H2O
(3 mL) and after 30 min stirring, solvents were evaporated under
reduced pressure. The residue was purified by flash column chro-
matography (dry loading) using EtOAc as eluent to yield product 5
umn chromatography was performed on silica gel 60 (40e63 mm)
as stationary phase. The 1H and 13C spectra were recorded at
500 MHz and 125 MHz respectively in a JEOL ECZR 500 instrument.
CDCl3 or D2O (in D2O samples 4
reference) were used as solvents for NMR analysis. Chemical shifts
) are reported in ppm and are referenced to the residual chloro-
form signal (
1H 7.26 ppm, 13C 77.16 ppm) or to the internal
ml of acetone was used as internal
(d
d
d
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S. Holmstedt, N.R. Candeias / Tetrahedron xxx (xxxx) xxx
5
as a clear oil (116 mg, 84%). 1H NMR (500 MHz, CDCl3):
d
4.35 (dd,
yield product 7 as a clear oil (54 mg, 77%).1H NMR (500 MHz,
CDCl3):
3), 3.6e3.46 (m, 2H-7), 2.79 (s, 1HeOH), 2.13 (d, J ¼ 14.9 Hz, 1H-6),
2.07e1.85 (m, 3H-4, 5, OH), 1.49 (s, 4H, overlapped peaks 6, CH3),
1.36 (s, 3HeCH3), 1.16e1.03 (m, 1H-4); 13C NMR (125 MHz, CDCl3):
J ¼ 11.5, 6.1 Hz, 1H-1), 4.09 (td, J ¼ 7.5, 3.8 Hz, 1H-3), 3.96 (t,
J ¼ 5.6 Hz, 1H-2), 3.64e3.55 (m, 2H-7), 2.07e1.98 (m, 2H-5 and 6),
1.91 (t, J ¼ 5.3 Hz, 1HeOH), 1.79 (d, J ¼ 4.6 Hz, 1HeOH), 1.76 (dd,
J ¼ 7.5, 3.9 Hz, 1H-4), 1.65e1.58 (m, 2H-6 and 4), 1.50 (s, 3HeCH3),
d
4.37 (bs,1H-1), 3.81 (t, J ¼ 5.8 Hz,1H-2), 3.77e3.67 (m,1H-
1.36 (s, 3HeCH3); 13C NMR (125 MHz, CDCl3):
d
108.77 (Cisop.), 78.71
d 108.81 (Cisop.), 81.27 (C2), 74.20 (C1), 72.25 (C3), 66.95 (C7), 33.17
(C2), 73.37 (C1), 68.64 (C3), 67.06 (C7), 31.87 (C5), 30.26 (C4), 29.25
(C6), 27.99 (CH3), 25.80 (CH3); HRMS calculated for [MþH]þ
203.1283, found 203.1296. The spectral data of the compound is
consistent with the literature data [10].
(C5), 33.15 (C4), 29.21 (C6), 28.42 (CH3), 26.23 (CH3); HRMS
calculated for [MþH]þ 203.1283, found 203.1290.
4.7. (1R,2R,3R,5R)-5-(hydroxymethyl)cyclohexane-1,2,3-triol (2)
4.4. (1R,2S,3R,5S)-5-(hydroxymethyl)cyclohexane-1,2,3-triol (1)
Protected alcohol 7 (20 mg, 0.1 mmol) was dissolved in MeOH
(1 mL) and aqueous 4M HCl (0.1 mL) was added. The mixture was
stirred for 18 h at room temperature after which MeOH was added
and the mixture neutralized with NaOH (4 M aq. soln.). Solvents
were evaporated and the mixture was purified using flash column
chromatography (EtOAc/MeOH 9:1) to yield product 2 as a white
Protected alcohol 5 (115 mg, 0.57 mmol) was dissolved in MeOH
(4 mL) and aqueous 4M HCl (0.4 mL) was added. The mixture was
stirred for 18 h at room temperature and then diluted with MeOH
and neutralized with NaOH (4 M aq. soln.). Solvents were evapo-
rated and crude compound was purified using flash column chro-
matography (EtOAc/MeOH 9:1) to yield product 1 as white solid
solid (15 mg, 94%). 1H NMR (500 MHz, D2O):
d 3.93 (bs, 1H-3), 3.59
(td, J ¼ 10.1, 4.2 Hz, 1H-1), 3.32e3.25 (m, 2H-7), 3.19 (dd, J ¼ 9.6,
2.9 Hz, 1H-2), 1.82e1.79 (m, 1H-5), 1.76e1.74 (m, 1H-4), 1.64 (d,
J ¼ 14.2 Hz, 1H-4), 1.10 (t, J ¼ 13.4 Hz, 1H-4), 0.87 (q, J ¼ 11.8 Hz, 1H-
(89 mg, 97%).1H NMR (500 MHz, D2O):
d
3.86 (q, J ¼ 3.3 Hz, 1H-3),
3.75 (ddd, J ¼ 11.7, 4.4, 3.1 Hz, 1H-1), 3.63 (t, J ¼ 3.4 Hz, 1H-2), 3.30
(dd, J ¼ 11.3, 6.6 Hz,1H-7), 3.26 (dd, J ¼ 11.3, 6.6 Hz,1H-7),1.76e1.66
(m, 1H-5), 1.54 (dt, J ¼ 12.2, 3.9 Hz, 1H-6), 1.43 (d, J ¼ 14.4 Hz, 1H-4),
1.27e1.19 (m, 1H-4), 1.12 (q, J ¼ 11.9 Hz, 1H-6); 13C NMR (125 MHz,
6); 13C NMR (125 MHz, D2O):
d 76.30 (C2), 70.04 (C3), 69.45 (C1),
66.25 (C7), 35.49 (C6), 33.50 (C4), 32.43 (C5).; HRMS calculated for
[MþCl]- 197.0581, found 197.0612. The spectral data of the com-
pound is consistent with the literature data [8].
D2O):
d 71.71 (C2), 70.04 (C3), 67.85 (C1), 66.55 (C7), 32.71 (C5),
30.36 (C6), 29.18 (C4). HRMS calculated for [MþCl]- 197.0581, found
197.0591. The spectral data of the compound is consistent with the
literature data [8].
4.8. Computational details
All calculations were performed using the Gaussian 09 software
package [37], without symmetry constraints. The optimized ge-
ometries were obtained employing the PBE1PBE functional with a
standard 6-31G(d,p) [38e42] basis set. That functional uses a
hybrid generalized gradient approximation (GGA), including 25%
mixture of Hartree-Fock [43] exchange with DFT [35] exchange-
correlation, given by Perdew, Burke and Ernzerhof functional
(PBE) [44,45]. Frequency calculations were performed to confirm
the nature of the stationary points, yielding no imaginary fre-
quency for the minima.
4.5. (3aR,5R,7R,7aS)-7-hydroxy-2,2-dimethylhexahydrobenzo[d]
[1,3]dioxole-5-carbaldehyde (6)
Alcohol 5 (430 mg, 2.1 mmol) was dissolved in CH2Cl2 (20 mL)
followed by addition of TEMPO (33 mg, 0.2 mmol, 0.1 equiv.) and
TBAB (68 mg, 0.2 mmol, 0.1 equiv.). Then 20 mL of aqueous buffer
solution (0.5M NaHCO3, 0.05M K2CO3) was added followed by
addition of N-chlorosuccinimide (560 mg, 4.3 mmol, 2 equiv.) and
the mixture was allowed to stir at room temperature for 45 min
after which layers were separated, aqueous phase was saturated
with NaCl and extracted with CH2Cl2 (5 ꢂ 10 mL). Combined
organic phases were dried with anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was purified
using flash column chromatography (CH2Cl2/EtOAc, 1:1) to yield
product 6 as a pale yellow oil (330 mg, 77%). 1H NMR (500 MHz,
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
CDCl3):
d 9.68 (s, 1H-7), 4.39e4.33 (m, 1H-1), 4.02e3.96 (m, 1H-3),
3.93 (t, J ¼ 5.5 Hz, 1H-2), 2.61e2.54 (m, 1H-5), 2.25 (ddd, J ¼ 10.3,
8.2, 4.4 Hz, 2H-4,6), 2.15 (ddd, J ¼ 14.9, 6.7, 4.4 Hz, 1H-6), 1.62 (ddd,
J ¼ 14.1, 8.5, 5.7 Hz, 1H-4), 1.41 (s, 3HeCH3), 1.34 (s, 3HeCH3); 13C
Acknowledgments
NMR (125 MHz, CDCl3):
d 203.19 (C7), 109.24 (Cisop), 79.00 (C2),
The Academy of Finland is duly acknowledged for financial
support to N. R. C. (Decisions No. 326487 and 326486), Finnish
Cultural Foundation is acknowledged for financial support to S. H.
(00190336). CSCeIT Center for Science Ltd, Finland is acknowl-
edged for the allocation of computational resources.
72.92 (C1), 68.08 (C3), 42.45 (C5), 27.69 (C4), 27.27 (CH3), 25.98
(C6), 25.93 (CH3); HRMS calculated for [MþNa]þ 223.0946, found
223.0918.
4.6. (3aS,4R,6S,7aR)-6-(hydroxymethyl)-2,2-
dimethylhexahydrobenzo[d][1,3]dioxol-4-ol (7)
Supplementary Material
Aldehyde 6 (70 mg, 0.34 mmol) was dissolved in MeOH (4 mL),
K2CO3 (48 mg, 0.34 mmol, 1.0 equiv.) was added and the mixture
was stirred 18 h at room temperature. The mixture was cooled
down to 0 ꢁC, stirred at 0 ꢁC for 2 h, NaBH4 (26 mg, 0.7 mmol, 2
equiv.) was added, and the reaction mixture was allowed to warm
up to room temperature over 2 h while stirring. Reaction mixture
was diluted with EtOAc and quenched with H2O (0.2 mL). The
solvents were evaporated and the residue was purified using flash
column chromatography (dry loading) using EtOAc as eluent to
Spectral characterization of the compounds prepared and co-
ordinates of the computational optimized structures are available
as supplementary material.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131346.
Please cite this article as: S. Holmstedt, N.R. Candeias, A concise synthesis of carbasugars isolated from Streptomyces lincolnensis, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131346

6
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of Epoxides in Comprehensive Organic Synthesis II, second ed., Elsevier,
References
Amsterdam, 2014, pp. 1086e1122.
[26] R.O. Hutchins, D. Hoke, J. Keogh, D. Koharski, Tetrahedron Lett. 10 (1969)
3495e3498.
[27] L. Banfi, E. Narisano, R. Riva, N. Stiasni, M. Hiersemann, T. Yamada, T. Tsubo,
Sodium Borohydride in Encyclopedia of Reagents for Organic Synthesis, John
Wiley & Sons, Ltd., 2014.
[28] H.C. Brown, S. Krishnamurthy, Tetrahedron 35 (1979) 567e607.
[29] K. Soai, H. Oyamada, M. Takase, A. Ookawa, Bull. Chem. Soc. Jpn. 57 (1984)
1948e1953.
[30] R.O. Hutchins, I.M. Taffer, W.J. Burgoyne, Org. Chem. 46 (1981) 5214e5215.
[31] H.C. Brown, N.M. Yoon, J. Am. Chem. Soc. 90 (1968) 2686e2688.
[32] V.A. Zagorevskii, Z.D. Kirsanova, Chem. Heterocycl. Compd. 6 (1970) 288e289.
[33] W. Zhang, J. Chu, A.M. Cyr, H. Yueh, L.E. Brown, T.T. Wang, J. Pelletier,
J.A. Porco Jr., J. Am. Chem. Soc. 141 (2019) 12891e12900.
[34] A.J. Flynn, A. Ford, A.R. Maguire, Org. Biomol. Chem. 18 (2020) 2549e2610.
[35] R.G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules, Oxford
University Press, New York, 1989.
[36] J.C. Rohloff, K.M. Kent, M.J. Postich, M.W. Becker, H.H. Chapman, D.E. Kelly,
W. Lew, M.S. Louie, L.R. McGee, E.J. Prisbe, L.M. Schultze, R.H. Yu, L. Zhang,
J. Org. Chem. 63 (1998) 4545e4550.
[1] O. Arjona, A.M. Gomez, J.C. Lopez, J. Plumet, Chem. Rev. 107 (2007)
1919e2036.
ꢀ
ꢀ
[2] R.G. Soengas, J.M. Otero, A.M. Estevez, A.P. Rauter, V. Cachatra, J.C. Estevez,
ꢀ
R.J. Estevez, An Overview of Key Routes for the Transformation of Sugars into
Carbasugars and Related Compounds in Carbohydrate Chemistry, vol. 38, The
Royal Society of Chemistry, 2012, pp. 263e302, 38.
[3] G.E. McCasland, S. Furuta, L.J. Durham, J. Org. Chem. 31 (1966) 1516e1521.
[4] T.W. Miller, B.H. Arison, G. Albers-Schonberg, Biotechnol. Bioeng. 15 (1973)
1075e1080.
[5] W.Q. Chen, Z.J. Song, H.H. Xu, Bioorg. Med. Chem. Lett 22 (2012) 5819e5822.
[6] Y.H. Jo, S.B. Kim, Q. Liu, S.G. Do, B.Y. Hwang, M.K. Lee, PloS One 12 (2017),
e0172069.
[7] T.G. Kim, J.H. Lee, M.Y. Lee, K.U. Kim, J.H. Lee, C.H. Park, B.H. Lee, K.S. Oh, Biol.
Pharm. Bull. 40 (2017) 1454e1462.
[8] P. Sedmera, P. Halada, S. Pospisil, Magn. Reson. Chem. 47 (2009) 519e522.
[9] R. Rej, N. Jana, S. Kar, S. Nanda, Tetrahedron: Asymmetry 23 (2012) 364e372.
[10] B.M. Trost, A.G. Romero, J. Org. Chem. 51 (1986) 2332e2342.
[11] N.R. Candeias, B. Assoah, S.P. Simeonov, Chem. Rev. 118 (2018) 10458e10550.
[12] S. Kobayashi, M. Sugiura, C. Ogawa, Adv. Synth. Catal. 346 (2004) 1023e1034.
[13] S.W. McCombie, W.B. Motherwell, M.J. Tozer, The Barton-McCombie Reaction
in Organic Reactions, vol. 77, John Wiley & Sons, Inc., 2012, pp. 161e432.
[14] C. Ogawa, H. Konishi, M. Sugiura, S. Kobayashi, Org. Biomol. Chem. 2 (2004)
446e448.
[37] M.J.T. Frisch, G W, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
G. Scalman, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, J, J.E. Peralta,
F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev,
A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma,
V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich,
[15] M. Yasuda, S. Yamasaki, Y. Onishi, A. Baba, J. Am. Chem. Soc. 126 (2004)
7186e7187.
[16] S. Rendler, M. Oestreich, Synthesis (2005) 1727e1747.
[17] S. Hanessian, Total Synthesis of Natural Products, the "Chiron" Approach, first
ed., Pergamon Press, Oxford Oxfordshire ; New York, 1983.
[18] S. Hanessian, J. Pan, A. Carnell, H. Bouchard, L. Lesage, J. Org. Chem. 62 (1997)
465e473.
[19] A. Barco, S. Benetti, C.D. Risi, P. Marchetti, G.P. Pollini, V. Zanirato, Tetrahe-
dron: Asymmetry 8 (1997) 3515e3545.
[20] T. Shinada, T. Fuji, Y. Ohtani, Y. Yoshida, Y. Ohfune, Synlett (2002) 1341e1343.
[21] S. Hanessian, Y. Sakito, D. Dhanoa, L. Baptistella, Tetrahedron 45 (1989)
6623e6630.
[22] H. Kawashima, M. Sakai, Y. Kaneko, Y. Kobayashi, Tetrahedron 71 (2015)
2387e2392.
[23] L. Rodrigues, M.S. Majik, S.G. Tilve, S. Wahidulla, Tetrahedron Lett. 59 (2018)
3413e3415.
[24] T.M. Flaherty, J. Gervay, Tetrahedron Lett. 37 (1996) 961e964.
[25] S. Florio, F.M. Perna, A. Salomone, P. Vitale, in: P. Knochel (Ed.), 8.29 Reduction
€
A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian
09, Revision D.01, Gaussian, Inc, Wallingford CT, 2009.
[38] R. Ditchfield, W.J. Hehre, J.A. Pople, J. Chem. Phys. 54 (1971) 724e728.
[39] W.J. Hehre, R. Ditchfield, J.A. Pople, J. Chem. Phys. 56 (1972) 2257e2261.
[40] P.C. Hariharan, J. Pople, A. Mol. Phys. 27 (1974) 209e214.
[41] M.S. Gordon, Chem. Phys. Lett. 76 (1980) 163e168.
[42] P.C. Hariharan, J.A. Pople, Theor. Chim. Acta 28 (1973) 213e222.
[43] W.J. Hehre, L. Radom, P.v.R. Schleyer, J. Pople, Ab Initio Molecular Orbital
Theory, John Wiley & Sons, New York, 1986.
[44] J.P. Perdew, Phys. Rev. B 33 (1986) 8822e8824.
[45] J.P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 78 (1997), 1396-1396.
Please cite this article as: S. Holmstedt, N.R. Candeias, A concise synthesis of carbasugars isolated from Streptomyces lincolnensis, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131346