Synthesis of 4-membered carbasugars by way of stereoselective SmI 2-mediated aldehyde-alkene cyclization

Article abstract of DOI:10.1021/jo400732a

A stereodivergent synthesis of the first examples of 4-membered carbasugars has been achieved from vitamin C by way of an efficient intramolecular SmI ₂-mediated aldehyde-alkene coupling. In this key step, cylobutanes with four contiguous asymmetric centers are generated with a high level of stereocontrol.

Full text of DOI:10.1021/jo400732a

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Note
Synthesis of 4-Membered Carbasugars by way of
Stereoselective SmI2-Mediated Aldehyde-alkene Cyclization
Pierre-Antoine Nocquet, Damien Hazelard, Guillaume Gruntz, and Philippe Compain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400732a • Publication Date (Web): 10 Jun 2013
Downloaded from http://pubs.acs.org on June 10, 2013
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Synthesis of 4-Membered Carbasugars by way of Stereoselective SmI2-Mediated
Aldehyde-alkene Cyclization
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PierreꢀAntoine Nocquet,a Damien Hazelard,a Guillaume Gruntz,a and Philippe Compaina,b,*
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(a) Laboratoire de Synthèse Organique et Molécules Bioactives, Université de Strasbourg/CNRS
(UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087
Strasbourg, France
(b) Institut Universitaire de France, 103 Bd SaintꢀMichel, 75005 Paris, France
* To whom correspondence should be addressed.
Tel.: (+33) 3ꢀ6885ꢀ2792; fax: (+33) 3ꢀ6885ꢀ2754
eꢀmail: philippe.compain@unistra.fr
RECEIVED DATE (will be automatically inserted after manuscript is accepted)
Abstract: A stereodivergent synthesis of the first examples of 4ꢀmembered carbasugars has been
achieved from vitamin C by way of an efficient intramolecular SmI2ꢀmediated aldehydeꢀalkene
coupling. In this key step, cylobutanes with four contiguous asymmetric centers are generated
with a high level of stereocontrol.
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Carbohydrate mimetics are structurally altered analogs of carbohydrate designed to simulate the
shape and most functionalities of the natural substrates in the ground state or in the transition
state with the goal of discovering drug candidates or useful biological probes.1 The most common
structural modification performed is the replacement of the endocyclic and/or the glycosidic
oxygen atom by a heteroatom or by a carbon atom. Carbasugars, named “pseudoꢀsugars” in the
pioneering article of Mc Casland et al.,2 are one of the most important class of glycomimetics.3 In
these analogues of furanoses or pyranoses, the ring oxygen is replaced by a methylene group
(branchedꢀchain cyclitols). Carbasugars are attractive in the context of drug discovery because of
their stability towards endogenous degradative enzymes as well as their interesting biological
properties mainly as antibiotic and as glycosidase inhibitors.3,4 For example, acarbose
(Glucobay®)5 and voglibose (Basen®)6 are now clinically useful therapeutic agents to control
diabetes. If not surprisingly most carbocyclic sugar mimetics are carbafuranoses or
carbapyranoses, few examples of sevenꢀ,7 eightꢀ8 and even nineꢀmembered9 carbasugars have
been reported recently in the literature. Beyond the synthetic challenges, the main motivation for
the synthesis of such mediumꢀring carbasugars is the access to a diversity of conformations other
than the traditional chair boat of sixꢀmembered rings. The original distributions of hydroxyl
groups thus obtained in addition to the fine tuning of the hydrophobicꢀhydrophilic balance are
thought to be of likely significance for receptor recognition purposes. In contrast, to our
knowledge, no example of 4ꢀmembered carbasugars has been reported in the literature to date.
These compounds are attractive as they offer opposite and complementary structural features
compared to the corresponding mediumꢀring analogues including conformational rigidity and
molecular simplicity. Based on these considerations and in conjunction with our continuing
studies on original glycomimetics,10 we have synthesized the first members of a new class of 4ꢀ
membered carbasugars, “carbaoxetanoses” from vitamin C (1).11 Our retrosynthetic analysis
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takes advantage of the chirality of 1 which provides two stereogenic centers (C1 and C2) of the
final compounds and secures the stereocontrol of the key reductive coupling reaction from γ,δꢀ
unsaturated aldehydes III (Scheme 1).
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Scheme 1. Retrosynthetic analysis.
This pivotal step based on an intramolecular SmI2ꢀmediated carbonylꢀalkene coupling12 was
expected to provide cyclobutanols II with the four contiguous stereogenic centers of the target
molecules of type I with predictable stereocontrol. The absolute configuration of the resulting
alcohol at C3 may be directly inverted to provide access to further members of carbaoxetanoses
of type I’. 4ꢀMembered carbasugars of type I and I’ may be seen as simplified structural
analogues of hexopyranoses in the
Dꢀgluco and Dꢀgalacto series respectively lacking the
endocyclic oxygen and the anomeric carbon. They may be seen also as analogues of
pentofuranoses in the
(Scheme 2).
Dꢀarabino (type I) or Dꢀlyxo (type I’) series lacking the endocyclic oxygen
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Scheme 2. αꢀ
analogues 5aꢀcarbaꢀαꢀ
D
ꢀGlucopyranose (2), αꢀ
D
ꢀarabinofuranose (3) and their corresponding carbasugar
D
ꢀglucopyranose (4)3 and carbaoxetanose 5 (this study).
The synthesis began with the Oꢀbenzylation of γꢀlactone 6 obtained in three steps from vitamin C
according to a procedure reported by Eschenmoser et al. (Scheme 3).13 Reduction of 2,3ꢀdiꢀOꢀ
benzylꢀL
ꢀthreonolactone (7)14 using DIBALꢀH provided the corresponding lactol 8 which was
readily converted to the α,βꢀunsaturated esters 9 obtained as a separable 1:2 mixture of Zꢀ and Eꢀ
isomers by treatment with ethyl(triphenylphosphoranylidene)acetate (11) in the presence of
catalytic amount of benzoic acid.15
Scheme 3. Reagents and conditions: (a) BnBr (5 equiv), CaSO4 (5 equiv), Ag2O (4 equiv),
CH3CN, rt, 48 h, 79%; (b) DIBALꢀH (1.9 equiv), THF, −78 °C, 2.5 h, 85%; (c) 11 (1.2 equiv),
PhCO2H (0.03 equiv), CH2Cl2, reflux, 97% (Z/E, 1:2); (d) (ClCO)2 (2.2 equiv), DMSO (4.6
equiv), NEt3 (5.5 equiv), CH2Cl2, −78 to −20 °C, 79% [(Z/E)-10)], 79% [(Z)-10)], 74% [(E)-10)].
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Swern oxidation performed on the mixture of alcohols 9, or on the corresponding pure (E)ꢀ or
(Z)ꢀstereoisomers, afforded the desired γ,δꢀunsaturated aldehydes 10 in good yields. The key
SmI2ꢀmediated 4ꢀexoꢀtrig radical cyclization was first evaluated from the pure alkene (E)ꢀ10. In a
first attempt, treatment of (E)ꢀ10 with SmI2 at ꢀ78°C in the presence of HMPA did not lead to the
formation of the expected cyclobutanol ring (Table 1, entry 1).16 The only identified product was
the conjugated aldehyde 13 resulting from the elimination of a benzyloxy group. The formation
of this sideꢀproduct which is favored by conjugation further highlights that γ,δꢀunsaturated
aldehyde 10 is a challenging substrate for 4ꢀexoꢀtrig radical cyclization reactions. Small amount
of the desired cyclized product 12 (~ 15%) could nevertheless be obtained by increasing the
reaction time and temperature (entry 2) or using MeOH17 as a proton source (entry 3).
Cyclization of 10 was found to proceed with complete anti selectivity12a affording the desired
cyclobutanol 12 as a single diastereoisomer with the desired stereochemistry. The absolute
configuration of the two new stereogenic centers were unambiguously determined by 2D COSY
and NOESY NMR experiments. In particular, the definite NOE effects between Hꢀ1 and Hꢀ3, and
between Hꢀ2 and Hꢀ4 were crucial to establish the Rꢀconfiguration at Cꢀ3 and Cꢀ4 (See
supporting information). In the presence of MeOH, the yield of the cyclization process could be
tripled to 42% by shortening the reaction time to 10 minutes (entries 3ꢀ6). Addition of more
equivalents of MeOH (entry 5) did not improve the efficiency of the coupling reaction. It is
noteworthy that the coupling process performed from the TBDMS protected analogues of 10 led
only to partial recovery of starting material. We then evaluated the impact of the double bond
configuration on the cyclization outcome. Pleasingly, treatment of alkene (Z)ꢀ10 under our first
optimized reaction conditions led to the desired cyclobutanol 12 in high diastereoselectivity and
in similar yield than from the corresponding Eꢀstereoisomer (entries 6ꢀ7). The SmI2ꢀmediated
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radical coupling reaction was then performed directly from the E/Z mixture of 10 leading to a
more efficient synthetic sequence and better overall yields, by avoiding the separation of
diastereoisomers. Further optimization was performed with a combination of SmI2 and
LiBr/proton source additives18 by analogy with the reaction conditions reported recently for the
crossꢀcoupling of nitrones with βꢀsilyl acrylates (entries 8ꢀ10).19 Similar to the results obtained
by S. Py et al.19 for this crossꢀcoupling, the optimum reaction conditions were obtained with the
use of hexafluoroisopropanol (HFIP) as a proton source, with 12 being isolated in 57ꢀ67% yield
(entries 9 and 10). The optimum reaction time was found to be related to the amount of substrate
used with one minute for ca. 0.06 mmol of 10 as a rule of thumb (entries 9 and 10).
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Table 1. SmI2ꢀmediated 4ꢀexoꢀtrig radical cyclization of 10.a
Entry
10
SmI2
Additives
(equiv.)
Time
(min.) (yield)
12b
(Z/E) (equiv.)
1
2c
3d
4
5
6
0/1
0/1
0/1
0/1
0/1
0/1
1/0
1/2
3
3
3
3
3
3
3
4
HMPA (6.8)
HMPA (6.8)
MeOH (3)
MeOH (3)
MeOH (22)
MeOH (3)
MeOH (3)
H2O/LiBr
(8/12)
120
960
960
150
135
10
ꢀ
15%
14%
28%
21%
42%
35%
48%
7
8
10
5
9
1/2
1/2
4
4
HFIP/LiBr
(8/12)
HFIP/LiBr
5
67%
57%
10e
19e
(8/12)
b
a Reaction performed with 0.3 mmol of 10. Isolated yield.c -78°C to r.t.
d 0°C to r.t. e Reaction performed with 1.2 mmol of 10.
The complete anti selectivity observed for the 4ꢀexoꢀtrig cyclization of aldehyde 10 can be
rationalized considering the four possible transition state structures depicted in Scheme 4.12a
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From Eꢀ or Zꢀalkene substrates 10, synꢀ(E)ꢀTS or synꢀ(Z)ꢀTS leading to the 1,4ꢀcis product are
disfavored mainly by electrostatic repulsion between the O1 oxygen lone pairs and the
developing electron density in α to the ester group. The all antiꢀ(E)ꢀTS and all antiꢀ(Z)ꢀTS
leading to the allꢀtrans product 12 are electronically and sterically favored since the above
mentioned electrostatic interactions as well as the steric hindrance between vicinal substituents
are minimized.
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(E)-10
x
BnO
1
SmIII
2
O
3
BnO
O
O
BnO
BnO
4
SmIII
OEt
.
O
syn-(E)-TS
all anti-(E)-TS
OEt
1,4-cis product
12
BnO
BnO
BnO
SmIII
BnO
O SmIII
.
O
.
O
O
OEt
x
OEt
(Z)-10
all anti-(Z)-TS
syn-(Z)-TS
Scheme 4. Possible transition states for the intramolecular SmI2-mediated aldehyde-alkene
coupling.
Having in hand the key intermediate 12, we first prepared 4ꢀmembered carbasugar 15 with a
hydroxyethyl group at C4 as its synthesis required only two steps. Reduction of ester 12 with
LAH followed by catalytic hydrogenolysis of the benzyl protecting groups provided tetrol 15
(Scheme 5). Synthesis of 5 that may be seen as a structurally simplified analogue of
Dꢀ
glucopyranose or αꢀ ꢀarabinofuranose required the dehomologation of the side chain in 14 by
D
one methylene unit. As a prelude to the dihydroxylationꢀdehomologation sequence, alkene 16
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was synthesized from alcohol 14 via Grieco elimination.20 Treatment of alcohol 14 with oꢀ
nitrophenylselenocyanate and tributylphosphine provided a selenide derivative. This intermediate
was directly oxidized with Davis oxaziridine20b to give the corresponding selenoxide in which a
Copeꢀtype elimination took place with expulsion of a selenol to afford the desired alkene 16.
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Scheme 5. Reagents and conditions: (a) SmI2 (4 equiv), LiBr (12 equiv), HFIP (8 equiv), THF,
−78 °C, 5 min, 67%; (b) LAH (1.5 equiv), THF, rt, 2.5 h, 68%; (c) Pd/C 10%, HCO2H, H2,
EtOH, rt, 16 h, quant.; (d) oꢀNO2PhSeCN (2.2 equiv), nꢀBu3P (2.2 equiv), THF, 35 min; (e)
Davis oxaziridine (1.2 equiv), CH2Cl2, 0 °C, 40 min, 84% in two steps; (f) TBSCl (1.5 equiv),
DMAP (0.5 equiv), NEt3 (2 equiv), CH2Cl2, rt, 14 h, 77%; (g) OsO4 (0.04 equiv), NaIO4 (1.9
equiv), THF/H2O (4:1), rt, 5 h; (h) NaBH4 (1.2 equiv), MeOH, rt, 15 min, 82% in two steps; (i)
TBAF (5 equiv), THF, rt, 4 h, quant.; (j) Pd/C 10%, HCO2H, H2, EtOH, rt, 16 h, quant.
Protection of the secondary alcohol as a TBS ether to provide compound 17 in 77% yield from 14
was found to be necessary for effective olefin cleavage. Olefin 17 was treated under Lemieuxꢀ
Johnson oxidative cleavage conditions to give the primary alcohol 18 in 82% yield after
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reduction with NaBH4. The deprotected carbaoxetanose 5 was finally obtained in quantitative
yield after removal of the TBS group in 18 using TBAF followed by hydrogenolysis of the
benzyl protecting groups. Access to other members of carbaoxetanoses as simplified mimetics of
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D
ꢀgalactopyranose or Dꢀlyxofuranose was easily achieved by inversion of configuration at C3
(Scheme 6). Benzylation of the primary hydroxyl group in 18 followed by treatment of the
resulting product 20 with TBAF afforded the key alcohol intermediate 21. Oxidation of 21 with
DessꢀMartin periodinane reagent provided the corresponding ketone 22 which was reduced with
Lꢀselectride. This diastereoselective process gave the desired alcohol 23 in 62% yield from the
corresponding C3 epimer 21. Deprotection of 23 by hydrogenolysis under acidic conditions
afforded cyclobutanic pseudo galactose 24.
Scheme 6. Reagents and conditions: (a) NaH (1.3 equiv), BnBr (1.2 equiv), THF, rt, 18 h, 49%
(73% based on recovered starting material); (b) TBAF (5 equiv), THF, rt, 3 h, 97%; (c) DMP (1.6
equiv), CH2Cl2, rt, 92%; (d) Lꢀselectride (1.1 equiv), THF, −78 °C, 1 h, 67%; (e) Pd/C 10%,
HCO2H, H2, EtOH, rt, 20 h, quant.
In conclusion, we have reported the stereodivergent synthesis of the first members of a new class
of carbasugars by way of an efficient intramolecular SmI2ꢀmediated aldehydeꢀalkene coupling
using a combination of LiBr/HFIP additives. In this key step, despite the high density of
functional groups, cylobutanes with four contiguous asymmetric centers are generated with a
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high level of stereocontrol in reproducible yields. Beyond the synthesis of carbaoxetanoses and
analogues, this process may find application in the stereocontrolled synthesis of functionalized
cyclobutanes.
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Experimental Section
(3R,4S)ꢀ3,4ꢀBis(benzyloxy)dihydrofuranꢀ2(3H)ꢀone (7). To lactone 6 (12.89 mmol, 1 equiv) in
dry CH3CN (73 mL) were added BnBr (7.7 mL, 64.5 mmol, 5 equiv) and CaSO4 (8.77 g, 64.5
mmol, 5 equiv). The solution was stirred for 5 min and the flask was covered with aluminium
foil. Ag2O (5.97 g, 25.8 mmol, 2 equiv) was added in 3 portions over 5 min. The solution was
stirred for 12 h at which point a second portion of Ag2O (5.97 g, 25.78 mmol, 2 equiv) was
added. The resulting mixture was stirred for 36 h. The reaction mixture was then filtered through
a pad of celite and the resulting filter cake was washed with CH3CN (3 × 30 mL). The solution
was concentrated under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether, 1:9 to 1:3) to afford the desired lactone 7 (3.04 g, 79%)
as a colorless oil. Spectroscopic data are in accordance with literature data.14
(3R,4S)ꢀ3,4ꢀBis(benzyloxy)tetrahydrofuranꢀ2ꢀol (8). DIBALꢀH (1 M in hexane, 9 mL, 9.0 mmol,
1.9 equiv) was added to a solution of lactone 7 (1.37 g, 4.59 mmol, 1 equiv) in THF (7 mL)
cooled to −78 °C. The solution was stirred at −78 °C for 2.5 h. MeOH (0.69 mL) was slowly
added and the reaction mixture was warmed up to rt. After 5 min, saturated aqueous sodium
potassium tartrate (6 mL) was added. The solution was stirred overnight. The organic phase was
washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (EtOAc/petroleum ether, 1:3 to 1:2) to
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afford the desired lactol 8 (1.18 g, 85%) as a colorless oil. TLC Rf 0.19 (silica gel,
5
6
1
EtOAc/petroleum ether, 1:3); H NMR (300 MHz, CDCl3) δ 7.42 – 7.24 (m, 10H), 5.44 (dd, J =
7
8
9
8.5, 4.2 Hz, 0.4H, α isomer), 5.33 (d, J = 9.9 Hz, 0.6H, β isomer), 4.66 – 4.60 (m, 2H), 4.56 –
4.47 (m, 2H), 4.22 – 4.05 (m, 2.6H), 4.01 – 3.94 (m, 1H), 3.84 – 3.78 (m, 0.4H, α isomer), 3.69
(d, J = 8.6 Hz, 0.4H, α isomer), 3.29 (d, J = 10.1 Hz, 0.6H, β isomer). Spectroscopic data are in
accordance with literature data of its enantiomer.21
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(4S,5S,E)ꢀEthyl 4,5ꢀbis(benzyloxy)ꢀ6ꢀhydroxyhexꢀ2ꢀenoate ((E)-9) and (4S,5S,Z)ꢀethyl 4,5ꢀ
bis(benzyloxy)ꢀ6ꢀhydroxyhexꢀ2ꢀenoate ((Z)-9). To a solution of lactol 8 (1.85 g, 6.17 mmol, 1
equiv) in CH2Cl2 (31 mL), was added (Ethoxycarbonylmethylene)triphenylphosphorane 11 (2.58
g, 7.40 mmol, 1.2 equiv) followed by benzoic acid (23 mg, 1.85 mmol, 0.03 equiv). The mixture
was refluxed for 15 h. After cooling, the solution was concentrated under reduced pressure. The
crude product was purified by flash chromatography (EtOAc/petroleum ether, 1:3 to 1:1) to
afford the desired alcohol 9 (2.22 g, 97%, Z/E (1:2)) as a colorless oil. (E)-9: TLC Rf 0.38 (silica
gel, EtOAc/petroleum ether, 1:2); [α]D20 = +7 (c 1.1, CHCl3); IR (film) 3417, 2873, 1715 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ 7.40 – 7.24 (m, 10H), 6.95 (dd, J = 15.9, 5.9 Hz, 1H), 6.11 (dd, J =
15.9, 1.3 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.7 Hz, 1H),
4.42 (d, J = 11.7 Hz, 1H), 4.27 – 4.18 (m, 3H), 3.73 (dd, J = 10.9, 3.8 Hz, 1H), 3.68 – 3.53 (m,
13
2H), 1.32 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 166.0, 144.2, 138.1, 137.7, 128.6,
128.1, 128.0, 123.8, 80.7, 78.6, 73.5, 71.9, 62.0, 60.7, 14.4; HRMS (ESI) m/z 393.166 ([M+Na]+,
calcd. for C22H26O5Na: 393.167).
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(Z)-9: TLC Rf 0.43 (silica gel, EtOAc/petroleum ether, 1:2); [α]D20 = +16 (c 1.0, CHCl3); IR (film)
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3463, 2870, 1715 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.31 – 7.17 (m, 10H), 6.22 (dd, J = 11.7,
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9.1 Hz, 1H), 5.92 (d, J = 11.7 Hz, 1H), 5.27 (dd, J = 9.0, 4.0 Hz, 1H), 4.68 (d, J = 11.7 Hz, 1H),
4.58 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H,), 4.39 (d, J = 11.7 Hz, 1H), 4.08 (q, J = 7.1
Hz, 2H), 3.75 – 3.68 (m, 3H), 2.45 – 2.17 (br s, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.0, 146.8, 138.4, 138.0, 128.5, 128.4, 128.10, 128.07, 127.9, 127.8, 123.2, 80.9,
75.6, 73.2, 71.9, 62.1, 60.6, 14.2; HRMS (ESI) m/z 393.167 ([M+Na]+, calcd. for C22H26O5Na:
393.167).
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(4S,5R,E)ꢀEthyl 4,5ꢀbis(benzyloxy)ꢀ6ꢀoxohexꢀ2ꢀenoate ((E)-10) and (4S,5R,Z)ꢀethyl 4,5ꢀ
bis(benzyloxy)ꢀ6ꢀoxohexꢀ2ꢀenoate ((Z)-10). A solution of DMSO (0.60 mL, 8.50 mmol, 4.6
equiv) in CH2Cl2 (4.6 mL) was slowly added to a solution of oxalyl chloride (0.35 mL, 4.07
mmol, 2.2 equiv) in CH2Cl2 (8.8 mL) cooled to −78 °C. The solution was stirred for 30 min. A
solution of alcohol 9 (685 mg, 1.85 mmol, 1 equiv) in CH2Cl2 (8.8 mL) was slowly added. The
solution was stirred for 1 h. A solution of NEt3 (1.4 mL, 10.16 mmol, 5.5 equiv) in CH2Cl2
(8.8 mL) was slowly added and the solution was stirred for 1.25 h. The reaction mixture was
warmed up to −20 °C. Water (58 mL) was added and the product was extracted with CH2Cl2
(3×). The combined organic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chromatography
(EtOAc/petroleum ether, 1:7 to 1:2) to afford the desired aldehyde 10 (554 mg, 79%, Z/E
(1:2)) as a pale yellow oil.
(E)-10: TLC Rf 0.59 (silica gel, EtOAc/petroleum ether, 1:2); [α]D20 = +61 (c 1.0, CHCl3); IR
(film) 1717 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 9.66 (d, J = 1.0 Hz, 1H), 7.40 – 7.20 (m, 10H),
6.95 (dd, J = 15.7, 7.2 Hz, 1H), 6.09 (dd, J = 15.9, 1.0 Hz, 1H), 4.80 – 4.55 (m, 4H), 4.35 (m,
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1H), 4.23 (q, J = 7.2 Hz, 2H), 3.83 (dd, J = 3.9, 1.1 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 202.0, 165.7, 143.1, 137.0, 136.7, 128.7, 128.6, 128.44, 128.41, 128.22,
128.16, 124.5, 84.0, 77.9, 73.7, 72.0, 60.8, 14.4; HRMS (ESI) m/z 391.151 ([M+Na]+, calcd. for
C22H24O5Na: 391.152).
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(Z)-10: TLC Rf 0.41 (silica gel, EtOAc/petroleum ether, 1:2); [α]D20 = +89 (c 1.0, CHCl3); IR
1
(film) 1732, 1714 cmꢀ1; H NMR (300 MHz, CDCl3) δ 9.60 (d, J = 1.0 Hz, 1H), 7.35 – 7.16 (m,
10H), 6.31 (dd, J = 11.7, 8.1 Hz, 1H), 5.86 (dd, J = 11.7, 1.5 Hz, 1H), 5.41 (ddd, J = 8.1, 3.6, 1.4
Hz, 1H), 4.72 (d, J = 12.1 Hz, 1H), 4.57 – 4.48 (m, 2H), 4.34 (d, J = 11.9 Hz, 1H), 4.07 (q, J =
7.2 Hz, 2H), 3.99 (dd, J = 3.6, 1.1 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 201.5, 165.6, 146.8, 137.4, 137.1, 128.53, 128.48, 128.4, 128.23, 128.21, 128.0, 122.8, 85.3,
75.1, 73.8, 72.2, 60.7, 14.3; HRMS (ESI) m/z 391.151 ([M+Na]+, calcd. for C22H24O5Na:
391.152).
Ethyl 2ꢀ((1R,2S,3S,4R)ꢀ2,3ꢀbis(benzyloxy)ꢀ4ꢀhydroxycyclobutyl)acetate (12). SmI2 (0.1 M in
THF, 12.5 mL, 1.25 mmol, 4 equiv) was added to LiBr (325 mg, 3.74 mmol, 12 equiv) in a flask
covered with aluminium foil. The solution was stirred for 20 min and then cooled to −78 °C.
HFIP (0.26 mL, 2.50 mmol, 8 equiv) followed by a solution of aldehyde 10 (115 mg, 0.31 mmol,
1 equiv) in degassed THF (10.6 mL) were added. The solution was stirred for 5 min and HCl 1N
(15.5 mL) was added. The solution was then stirred at rt for 30 min. The product was extracted
with CH2Cl2 (3×). The combined organic layer was washed with saturated aqueous NaHSO3,
dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by flash chromatography (EtOAc/petroleum ether, 1:5 to 1:1) to afford the desired
cyclobutane 12 (78 mg, 67%) as a yellow oil. TLC Rf 0.34 (silica gel, EtOAc/petroleum ether,
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1:2); [α]D20 = −32 (c 1.0, CHCl3); IR (film) 3444, 1731 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.34
– 7.17 (m, 10H), 4.62 (d, J = 11.7 Hz, 1H), 4.57 – 4.47 (m, 2H), 4.42 (d, J = 11.9 Hz, 1H), 4.07
(q, J = 7.2 Hz, 2H), 3.81 (t, J = 5.8 Hz, 1H), 3.51 (t, J = 6.6 Hz, 1H), 3.32 (m, 1H), 3.17 (br s,
1H), 2.65 (dd, J = 16.7, 4.7 Hz, 1H), 2.65 (dd, J = 16.7, 10.7 Hz, 1H), 1.93 (m, 1H), 1.19 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 138.2, 138.1, 128.6, 128.5, 128.0, 127.9,
127.8, 85.1, 76.9, 72.3, 71.63, 71.56, 61.1, 40.2, 36.7, 14.3; HRMS (ESI) m/z 393.167 ([M+Na]+,
calcd. for C22H26O5Na: 393.167).
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(1R,2S,3S,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ(2ꢀhydroxyethyl)cyclobutanol (14). LAH (13 mg, 0.33
mmol, 1.5 equiv) was added to a solution of ester 12 (82 mg, 0.22 mmol, 1 equiv) in THF (1.2
mL) cooled at 0 °C. The solution was stirred at rt for 2.5 h. After cooling at 0 °C, H2O (0.01
mL) followed by aqueous 10% NaOH (0.02 mL) and H2O (0.03 mL) were added. The solution
was filtered and concentrated under reduced pressure. The crude product was purified by
flash chromatography (EtOAc/petroleum ether, 1:1 to 4:1) to afford the desired diol 14 (50
mg, 68%) as a white solid. TLC Rf 0.16 (silica gel, EtOAc/petroleum ether, 2:1); [α]D20 = −9 (c
1.0, CHCl3); IR (film) 3379 cm-1; H NMR (300 MHz, CDCl3)
δ
7.41 – 7.25 (m, 10H), 4.67 –
1
4.57 (m, 3H), 4.53 (d, J = 11.7 Hz, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.71 (m, 1H), 3.61 (m, 1H),
3.42 (t, J = 6.5 Hz, 1H), 3.36 (m, 1H), 2.96 – 2.75 (br s, 2H), 1.79 (m, 1H), 1.73 – 1.59 (m,
2H); 13C NMR (75 MHz, CDCl3)
δ
138.3, 138.0, 128.6, 128.5, 128.03, 127.95, 127.9, 85.8, 76.9,
72.4, 71.71, 71.66, 62.0, 42.7, 34.6; HRMS (ESI) m/z 351.155 ([M+Na]+, calcd. for
C20H24O4Na: 351.157).
General method A for debenzylation. Pd/C 10% (10% weight) and HCO2H (2 drops) were
added to a solution of cyclobutane derivatives in EtOH (0.083 M). The solution was placed under
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H2 atmosphere and stirred until disappearance of the starting material (16 h). The solution was
filtered through celite and concentrated under reduced pressure. The crude product was purified
by flash chromatography.
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(1R,2r,3S,4s)ꢀ4ꢀ(2ꢀHydroxyethyl)cyclobutaneꢀ1,2,3ꢀtriol (15). According to general method A: 14
(250 mg, 0.76 mmol) afforded the tetrol 15 (112 mg, quant.) as a colorless oil. TLC Rf 0.19 (silica
gel MeOH/CH2Cl2, 2:8); IR (neat) 3274, 1050, 1024 cmꢀ1; 1H NMR (300 MHz, MeOD) δ 3.65 (t,
J = 6.9 Hz, 2H), 3.55 (t, J = 6.3 Hz, 1H), 3.17 (dd, J = 7.8, 6.2 Hz, 2H), 1.79 (q, J = 7.1 Hz, 2H),
1.47 (m, 1H); 13C NMR (75 MHz, MeOD) δ 81.7, 73.8, 61.5, 44.0, 36.0; HRMS (ESI) m/z
171.065 ([M+Na]+, calcd. for C6H12O4Na: 171.063).
(1R,2S,3S,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀvinylcyclobutanol (16). To a solution of diol 14 (200 mg,
0.61 mmol, 1 equiv) in THF (20 mL) were added 2ꢀnitrophenyl selenocyanate (304 mg, 1.34
mmol, 2.2 equiv) in one portion followed by tributylphosphine (0.33 mL, 1.34 mmol, 2.2 equiv)
dropwise. The solution was stirred at rt for 35 min. Water was added and the product was
extracted with Et2O (3×). The combined organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure. A solution of the crude selenyl derivative in CH2Cl2 (8 mL)
was added to a solution of Davis oxaziridine20b (191 mg, 0.73 mmol, 1.2 equiv) in CH2Cl2 (10
mL) cooled to 0 °C. The solution was stirred at 0 °C for 40 min. Saturated aqueous Na2CO3 (6
mL) was added and the solution was stirred at rt for 1 h. The product was extracted with CH2Cl2
(3×). The combined organic layer was washed with saturated aqueous NaHSO3, dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
flash chromatography (EtOAc/petroleum ether, 1:7 to 1:3) to afford the desired vinylcyclobutanol
20
16 (160 mg, 84%) as a yellow oil. TLC Rf 0.49 (silica gel, EtOAc/petroleum ether, 1:2); [α]D
=
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+14 (c 1.0, CHCl3); IR (film) 3392, 2871, 1087 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.33 − 7.16
(m, 10H), 5.80 (ddd, J = 17.3, 10.1, 7.4 Hz, 1H), 5.09 (d, J = 17.0 Hz, 1H), 5.01 (d, J = 10.2 Hz,
1H), 4.59 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.44 (d, J =
11.9 Hz, 1H), 3.73 (t, J = 5.9 Hz, 1H), 3.50 (m, 1H), 3.42 (m, 1H), 2.25 (q, J = 7.7 Hz, 1H), 2.19
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− 2.10 (br s, 1H); C NMR (75 MHz, CDCl3) δ 138.2, 138.0, 137.0, 128.6, 128.5, 128.1, 128.0,
127.9, 127.8, 116.2 , 85.4, 76.9, 71.83, 71.81, 71.4, 48.3; HRMS (ESI) m/z 333.145 ([M+Na]+,
calcd. for C20H22O3Na: 333.146).
((1R,2R,3S,4S)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀvinylcyclobutoxy)(tertꢀbutyl)dimethylsilane (17). To
a
solution of 16 (99 mg, 0.32 mmol, 1 equiv) in CH2Cl2 (0.61 mL) cooled to 0 °C were added
TBSCl (72 mg, 0.48 mmol, 1.5 equiv), DMAP (20 mg, 0.16 mmol, 0.5 equiv) and NEt3
(0.09 mL, 0.64 mmol, 2 equiv). The solution was stirred at rt for 14 h. Water was added and the
product was extracted with CH2Cl2 (3×). The combined organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether, 3:97) to afford the desired cyclobutane 17 (105 mg,
77%) as a yellow oil. TLC Rf 0.42 (silica gel, EtOAc/petroleum ether, 1:19); [α]D20 = +6.5 (c 1.0,
CHCl3); IR (film) 2928, 2857, 1096 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.42 − 7.22 (m, 10H),
1
5.87 (ddd, J = 17.2, 10.1, 8.3 Hz, 1H), 5.14 (d, J = 17.2 Hz, 1H), 5.07 (d, J = 10.1 Hz, 1H), 4.65
(d, J = 11.7 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.7 Hz,
1H), 3.83 (t, J = 5.9 Hz, 1H), 3.62 (t, J = 6.5 Hz, 1H), 3.49 (t, J = 6.3 Hz, 1H), 2.33 (q, J = 7.6
13
Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); C NMR (75 MHz, CDCl3) δ 138.31, 138.26,
137.8, 128.5, 127.9, 127.7, 116.2, 85.5, 77.4, 72.4, 71.6, 71.3, 49.0, 25.9, 18.0, ꢀ4.0, ꢀ4.6. HRMS
(ESI) m/z 447.236 ([M+Na]+, calcd. for C26H36O3SiNa: 447.233).
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((1S,2S,3R,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ((tertꢀbutyldimethylsilyl)oxy)cyclobutyl)methanol (18). To a
solution of 17 (99 mg, 0.23 mmol, 1 equiv) in a mixture of THF/H2O (4:1, 0.7 mL) were added
OsO4 (2.5%wt in tBuOH, 0.09 mL, 0.009 mmol, 0.04 equiv) and NaIO4 (94 mg, 0.44 mmol, 1.9
equiv). The solution was stirred at rt for 5 h. Saturated aqueous Na2S2O3 was added and the
product was extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was dissolved in MeOH and the
solution was cooled to 0 °C. NaBH4 (11 mg, 0.29 mmol, 1.2 equiv) was added and the solution
was stirred at rt for 15 min. Acetone (0.5 mL) was added. The solution was stirred 5 min and then
concentrated under reduced pressure. The residue was dissolved in EtOAc and H2O and the
product was extracted with EtOAc (4×). The combined organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether, 3:97) to afford the desired alcohol 18 (82 mg, 82%) as
a colorless oil. TLC Rf 0.18 (silica gel, EtOAc/petroleum ether, 1:5); [α]D20 = +0.1 (c 1.0, CHCl3);
IR (film) 3454, 2929, 2857 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.38 – 7.25 (m, 10H), 4.64 (d, J
= 11.6 Hz, 1H), 4.58 (d, J = 12.7 Hz, 1H), 4.56 (s, 2H), 3.84 (t, J = 5.8 Hz, 1H), 3.76 (dd, J =
11.1, 4.5 Hz, 1H), 3.72 – 3.64 (m, 2H), 3.50 (m, 1H), 1.91 (m, 1H), 0.90 (s, 9H), 0.10 (s, 3H),
0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4, 138.3, 128.6, 128.5, 127.94, 127.87, 127.8,
127.7, 85.9, 74.8, 71.7, 71.6, 68.2, 62.0, 47.0, 25.9, 18.1, ꢀ4.4, ꢀ4.6; HRMS (ESI) m/z 451.230
([M+Na]+, calcd. for C25H36O4SiNa: 451.228).
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(1R,2S,3S,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ(hydroxymethyl)cyclobutanol (19). TBAF (1 M in THF, 3.1
mL, 3.1 mmol, 5 equiv) was added to a solution of 18 (264 mg, 0.62 mmol, 1 equiv) in THF (1
mL). The solution was stirred at rt for 4 h. Saturated aqueous NH4Cl was added and the product
was extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, filtered and
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concentrated under reduced pressure. The crude product was purified by flash chromatography
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(MeOH/CH2Cl2, 3:97 to 5:95) to afford the desired diol 19 (197 mg, quant.) as a colorless oil.
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TLC Rf 0.49 (silica gel, MeOH/CH2Cl2, 10:90); [α]D = +21 (c 1.0, MeOH); IR (neat) 3369,
2930, 2871 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.40 – 7.35 (m, 10H), 4.65 (d, J = 11.9 Hz, 1H),
4.58 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H), 3.80 (t, J = 5.7
Hz, 1H), 3.73 (dd, J = 11.1, 5.0 Hz, 1H), 3.65 – 3.55 (m, 2H), 3.45 (m, 1H), 2.68 – 2.56 (br s,
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1H), 2.18 – 2.07 (br s, 1H), 1.89 (m, 1H); C NMR (100 MHz, CDCl3) δ 138.3, 138.2, 128.63,
128.58, 128.1, 128.01, 127.98, 127.94, 85.8, 74.2, 71.79, 71.77, 69.3, 62.4, 46.5; HRMS (ESI)
m/z 337.143 ([M+Na]+, calcd. for C19H22O4Na: 337.141).
(1R,2r,3S,4s)ꢀ4ꢀ(Hydroxymethyl)cyclobutaneꢀ1,2,3ꢀtriol (5). According to general method A: 19
(80 mg, 0.25 mmol) afforded the tetrol 5 (33 mg, quant.) as a colorless oil. TLC Rf 0.28 (silica
gel, CH3CN/H2O/NH4OH, 5:1:1); IR (film) 3237, 1068 cmꢀ1; 1H NMR (300 MHz, D2O) δ 3.80 −
13
3.71 (m, 3H), 3.50 − 3.42 (m, 2H), 1.76 (m, 1H); C NMR (75 MHz, D2O) δ 79.1, 68.1, 60.2,
46.2; HRMS (ESI) m/z 157.048 ([M+Na]+, calcd. for C5H10O4Na: 157.047).
((1R,2R,3S,4S)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ((benzyloxy)methyl)cyclobutoxy)(tertꢀbutyl)dimethylsilane
(20). NaH (17 mg, 0.41 mmol, 1.3 equiv) was added to a solution of 18 (136 mg, 0.32 mmol, 1
equiv) in THF (1.7 mL) cooled at 0 °C. The solution was stirred at rt for 30 min. BnBr (45 ꢁL,
0.38 mmol, 1.2 equiv) was then added. The solution was stirred at rt for 18 h. Water was added
and the product was extracted with CH2Cl2 (3×). The combined organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
flash chromatography (EtOAc/petroleum ether, 3:97 to 15:85) to afford the desired cyclobutane
20 (80 mg, 49%) as a colorless oil. TLC Rf 0.51 (silica gel, EtOAc/petroleum ether, 1:9); IR
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(film) 2929, 2856, 1096 cmꢀ1; [α]D20 = +2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.40 –
1
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7.23 (m, 15H), 4.64 (d, J = 11.7 Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 12.1 Hz, 1H),
4.54 – 4.46 (m, 3H), 3.84 (t, J = 5.7 Hz, 1H), 3.73 (m, 1H), 3.60 – 3.47 (m, 3H), 1.97 (m, 1H),
0.89 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 138.5, 138.4, 128.5,
127.89, 127.86, 127.81,127.7, 86.0, 75.1, 73.2, 71.6, 71.5, 68.9, 68.4, 45.3, 25.9, 18.1, ꢀ4.4, ꢀ4.6;
HRMS (ESI) m/z 541.274 ([M+Na]+, calcd. for C32H42O4SiNa: 541.274).
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(1R,2S,3S,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ((benzyloxy)methyl)cyclobutanol (21). TBAF (1 M in THF,
1.1 mL, 1.10 mmol, 5 equiv) was added to a solution of 20 (113 mg, 0.22 mmol, 1 equiv) in THF
(0.4 mL). The solution was stirred at rt for 3 h. Saturated aqueous NH4Cl was added and the
product was extracted with EtOAc (3×). The combined organic layer was dried over MgSO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether, 3:97 to 15:85) to afford the desired cyclobutanol 21
(85 mg, 97%) as a colorless oil. TLC Rf 0.29 (silica gel, EtOAc/petroleum ether, 1:2); IR (film)
3406, 2861, 1051 cmꢀ1; [α]D20 = −3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42 – 7.25 (m,
15H), 4.67 (d, J = 11.9 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 4.56 (s, 2H), 4.52 (s, 2H), 3.83 (t, J =
13
5.9 Hz, 1H), 3.65 (m, 1H), 3.61 – 3.47 (m, 3H), 2.41 – 2.26 (br s, 1H), 2.00 (m, 1H); C NMR
(75 MHz, CDCl3) δ 138.3, 128.55, 128.50, 128.46, 128.1, 127.9, 127.7, 85.7, 74.6, 73.2, 71.7,
71.6, 69.5, 69.3, 44.8; HRMS (ESI) m/z 427.191 ([M+Na]+, calcd. for C26H28O4Na: 427.188).
(2R,3S,4S)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ((benzyloxy)methyl)cyclobutanone
(22).
DessꢀMartin
Periodinane (0.3 M in CH2Cl2, 0.5 mL, 0.15 mmol, 1.6 equiv) was added to a solution of alcohol
21 (37.5 mg, 0.093 mmol, 1 equiv) in CH2Cl2 (0.35 mL) cooled at 0 °C. The solution was stirred
at rt for 1 h. Saturated aqueous Na2S2O3 was added and the product was extracted with CH2Cl2
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(3×). The combined organic layer was washed with saturated aqueous NaHCO3, dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
flash chromatography (EtOAc/petroleum ether, 1:7 to 1:5) to afford the desired cyclobutanone 22
(34.5 mg, 92%) as a colorless oil. TLC Rf 0.62 (silica gel, EtOAc/petroleum ether, 1:2); IR (film)
2862, 1786, 1116 cmꢀ1; [α]D20 = +33 (c 1.0, CHCl3); 1H NMR (300 MHz, C6D6) δ 7.31 – 7.01 (m,
15H), 4.69 (d, J = 11.9 Hz, 1H), 4.58 (m, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 12.2 Hz,
1H), 4.44 (d, J = 12.2 Hz, 1H), 4.31 (m, 1H), 4.18 (s, 2H), 3.35 (d, J = 2.0 Hz, 1H), 3.33 (d, J =
0.7 Hz, 1H), 2.84 (m, 1H); 13C NMR (75 MHz, C6D6) δ 203.2, 138.6, 138.5, 138.0, 128.63,
128.61, 128.2, 127.9, 127.8, 91.3, 74.4, 73.2, 72.4, 72.2, 65.8, 58.2; HRMS (ESI) m/z 425.174
([M+Na]+, calcd. for C26H26O4Na: 425.172).
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(1S,2S,3S,4R)ꢀ2,3ꢀBis(benzyloxy)ꢀ4ꢀ((benzyloxy)methyl)cyclobutanol (23). LꢀSelectride (1 M in
THF, 0.18 mL, 0.18 mmol, 1.1 equiv) was added to a solution of ketone 22 (66 mg, 0.16 mmol, 1
equiv) in THF (0.66 mL) cooled to −78 °C. The solution was stirred for 1 h. Water (0.01 mL)
was added and the solution was warmed up to 0 °C. Aqueous 35% H2O2 (0.02 mL) was added
and the solution was diluted in EtOAc. The organic layer was washed with saturated aqueous
Na2SO3, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether, 1:5 to 1:2) to afford the desired cyclobutanol 23 (44
mg, 67%) as a colorless oil. TLC Rf 0.34 (silica gel, EtOAc/petroleum ether, 1:2); IR (film) 3455,
2863, 1100 cmꢀ1; [α]D20 = +9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.39 – 7.24 (m, 15H),
4.57 (s, 2H), 4.54 – 4.46 (m, 4H), 4.31 (m, 1H), 4.04 (dd, J = 8.2, 6.2 Hz, 1H), 3.87 (m, 1H), 3,73
(dd, J = 9.7, 7.4 Hz, 1H), 3.63 (dd, J = 9.7, 5.5 Hz, 1H), 2.40 (d, J = 4.1 Hz, 1H), 2.19 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 138.4, 138.3, 137.8, 128.7, 128.5, 128.21, 128.18, 127.9, 127.85,
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127.80, 127.76, 81.3, 78.1, 73.3, 72.0, 71.9, 67.4, 64.7, 41.6; HRMS (ESI) m/z 427.187
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([M+Na]+, calcd. for C26H28O4Na: 427.188).
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(1S,2R,3S,4S)ꢀ4ꢀ(Hydroxymethyl)cyclobutaneꢀ1,2,3ꢀtriol (24). General method A was used: 23
(44 mg, 0.11 mmol) to afford the tetrol 24 (14.5 mg, quant.) as a white solid. TLC Rf 0.26 (silica
gel, CH3CN/H2O/NH4OH, 5:1:1); IR (neat) 3207, 1051 cmꢀ1; [α]D20 = −42 (c 0.5, H2O); 1H NMR
13
(300 MHz, D2O) δ 4.32 (m, 1H), 3.99 – 3.87 (m, 2H), 3.87 – 3.71 (m, 2H), 2.04 (m, 1H); C
NMR (75 MHz, D2O) δ 74.8, 72.0, 64.8, 58.0, 43.0; HRMS (ESI) m/z 157.047 ([M+Na]+, calcd.
for C5H10O4Na: 157.047).
Acknowledgment. This work was supported by the CNRS, the University of Strasbourg, and
the Institut Universitaire de France (IUF). P.ꢀA. N. thanks the French ministry of research for a
fellowship.
1
Supporting Information Available. H NMR and 13C NMR for all new compounds. This
material are available free of charge via the Internet at http://pubs.acs.org.
References and notes
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