Reductive opening of glycal derived highly functionalized 2,3-epoxy-1-iodides with zinc dust: An efficient method for the synthesis of acyclic long chain polyhydroxylated terminal alkenic alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.01.043

The synthesis of densely functionalized acyclic long chain terminal alkenic alcohols was achieved by reductive opening of glycal derived 2,3-epoxy-1-iodides, with commercial zinc dust alone in a short reaction time with excellent yields involving a simple

Full text of DOI:10.1016/j.tetlet.2006.01.043

Tetrahedron Letters 47 (2006) 1753–1756
Reductive opening of glycal derived highly functionalized
2,3-epoxy-1-iodides with zinc dust: an efficient method for
the synthesis of acyclic long chain polyhydroxylated
terminal alkenic alcoholsI
L. Vijaya Raghava Reddy, Ram Sagar and Arun K. Shaw*
Division of Medicinal and Process Chemistry, Central Drug Research Institute (CDRI), Lucknow 226 001, India
Received 15 November 2005; revised 26 December 2005; accepted 11 January 2006
Available online 26 January 2006
Abstract—The synthesis of densely functionalized acyclic long chain terminal alkenic alcohols was achieved by reductive opening of
glycal derived 2,3-epoxy-1-iodides, with commercial zinc dust alone in a short reaction time with excellent yields involving a simple
reaction procedure and easy work-up. A mechanism involving an organometallic intermediate is proposed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
A great deal of interest has been devoted in recent years
towards the synthesis of acyclic, long chain, polyhydr-
oxylated, terminal alkenic alcohols owing to their vari-
ous applications in diverse areas such as synthetic,
medicinal and pharmaceutical chemistry.1 Recent litera-
ture reports have also revealed that long chain polyhydr-
oxylated (highly functionalized) terminal alkenic
alcohols serve as valuable building blocks for many natu-
ral and bioactive compounds.2 Moreover, highly func-
tionalized terminal olefins comprise one of the most
important classes of compounds for functional group
transformation, giving alcohols, amines, aldehydes, car-
boxylic acid derivatives, ethers and epoxides as the
products of catalytic reactions.3
give low yields of products. Therefore, the search for
effective reagents for the preparation of densely func-
tionalized terminal alkenic alcohols starting from 2,3-
epoxy-1-iodides is still of interest.
For the last few years, our group has been actively
involved in the synthesis of glycal derived, acyclic, long
chain compounds as antimycobacterial agents.6 In the
context of our interest in this area, we required highly
functionalized terminal alkenic alcohols that could be
obtained by literature methods4,5 from 2,3-epoxy alco-
hols7 via 2,3-epoxy-1-iodides. Therefore, when the
epoxy alcohol 1a, derived from an enantiopure a,b-
unsaturated sugar aldehyde8 was subjected to iodin-
ation9 as per the conditions given in Scheme 1, iodide
2a was obtained in moderate yield. Our initial attempt
to brominate10 1a afforded a mixture of several prod-
ucts, which were difficult to separate even by repeated
column chromatography. After optimization of the
iodination of 1a, the series 1b–e was submitted to iodin-
ation under similar conditions (Scheme 1) to yield the
respective iodides 2b–e. All the iodination reactions pro-
ceeded quickly to produce iodides in good yields (Table
1). The moderate yields of 2a and 2d, obtained from 1a
and 1d, respectively, were attributed to participation of
the free 5-OH in the reaction.
The usefulness of terminal alkenic alcohols as valuable
intermediates has attracted a number of synthetic stra-
tegies for their synthesis.4,5 Reduction of 2,3-epoxy-1-
halides is one among them. The reductive opening of
epoxy halides is very interesting from the mechanistic
as well as the synthetic viewpoint. However, many of
the literature methods involve the use of expensive
reagents, vigorous reaction conditions,5a tedious work-
up procedures, long reaction times and in some cases
Keywords: Zinc dust; 2,3-Epoxy-1-iodide; Terminal alkenic alcohol;
Selective reduction; Sharpless epoxidation.
q CDRI Communication No. 6819.
The next challenge was to reduce selectively the epoxy
C–O bond in lieu of the C–C bond of the 2,3-epoxy-1-
iodides to obtain terminal alkenic alcohols. To achieve
*
Corresponding author. Tel.: +91 0522 2612411; e-mail: akshaw55@
yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.043

1754
L. V. R. Reddy et al. / Tetrahedron Letters 47 (2006) 1753–1756
R2
R2
Imidazole (3.0 equiv.)
R1
R1
PPh3 (1.5 equiv.)
I2 (1.5 equiv.)
I
R4O
CH2OH
R4O
O
O
OR3
OR3
°
toluene (dry), 40-45 C
1a R1=OBn, R2=R3=H, R4=Bn
1b R1=OBn, R2=H, R3=R4=Bn
1c R1=OBn, R2=H, R3=Ac, R4=Bn
1d R1=R3=H, R2=OBn, R4=Bn
1e R1=H, R2=OBn, R3=R4=Bn
2a R1=OBn, R2=R3=H, R4=Bn
2b R1=OBn, R2=H, R3=R4=Bn
2c R1=OBn, R2=H, R3=Ac, R4=Bn
2d R1=R3=H, R2=OBn, R4=Bn
2e R1=H, R2=OBn, R3=R4=Bn
Scheme 1. Iodination of epoxy alcohols.
R2
Table 1. Iodination of epoxy alcohols
R1
R2
R1
Zn dust (10-15 equiv.)
EtOH, reflux
Substrate
dra
Time (h)
Product
Yieldb (%)
R4O
I
R4O
OR3
O
OH
1a
1b
1c
1d
1e
29:71
60:40
32:68
58:42
28:72
1.5
1.1
2.0
2.0
1.3
2a
2b
2c
2d
2e
48
70
60
45
68
OR3
3a R1=OBn, R2=R3=H, R4=Bn
3b R1=OBn, R2=H, R3=R4=Bn
3c R1=OBn, R2=H, R3=Ac, R4=Bn
3d R1=R3=H, R2=OBn, R4=Bn
3e R1=H, R2=OBn, R3=R4=Bn
2a R1=OBn, R2=R3=H, R4=Bn
2b R1=OBn, R2=H, R3=R4=Bn
2c R1=OBn, R2=H, R3=Ac, R4=Bn
2d R1=R3=H, R2=OBn, R4=Bn
2e R1=H, R2=OBn, R3=R4=Bn
a Determined by 1H NMR of crude material.
b Isolated yields.
Scheme 2. Selective reduction of 2,3-epoxy-1-iodides.
this we tried various reagents such as NaBH4/InCl3, tri-
ethylsilane and activated magnesium metal under differ-
ent reaction conditions but none of the reagents worked
well except NaBH4/InCl3 which furnished the desired
terminal alkenic alcohol 3b from 2b in moderate yield
aged by this result, the same protocol was applied to
the remaining substrates (Table 2). Here, it is worth
mentioning that the results were identical irrespective
of the quality and batch of zinc dust used.16 To our
delight the result was the same even on a gram scale.17
5b
(46%).
We came across Vasella’s pioneering work,11 and the
extended report by Weidmann,12 which dealt with reduc-
tive dealkoxyhalogenation of 6-deoxy-6-halopyranose
and 5-deoxy-5-halofuranose derivatives with metal
reagents to form acyclic olefinic sugar derivatives. A close
examination of these halosugar derivatives revealed
some similarities with our substrates. Both substrates
contained cyclic ether functionality with the only differ-
ence being their ring sizes. Several references of synthetic
applications of zinc-induced reductive ring openings are
available in the literature.13
Table 2. Selective reduction of 2,3-epoxy-1-iodides
Substrate
Time (h)
Product
dra
Yieldc (%)
2a
2b
2c
2d
2e
3
3
1
3
3
3a
3b
3c
3d
3e
29:71
60:40
33:67
56:44
ndb
87
92
85
86
90
a Determined by 1H NMR of crude spectra.
b Not detectable, but we presume the ratio to be same as that of 1e.
c Isolated yields.
A combination of purified zinc dust and sodium iodide
or n-BuLi/THF at ꢀ23 ꢁC involving radical chemistry
are also effective for the conversion of 2,3-epoxy halides
to allylic alcohols under an argon atmosphere.14 As it is
well known that iodides are more reactive,15 we tried
first with commercial zinc dust as activated zinc dust
was reported to form unwanted products in some
cases.13i The reductive cleavage of 2,3-epoxy-1-iodide
2b was attempted in a protic solvent as the final product
here that we needed was the alcohol. Our preliminary
experiments for reductive cleavage of 2b with commer-
cial as well as purified zinc dust in ethanol at ambient
temperatures were unsuccessful even under an inert
atmosphere.
From these results it appears that the reaction
proceeded through an organometallic intermediate b
followed by opening of the epoxy ring to form the
alkoxide c which abstracts proton from the solvent
furnishing the terminal alkenic alcohol d as shown in
Figure 1.
R2
R2
R1
R1
_
δ
δ
+
Zn dust
I
R4O
R4O
CH2ZnI
O
O
OR3
OR3
b
a
R1
R2
R2
R1
However, at reflux in ethanol we found 100% conversion
of the reactant 2b in 3 h (TLC) when commercial zinc
dust was used. The spectral analysis (1H and 13C NMR)
of chromatographically pure compound obtained
from this reaction (Scheme 2) indicated a mixture of
inseparable diastereomers 3b in 92% yield. Encour-
+
R4O
H
R4O
OR3
OR3
OH
OZnI
c
d
Figure 1.

L. V. R. Reddy et al. / Tetrahedron Letters 47 (2006) 1753–1756
1755
4. For rearrangement of epoxides to allylic alcohols, see
the review: synthetically useful reactions of epoxides
(a) Smith, J. G. Synthesis 1984, 629–656; (b) Aspinall,
G. O.; Carpenter, R. C.; Khondo, L. Carbohydr. Res.
1987, 165, 281–298; (c) Bernotas, R. C.; Pezzone, M. A.;
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hedron Lett. 1993, 34, 867–868; (j) Hasegawa, E.; Taka-
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5215–5218.
Finally, the whole process was also repeated using stereo-
chemically pure epoxy alcohol 1f (de >99%), prepared
by Sharpless epoxidation18 of its allylic alcohol in the
presence of L-(+)-DET. The stereochemically pure 2,3-
epoxy alcohol 1f, on iodination gave the epoxy iodide
2f in 50% yield. This on further reduction with commer-
cial zinc dust gave the diastereomerically pure terminal
alkenic alcohol 3f19 in 86% yield. The structures of all
new compounds synthesized were in accordance with
their spectral data.
H
H
H
BnO
BnO
BnO
I
OH
BnO
BnO
BnO
O
O
OH
2f
OH OH
OH
1f
5. (a) Park, H. S.; Chung, S. H.; Kim, Y. H. Synlett 1998,
1073–1074; (b) Ranu, B. C.; Banerjee, S.; Das, A.
Tetrahedron Lett. 2004, 45, 8579–8581.
3f
6. (a) Pathak, R.; Shaw, A. K.; Bhaduri, A. P.; Chandra-
sekhar, K. V. G.; Srivastava, A.; Srivastava, K. K.;
Chaturvedi, V.; Srivastava, R.; Srivastava, B. S.; Arora,
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K.; Chaturvedi, V.; Srivastava, R.; Srivastava, B. S.
Bioorg. Med. Chem. 2002, 10, 3187–3196.
In summary, zinc dust can be used for reductive opening
of sugar derived 2,3-epoxy-1-iodides, without any acti-
vation/external iodide source, to furnish highly func-
tionalized acyclic long chain terminal alkenic alcohols.
Acknowledgements
7. Sagar, R. Ph.D. Dissertation, Dr. B. R. Ambedkar
University, 2005.
We are thankful to the Sophisticated Analytical Instru-
ment Facility (SAIF) CDRI, for providing spectral data
and Mr. Anup Kishore Pandey, for technical assistance.
L.V.R.R. is grateful to CSIR and R.S. to DOD, New
Delhi, for financial assistance.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.01.043.
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Tyler, P. C.; Brown, K. L.; Gainsford, G. J.; Diehl, J. W.
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J. Org. Chem. 2005, 70, 3299–3302.
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Hoveyda, A. H. Tetrahedron 1997, 53, 16377–16390; (b)
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L. V. R. Reddy et al. / Tetrahedron Letters 47 (2006) 1753–1756
19. General procedure for reductive opening of 2,3-epoxy-1-
iodides: To 500 mg (1.10 mmol) of 2,3-epoxy-1-iodide 2f
distilled ethanol (20 ml) was added and allowed to be
stirred under reflux. Zinc dust (10 equiv.) was added and
the stirring was continued on till completion of the
reaction. Once the reaction was judged complete (TLC)
the reaction mixture was allowed to cool to room
temperature. After cooling, the reaction mixture was
filtered through a Celite bed and washed thrice with
DCM. The filtrate obtained was concentrated and passed
through a silica gel column to isolate the pure terminal
alkenic alcohol 3f.
(c 0.197, CHCl3); IR (neat, cmꢀ1): 3434 (O–H str), 3018
(@C–H str), 1638, 1545, 1496, 1453 (C@C str), 1217, 1071
1
(C–O str); H NMR (200 MHz, CDCl3): d 7.37–7.27 (m,
10H, ArH), 5.93 (ddd, J2,1E = 17.1 Hz, J2,1Z = 10.5 Hz,
J2,3 = 5.3 Hz, 1H, H-2), 5.38 (dt, J1E,2 = 17.2 Hz and
J = 1.5 Hz, 1H, H-1E), 5.23 (dt, J1Z,2 = 10.5 Hz and
J = 1.4 Hz, 1H, H-1Z), 4.74–4.50 (m, 4H, 2 · OCH2Ph),
4.49–4.43 (m, 1H, H-5), 4.08 (m, 1H, H-3), 3.62–3.46 (m,
3H, H-6, H-4); 13C NMR (50 MHz, CDCl3): d 138.2, 137.8
(ArqC), 137.7 (C-2), 128.8, 128.5, 128.2, (ArC), 116.8 (C-
1), 80.0 (C-4), 73.8 (C-3), 73.4, 73.0 (2 · OCH2Ph), 71.4 (C-
5), 70.5 (C-6); FAB MS calcd for C20H24O4 m/z 328; found
329 [M+1]+Å, 237 [MꢀCH2Ph]+Å, 228, 203, 181. Elemental
analysis calcd for C20H24O4Æ0.5H2O; calcd: C, 71.19; H,
7.46, found: C, 70.79; H, 7.68.
Compound 3f: 4,6-Di-O-benzyl-1,2-dideoxy-D-xylo-hex-1-
enitol: Oil, eluent for column chromatography, 7:43
20
EtOAc–Hex v/v, Rf 0.56 (3:7 EtOAc/hexane), ½aꢁD ꢀ7.6