Stereodivergent route to the carbocyclic core of 2′,3′-olefinic carbanucleosides: Toward the synthesis of (l)-(+)- and (d)-( - )-carbovir

Article abstract of DOI:10.1021/jo200670v

(R)-2,3-Cyclohexylideneglyceraldehyde (1) has been elegantly exploited for a stereodivergent construction of the potential precursors (11a and 11b) of (l)-(+)- and (d)-( - )-carbovirs, respectively. The key steps in this approach were Luche's allylation of formaldehyde with allylic bromide 4c to produce 5 and ring-closing metathesis of 10b using Grubbs' first-generation catalyst to obtain 11. The moderate stereoselectivity of Luche's allylation reaction resulted in attaining stereodivergence in this approach which could be realized finally through easy chromatographic separation of the two isomers of the metathesis product to obtain homochiral precursors 11a and 11b in good amounts.

Full text of DOI:10.1021/jo200670v

NOTE
pubs.acs.org/joc
Stereodivergent Route to the Carbocyclic Core of 20,30-Olefinic
Carbanucleosides: Toward the Synthesis of (L)-(þ)- and (D)-(ꢀ)-
Carbovir
Angshuman Chattopadhyay* and Sibanarayan Tripathy
Bio-Organic Division, Bhabha Atomic Research Center, Mumbai-400085, India
S Supporting Information
b
ABSTRACT: (R)-2,3-Cyclohexylideneglyceraldehyde (1) has
been elegantly exploited for a stereodivergent construction of
the potential precursors (11a and 11b) of (L)-(þ)- and
(D)-(ꢀ)-carbovirs, respectively. The key steps in this approach
were Luche’s allylation of formaldehyde with allylic bromide 4c
to produce 5 and ring-closing metathesis of 10b using Grubbs’
first-generation catalyst to obtain 11. The moderate stereose-
lectivity of Luche’s allylation reaction resulted in attaining
stereodivergence in this approach which could be realized
finally through easy chromatographic separation of the two isomers of the metathesis product to obtain homochiral precursors
11a and 11b in good amounts.
he emerging drug-resistant viral strains and toxicity are
major concerns in antiviral chemotherapy. To overcome
β-L-carbovir triphosphate exhibited more potent anti-HBV
activity.15,16 The above-mentioned findings prompted synthetic
chemists to develop various methodologies until recently for the
synthesis6,17 of both D- and L-carbovirs (III) and their various
analogues with a view to combating a wide range of viral diseases.
Furthermore, as representative examples of 20,30-olefinic carba-
nucleosides, any synthesis of either D-(III) or L-(III) assumes
considerable significance in view of its application for the
preparation of the similar isomers of other members of this class.
Retrosynthetic analysis (Scheme 1) of III suggested that for
convergent preparation of its (L)-(þ)- and (D)-(ꢀ)-enantiomers
it is desirable to construct the basic carbocyclic core, i.e., 1,4-
disubstituted 2,3-cyclopentene precursors (X1 and X2) which
should be amenable for stereodifferentiating necleobase addi-
tions in the desired manner compatible with the enantiomer of
III to be obtained. In this regard, there is a scope to develop
efficient strategies to have access to branched 1,6-dienes D1 and
D2 that would give rise to X1 and X2, respectively, through ring-
closing metathesis reaction.18 In our ongoing program on the
synthesis of bioactive compounds, we have been making versatile
application of easily accessible (R)-2,3-cyclohexylideneglyceral-
dehyde (1)19a for the synthesis of a number of biomolecules
possessing varied structural features.19 We present here another
novel application of 1 to develop a very simple and stereodiver-
gent route (Scheme 2) for simultaneous entry into two inter-
mediates 11a and 11b, which due to their structural similarity
with X2 and X1 are potentially useful precursors for formal
synthesis of L-(III) and D-(III), respectively.
T
such difficulties, there has been a continuing search for new
antiviral compounds that led to the synthesis of a variety of sugar-
modified nucleosides.1 Many nucleoside-based drugs are cur-
rently in use against viral infections.2 Carbocyclic nucleosides
(alternately called carbanucleosides in short form) are structural
analogues of natural and synthetic nucleosides where the ring
oxygen is replaced by a methylene unit. They have emerged as
the target of intense investigation due to their interesting
biological activities and greater metabolic stabilities to nucleoside
phosphorylases, which cleave the glycosidic bond of the normal
nucleosides.3 Since the discovery of naturally occurring carba-
nucleosides aristeromycin I4 and neplanocin A II5 that exhibited
good antiviral and antitumor activities, syntheses of their un-
natural analogues became a topic of immense attention.6 Some
prominent members among them are (ꢀ)-carbovir D-III,7 a
potent and selective inhibitor of HIV reverse transcriptase (as its
triphosphate), its pro-drug abacavir IV,8 carbocyclic 20,30-dide-
hydro-20,30-dideoxyadenine V,8,9 entecavir VI,10 etc (Figure 1).
The aforementioned nucleosides (IꢀVI) have D-configura-
tion. Among them, compounds III, IV, and V are structurally
classified as 20,30-olefinic carbanucleosides. Of all, D-carbovir
(D-III) was the first analogue which exhibits potent anti-HIV
activity in vitro. The first preparation of this isomer of carbovir
was reported by Vince et al. in 1988.11a The preparation of its
enantiomer (L-III) (Figure 1) was initially attended through
approaches like chemoenzymatic11b,12,13 and [2 þ 3] asym-
metric cycloaddition.14 The anti-HIV and anti-HBV activities
reside in its β-D enantiomer.15 However, it is reported that the
triphosphates of β-D- and β-L-carbovirs were approximately
equipotent as HIV-reverse transcriptase inhibitors, and the
Received: April 12, 2011
Published: May 25, 2011
r
2011 American Chemical Society
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Figure 1. Some well-known carbanucleosides.
Scheme 1
In this mission, we started with silylated homoallylic alcohol
(2a)19d derived from 1. Ozonolysis of its olefin and reduction of
the resulting ozonide in situ with PPh3 gave relatively unstable
aldehyde 2b. This was quickly subjected to WittigꢀHorner
olefination to obtain unsaturated ester 3. Dibal reduction of 3
afforded allylic alcohol 4a in good yield. This was converted into
the allylic bromide 4c in two steps [mesylation and bromination
of the corresponding mesylate (4b) with NaBr] in good overall
yield. In the next crucial step, formaldehyde (separately produced
by heating paraformaldehyde) was subjected to allylation on
treatement with compound 4c following Luche’s procedure.20
The allylation reaction took place efficiently (73.5% yield) to
obtain homoallylic alcohol 5 as a mixture of diastereomers 5a and
5b which could not be separated from each other by column
chromatography. The mixture of 5a and 5b was benzoylated to
produce 6a,b, also obtained as an inseparable mixture of diaster-
eomers. This was deketalized in the presence of aqueous
trifluoroacetic acid to produce diol 7 as a mixture of diastere-
oisomers 7a,b. Conversion of the 1,2-diol unit of 7 into the
bisolefin diastereomeric mixture 9a,b was accomplished in two
steps, viz., (a) dimesylation and (b) treatment of the resulting
dimesylate 8 with zinc. Desilylation of 9 on treatment with TBAF
afforded an inseparable diastereomeric mixture of 1,6-dienes 10a,
b which was subjected to ring-closing metathesis reaction using a
first-generation Grubbs’ catalyst [Cl2(PCy3)2RuCHPh].18c The
metathesis reaction produced 1,4-disubstituted 2-cyclopentene
11 in 90.5% yield, as a mixture of cis-11a and trans-11b. To our
delight, compounds 11a and 11b were found to be easily separable
from each other by column chromatography (silica gel, 0ꢀ10%
EtOAc in hexane) to obtain both of them in homochiral form
(cis-11a:trans-11b 48.3:51.7). In hindsight, the stereoselectivity in
Luche’s allylation (step vi, Scheme2) for the preparation of5 could
be tentatively reflected from the relative ratio of the isolated
amounts of 11a and 11b, as the subsequent steps did not involve
any stereodifferentiating reactions. The relative stereochemistry
(cis-11a and trans-11b) between the substituents at C-1 and C-4 in
the 2,3-cyclopentene 11 could be determined by analyzing the
chemical shifts of their CH2 protons at C-5 in their respective 1H
NMR spectra that were found to be comparable with the reported
pattern.17f,n The signals due to H5R and H5β [H5R: 1.52 (d, t,
J = 13.8, 4.5 Hz); H5β: 2.4ꢀ2.6 (m, 1H)] in cis-11a were found to
be widely separated from each other, whereas the corresponding
signals of trans-11b were found to be almost overlapping [H5R and
H5β: δ-1.9ꢀ2.1, m, 2H].
Both compounds 11a and 11b, possessing a free secondary
hydroxyl at C-1 and a benzoyloxymethyl at C-4, have good
skeletal as well as stereochemical resemblance with the known
precursors17b,c,e of (L)-(þ)- and (D)-(ꢀ)-III, respectively. For
example, the 4-O-silyl ether analogue17c of trans-11b has been
utilized for the synthesis of D-(ꢀ)-III through Mitsunobu
coupling with 2-amino-6-chloropurine that was associated with
inversion at C-1. On the other hand, the corresponding
dicarbonate17e and 4-O-tritylhydroxymethyl-1-acetyl17b analo-
gues of cis-11a have individually been utilized for the synthesis
of L-(þ)-III through tetrakis-Pd-mediated coupling with the
same base employing Trost’s procedure6g,17a that took place
along with stereochemical retention at C-1.
Thus, a simple and stereodivergent approach has been devel-
oped for the formal synthesis of both enantiomers of carbovir
(III) through judicious utilization of 1.19a This work also
demonstrates another application of Grubb's metathesis18 for
the syntheses of different carbocycles21 by constructing the
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NOTE
Scheme 2a
a (i) O3, PPh3, Dry CH2Cl2, ꢀ78 °C; (ii) NaH, C2H5COOCH2P(O)(OC2H5)2, Dry THF, 25 °C; (iii) DIBAL-H, Dry THF, ꢀ78 °C ; (iv) MsCl, Et3N,
Dry CH2Cl2, 0 °C; (v) NaBr, NaHCO3, Dry Acetone, 25 °C; (vi) Zn/NH4Cl, CH2O, THF, 25 °C; (vii) BzCN, Et3N, Dry CH2Cl2, 25 °C; (viii) Aq.
TFA (80%), CH2Cl2, 0 °C; (ix) TsCl, Py, DMAP, 25 °C; (x) Zn, NaI, Dry DMF, 80 °C; (xi) TBAF, Dry THF, 0 °C; (xii) (PCy3)2Cl2RuCHPh, Dry
Benzene, 60 °C, 24 h.
20,30-olefinic carbocycle skeleton of III. The efficacy of this approach
was due to its use of 1 as the staring material which is available in
multigram scale19a and its involvement with a series of oper-
ationally simple and efficiently scaleable reactions. Among them,
Luche’s allylation20 of formaldehyde with 4c (step vi, Scheme 2)
to obtain a C-branched homoallylic alcohol 5 has been judi-
ciously exploited to ultimately have a smooth access to the
precursor (10a,b) of the methathesis reaction. It is worth noting
that the moderate stereoselectivity of this crucial allylation
reaction proved highly advantageous to achieve its stereodiver-
gence in this route. This was finally realized by column chroma-
tographic separation of the Grubb’s metathesis product 11 to
obtain good amount of both diastereomers 11a and 11b which
eventually could be treated as the potential precursors of both
enantiomers of carbovir. It can be presumed that the same
intermediates 11a and 11b, either themselves or in their other
hydroxyl protected forms, could be useful for the syntheses of
other 20,30-olefinic carbocyclic nucleosides possessing (L)- and
(D)- configurations, respectively.
(3S,4R)-3-O-tert-Butyl-diphenylsilyl-4,5-O-cyclohexylidene-
3,4,5-trihydroxy-pentanal (2b). To a cooled (ꢀ78 °C) solution of
2a (4.8 g, 10.65 mmol) in dichloromethane (40 mL) was bubbled ozone
gas for 5 min until the reaction mixture became blue. The bluish solution
was stirred for 10 min more and treated with dry triphenylphosphine
(4.2 g, 15.97 mmol). The mixture was gradually brought to room
temperature and stirred for 3 h more. The reaction mixture was
concentrated in vacuo, and the residue was passed through a short silica
gel column eluting with 10% EtOAc in hexane to afford 2b (4.14 g, 86%)
as a colorless oil. This was found to be unstable on long-standing and
hence was used immediately for the next step without further purifica-
tion. A small portion of 2b was used for its spectroscopic characteriza-
tion. [R]D = ꢀ13.52 (c, 1.12, CHCl3). H NMR: δ 1.09 (s, 9H),
1.2ꢀ1.5 (m, 10H), 2.56 (m, 2H), 3.55ꢀ3.62 (m, 1H), 3.8ꢀ3.9 (m, 1H),
4.0ꢀ4.1 (m0, 2H), 7.5 (m, 6H), 7.6ꢀ7.8 (m, 4H), 9.61 (t, J = 2.5 Hz,
1H). 13C NMR: 19.2, 23.6, 23.7, 25.0, 26.8, 34.4, 35.8, 48.1, 66.8, 70.6,
78.2, 110.1, 127.6, 127.7, 129.9, 130.0, 132.9, 135.7, 200.3.
(5S,6R)-Ethyl-5-O-tert-butyl-diphenylsilyl-6,7-O-cyclohex-
ylidene-5,6,7-trihydroxy-hept-2E-enoate 3. To a cooled (0 °C)
suspension of sodium hydride (0.47 g, 50% suspension in oil, 9.8 mmol,
washed once with dry hexane) in THF (20 mL) was added dropwise
triethyl phosphonoacetate (2.21 g, 9.86 mmol) in THF (10 mL) over a
period of one hour under argon atmosphere. After the addition was over,
the reaction mixture was gradually brought to room temperature and
stirred until it became clear. Again the temperature was brought down to
0 °C, and a solution of 2b (4.06 g, 8.97 mmol) in dry THF (20 mL) was
25
1
’ EXPERIMENTAL SECTION
Chemicals used as starting materials are commercially available and
were used without further purification. All solvents used for extraction
and chromatography were distilled twice at atmospheric pressure prior
to use. The organic extracts were desiccated over dry Na2SO4.
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NOTE
added dropwise over a period of 1 h. The mixture was stirred at 0 °C for
1 h and stirred at room temperature overnight (completion of reaction
confirmed from TLC). The mixture was cooled to 0 °C, treated with
water, neutralized by dropwise addition of dilute HCL (2%), and
extracted twice with EtOAc. The combined organic layer was washed
successively with water and brine and dried over Na2SO4. Solvent
removal under reduced pressure and column chromatography (silica
gel, hexane:EtOAc 20:1) of the residue afforded pure 3 (3.75 g,
7.175 mmol, 80%) as a colorless oil. [R]D29 = þ19.54 (c, 0.87, CHCl3).
1H NMR: δ 1.04 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H), 1.35ꢀ1.59 (m, 10H),
2.27ꢀ2.37 (m, 2H), 3.6ꢀ3.7 (m, 1H), 3.8ꢀ4.0 (m, 3H), 4.15 (q, J = 7.2
Hz, 2H), 5.66 (d, J = 15.6 Hz, 1H), 6.90 (td, J = 8, 15.6 Hz, 1H), 7.5 (m,
6H), 7.6ꢀ7.8 (m, 4H). 13C NMR: 14.2, 19.3, 23.7, 23.9, 25.1, 26.5, 26.9,
34.7, 36.1, 37.0, 60.0, 66.5, 73.3, 77.5, 109.6, 123.7, 127.60, 127.68,
129.82, 129.89, 133.2, 133.4, 134.8, 135.9, 144.7, 166.2. Anal. Calcd for
C31H42O5 Si: C, 71.23; H, 8.10. Found: C, 71.51; H, 8.24.
The mixture was stirred for 10 min. To this stirred mixture, gaseous
formaldehyde (formed by heating paraformaldehyde in another contain-
er at 180 °C in a heating mantle under the flow of argon) was bubbled
through an inlet tube. After stirring this reaction mixture for 30 min,
saturated NH4Cl (2 mL) was added dropwise into it with continued
bubbling of formaldehyde gas. After 1 h, heating of paraformaldehyde
was stopped, while the reaction mixture was stirred overnight at room
temperature. The bromide was found to be consumed totally (TLC).
The mixture was filtered, and the filtrate was thoroughly washed with
EtOAc. The organic layer was washed with dilute aqueous HCl to
dissolve the turbid suspension. The aqueous layer was extracted with
EtOAc. The combined organic layer was washed with water and brine
and dried over Na2SO4. Solvent removal under reduced pressure and
column chromatography (silica gel, 0ꢀ20% EtOAc in hexane) of the
residue afforded pure 5 (1.27 g, 70%) containing a chromatographically
1
inseparable mixture of diastereomers 5a and 5b as a colorless oil. H
NMR: δ 1.04 (s, 9H), 1.3ꢀ1.6 (m, 12H, overlapped with a brs, 1H), 2.28
(m, 1H), 3.0ꢀ3.3 (m, 2H), 3.6ꢀ4.0 (m, 4H), 4.8ꢀ5.0 (m, 2H), 5.1ꢀ5.2
(m, 1H), 7.2ꢀ7.4 (m, 6H), 7.6ꢀ7.7 (m, 4H). 13C NMR: 19.2, 19.3, 23.7,
23.8, 25.0, 26.8, 34.5, 34.6, 35.1, 35.9, 36.1, 42.4, 42.6, 65.0, 65.4, 66.3,
66.5, 71.8, 72.3, 78.1, 78.3, 109.6, 116.8, 117.2, 127.4, 129.6, 133.2, 133.5,
133.7, 135.8, 139.3. Anal. Calcd for C30H42O4 Si: C, 72.83; H, 8.56.
Found: C, 73.01; H, 8.24.
(5S,6R)-5-O-tert-Butyl-diphenylsilyl-6,7-O-cyclohexyli-
dene-1,5,6,7-tetrahydroxy-hept-2E-ene 4a. To
a cooled
(ꢀ78 °C) solution of 3 (3.7 g, 7.08 mmol) in dry THF (30 mL) was
added dropwise DIBALH (14.2 mL, 1.0 M solution in hexane) over a
period of one hour. The mixture was stirred for 1 h at the same
temperature until the reaction was complete (confirmed by TLC). To
the mixture was added methanol (15 mL). The mixture was stirred at
room temperature for 2 h, and the resulting solid was filtered through a
celite pad. Concentration of the filtrate under reduced pressure and
column chromatography (silica gel, 0ꢀ25% EtOAc in hexane) of the
residue afforded pure 4a (3.1 g, 91%) as a colorless oil. [R]D26 = þ18.71
(5S,6R)-3-Benzyloxymethyl-5-O-tert-butyl-diphenylsilyl-
6,7-O-cyclohexylidene-5,6,7-trihydroxy-hept-1-ene (6a,b).
To a cooled (0 °C) solution of the alcohol 5 (1.25 g, 2.52 mmol) and
triethylamine (303 mg, 3 mmol) in dry CH2Cl2 (20 mL) was added a
solution of benzoylcyanide (0.36 g, 2.7 mmol) in CH2Cl2 (10 mL) in
5 min. The mixture was stirred at 0 °C for 1 h and then at room
temperature for 4 h. The solution was treated with water. The organic
layer was separated, and the aqueous layer was extracted with CHCl3.
The combined organic layer was washed with diluted aqueous HCl until
neutral, water, and brine and dried over Na2SO4. Solvent removal under
reduced pressure and column chromatography (silica gel, EtOAc/
hexane 0ꢀ5%) of the residue afforded pure 6 (1.12 g, 92%) as a mixture
1
(c, 0.962, CHCl3). H NMR: δ 1.04 (s, 9H), 1.35ꢀ1.59 (m, 10H,
overlapped with brs, 1H), 2.1ꢀ2.2 (m, 2H), 3.7ꢀ4.1 (m, 6H), 5.4ꢀ5.5
(m, 2H), 7.3 ꢀ7.4 (m, 6H), 7.6ꢀ7.7 (m, 4H). 13C NMR: 19.2, 23.7,
23.8, 25.0, 26.8, 34.6, 36.0, 36.9, 63.2, 65.8, 73.3, 77.3, 109.3, 127.4,
127.6, 129.5, 131.8, 133.3, 133.9, 135.81, 135.86. Anal. Calcd for
C29H40O4 Si: C, 72.46; H, 8.39. Found: C, 72.21; H, 8.29.
(5S,6R)-1-Bromo-5-O-tert-butyl-diphenylsilyl--6,7-O-
cyclohexylidene-5,6,7-trihydroxy-hept-2E-ene (4c). To the
cooled (0 °C) solution of 4a (3.0 g, 6.25 mmol) and tryethylamine
(1.07 g, 10.60 mmol) in dry DCM (15 mL) was added methanesulfo-
nylchloride (0.93 g, 8.11 mmol) dropwise over a period of 15 min. The
mixture was stirred for 3 h at room temperature and treated with water.
The aqueous layer was extracted with chloroform. The combined
organic layer was washed with water and brine and dried over Na2SO4,
Solvent removal under reduced pressure afforded yellow oily liquid
containing the crude mesylated product (4b) in almost quantitative yield
which was used in the next reaction without further purification.
To a solution of crude mesylate (4b) in dry acetone (20 mL) were
added dry NaBr (0.78 g, 7.5 mmol) and a catalytic amount of NaHCO3. It
was then stirred overnight while 4b disappeared totally (cf. TLC). The
reaction mixture was concentratedunder reducedpressure to get rid of the
acetone, washed with dilute aqueous HCl (2%) for neutrality, and
extracted with CHCl3. The combined organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure to
afford a colorless liquid which was chromatographed on silica gel (EtOAc/
hexane 0ꢀ2%) to afford pure 4c (3.06 g, 5.63 mmol, 90%). The
compound tended to become colored on long-standing probably due to
its being unstable and hence was immediately used for the next step.
[R]D27 = þ28.71 (c, 1.01, CHCl3). 1H NMR: δ 1.04 (s, 9H), 1.36ꢀ1.59
(m, 10H), 2.1ꢀ2.2 (m, 2H), 3.6ꢀ3.7 (m, 1H), 3.8ꢀ4.0 (m, 5H), 5.4ꢀ5.7
(m, 2H), 7.3ꢀ7.4 (m, 6H), 7.6ꢀ7.7 (m, 4H). 13C NMR: 19.3, 23.8, 23.9,
25.1, 26.9, 34.7, 36.1, 36.8, 45.0, 66.3, 73.4, 77.4, 109.4, 127.53, 127.57,
128.5, 129.7, 131.0, 133.3, 133.8, 135.9.
1
of diastereomers 6a and 6b. H NMR: δ 1.04 (s, 9H), 1.35ꢀ1.7 (m,
12H), 2.6 (m, 1H), 3.7ꢀ4.1 (m, 6H), 4.8ꢀ4.9 (m, 2H), 5.1ꢀ5.5 (m,
1H), 7.3ꢀ7.4 (m, 9H), 7.6ꢀ7.7 (m, 4H), 7.8ꢀ8.0 (m, 2H). 13C NMR:
19.3, 23.7, 23.8, 25.0, 26.8, 34.6, 34.7, 35.6, 35.9, 36.639.0, 39.2, 66.3,
66.5, 67.3, 67.5, 71.6, 72.1, 78.4, 109.6, 116.5, 116.7, 127.5, 128.1, 129.3,
129.6, 130.1, 130.2, 132.6, 133.2, 133.6, 133.7, 135.8, 138.4, 166.1. Anal.
Calcd for C37H46O5 Si: C, 74.21; H, 7.74. Found: C, 74.35; H, 7.46.
(5S,6R)-3-Benzyloxymethyl-5-O-tert-butyl-diphenylsi-
lyl-5,6,7-trihydroxy-hept-1-ene (7a,b). To a cooled (0 °C) solu-
tion of 6a,b (2.20 g, 2.12 mmol) in distilled CH2Cl2 (30 mL) was added
80% aqueous trifluoroacetic acid (10 mL). The mixture was stirred for
three hours at 0 °C. The reaction mixture was diluted with CHCl3 and
water. The aqueous layer was extracted with CHCl3. The combined
organic layer was washed successively with 2% NaHCO3 for neutrality,
water, and brine and dried over Na2SO4. Solvent removal under reduced
pressure and column chromatography (silica gel, MeOH/CHCl3 0ꢀ5%)
of the residue afforded pure 7 (1.32 g, 70%) as a mixture of diastereomers
7a and 7b. 1H NMR: δ 1.06 (s, 9H), 1.2ꢀ1.6 (m, 2H), 2.02 (bs, 2H), 2.41
(m, 1H), 3.5ꢀ4.0 (m, 6H), 4.8ꢀ4.9 (m, 2H), 5.0ꢀ5.5 (m, 1H), 7.2ꢀ7.6
(m, 9H), 7.8ꢀ7.96 (m, 4H), 8.08ꢀ8.5 (m, 2H). 13C NMR: 19.3, 26.9,
34.5, 34.7, 39.4, 39.5, 62.7, 62.9, 67.0, 67.5, 73.1, 73.4, 77.2, 116.9, 117.1,
127.6, 127.7, 128.2, 129.4, 129.91, 129.96, 130.1, 132.7, 132.84, 132.89,
133.1, 133.2, 135.8, 137.7, 138.0, 166.2. Anal. Calcd for C31H38O5 Si: C,
71.78; H, 7.38. Found: C, 71.61; H, 7.44.
(5S)-3-Benzyloxymethyl-5-O-tert-butyl-diphenylsilyl-1,6-
hexadiene (9a,b). To a cooled (0 °C) solution of 7 (1.30 g, 2.5
mmol) in dry pyridine (10 mL) were added p-tolunesulfonylchloride
(1.2 g, 6.26 mmol) and dimethylaminopyridine (100 mg). The mixture
was gradually brought to room temperature over a period of 6 h and then
(5S,6R)-3-Hydroxymethyl-5-O-tert-butyl-diphenylsilyl-
6,7-O-cyclohexylidene-5,6,7-trihydroxy-hept-1-ene (5a,b).
To a solution of bromide 4c (2.0 g, 3.67 mmol) in distilled THF
(10 mL) at room temperature was added zinc dust (0.5 g, 7.65 mmol).
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stirred overnight. The reaction mixture was treated with 5% aqueous
HCl and water for neutrality. The aqueous layer was extracted with
CHCl3. The combined organic layer was washed with water and brine
and dried. It was concentrated under reduced pressure to afford the
crude ditosylated product 8 (confirmed by TLC and IR of crude) which
was taken in dry DMF (15 mL). To this solution were added Zn dust
(0.50 g, 7.52 mmol) and dry NaI (1.12 g, 7.50 mmol). The mixture was
stirred overnight at 90 °C. The mixture was filtered, and the residue was
thoroughly washed with EtOAc. The combined organic layer was
washed with dilute aqueous HCl to dissolve the turbid material. The
aqueous layer was separately extracted with EtOAc. The combined
organic layer was washed with water and brine and dried. Solvent removal
under reduced pressure and column chromatography (silica gel, 0ꢀ10%
EtOAc in hexane) of the residue afforded pure diene 9 (1.05 g, 86.6%) as a
mixture ofdiastereomers9aand 9b. 1H NMR:δ 1.06 (s, 9H), 1.2ꢀ1.8 (m,
2H), 2.3ꢀ2.8 (m, 1H), 4.0ꢀ4.2 (m, 3H), 4.8ꢀ5.0 (m, 4H), 5.1ꢀ5.9 (m,
2H), 7.2ꢀ7.6 (m, 9H), 7.8ꢀ7.96 (m, 4H), 8.08ꢀ8.5 (m, 2H). 13C NMR:
19.2, 19.3, 39.0, 39.5, 39.7, 67.5, 67.6, 72.8, 72.9, 115.0, 115.3, 116.3, 116.7,
127.31, 127.36, 127.4, 127.8, 128.2, 129.5, 130.3, 132.8, 133.9, 134.1,
134.2, 135.9, 138.3, 138.7, 140.0, 140.7, 166.3. Anal. Calcd for C31H36O3
Si: C, 76.82; H, 7.49. Found: C, 77.04; H, 7.34.
11b. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: achat@barc.gov.in.
’ ACKNOWLEDGMENT
S. Tripathy gratefully acknowledges the Homi Bhabha Na-
tional Institute (HBNI), Department of Atomic Energy (DAE),
India, for the award of a Senior Research Fellowship for his PhD
work (guide: Dr A. Chattopadhyay).
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b). Tetrabutylammonium fluoride in THF (8 mL, 1 M solution) was
added to a cooled (0 °C) solution of 9 (968 mg, 2 mmol) obtained above
in THF (30 mL). The resulting solution was stirred overnight at room
temperature. The reaction was quenched by the addition of saturated
aqueous solution of NH4Cl (10 mL). The mixture was diluted with
EtOAc while two phases were separated. The aqueous phase was
extracted with EtOAc. The combined organic layer was washed succes-
sively with water and brine and dried. Solvent removal under reduced
pressure and column chromatography of the residue (silica gel, 0ꢀ5%
MeOH/CHCl3) afforded pure 10 (459 mg, 93.2%) as a mixture of
diastereomers 10a and 10b. 1H NMR: 1.5ꢀ1.7 (m, 2H), 1.9 (bs, 1H),
2.5ꢀ2.9 (m, 1H), 4.1ꢀ4.3 (m, 3H), 5.0ꢀ5.2 (m, 4H), 5.6ꢀ5.9 (m, 2H),
7.3ꢀ7.5 (m, 3H), 8.02 (d, J = 8.1 Hz, 2H). 13C NMR: 38.1, 38.2, 39.7,
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73.15; H, 7.37. Found: C, 73.44; H, 7.36.
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(1S,4S)-4-(Benzyloxymethyl)-cyclopenten-2-enol (11a)
and (1S,4R)-4-(Benzyloxymethyl)-cyclopenten-2-enol (11b).
A solution of diene 10 (150 mg, 0.6097 mmol) in dry benzene (50 mL)
was degassed by bubbling argon. To it was added Grubb’s first -
generation catalyst18 (30.57 mg, 0.0372 mmol) in one portion. The
resulting pink solution was stirred under heating (60 °C) for 24 h. The
solvent was removed under reduced pressure, and the dark residue was
purified by column chromatography (silica gel, 0ꢀ10% hexane in
EtOAc) to afford 11a (57.9 mg) and 11b (62.0 mg) in homochiral form.
24
Compound 11a. Rf 0.5 (EtOAc:hexane 1:9). [R]D = þ52.31 (c,
1.51, CHCl3). 1H NMR: 1.52 (dt, J = 13.8, 4.5 Hz, 1H), 2.25 (bs, 1H),
2.4ꢀ2.6 (m, 1 H), 2.9ꢀ3.1 (m, 1H), 4.2ꢀ4.4 (m, 2H), 4.81ꢀ4.86 (m,
1H), 5.9 (m, 2H), 7.3ꢀ7.5 (m, 3H), 7.9ꢀ8.0 (m, 2H). 13C NMR: 36.8,
43.7, 67.7, 76.5, 128.2, 129.3, 130.0, 132.7, 134.1, 135.4, 166.3. Anal.
Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.32; H, 6.53.
Compound 11b. Rf 0.4 (EtOAc:Hexane 1:9). [R]D24 = ꢀ139.55 (c,
1.34, CHCl3). 1H NMR: 1.69 (s, 1H), 1.9ꢀ2.1 (m, 2H), 3.3ꢀ3.4 (m,
1H), 4.1ꢀ4.3 (m, 2H), 4.9 (m, 1H), 5.9ꢀ6.0 (m, 2H), 7.3ꢀ7.6 (m, 3H),
8.0 (m, 2H). 13C NMR: 37.1, 44.0, 67.6, 76.6, 128.2, 129.4, 130.1, 132.8,
135.2, 135.3, 166.4. Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found:
C, 71.87; H, 6.42.
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’ ASSOCIATED CONTENT
(16) Davis, M. G.; Wilson, J. E; VanDraanen, N. A.; Miller, W. H.;
Freeman, G. A.; Daluge, S. M.; Boyd, F. L.; Aulabaugh, A. E.; Painter,
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Supporting Information. 1H and 13C NMR spectra of
S
b
compounds 2b, 3, 4a, 4c, 5a,b, 6a,b, 7a,b, 9a,b, 10a,b, 11a, and
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The Journal of Organic Chemistry
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