(R)-2,3-Cyclohexylideneglyceraldehyde: a novel template for simple entry into both cis- and trans-2,5-disubstituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2007.02.093

Sharpless asymmetric dihydroxylation at the terminal olefin of benzoates 3a and 3b, using both AD-mix α and AD-mix β afforded only one diastereomer of diols 5a and 5b, respectively. Diols 5a and 5b were easily transformed into cis- and trans-2,5-disubstit

Full text of DOI:10.1016/j.tetlet.2007.02.093

Tetrahedron Letters 48 (2007) 2871–2873
(R)-2,3-Cyclohexylideneglyceraldehyde: a novel template
for simple entry into both cis- and
trans-2,5-disubstituted tetrahydrofurans
Angshuman Chattopadhyay,* Prasad Vichare and Bhaskar Dhotare
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 27 November 2006; revised 14 February 2007; accepted 22 February 2007
Available online 24 February 2007
Abstract—Sharpless asymmetric dihydroxylation at the terminal olefin of benzoates 3a and 3b, using both AD-mix a and AD-mix b
afforded only one diastereomer of diols 5a and 5b, respectively. Diols 5a and 5b were easily transformed into cis- and trans-2,5-
disubstituted tetrahydrofurans 7 and 14, respectively, which were subsequently converted into known compounds 12 and 19.
Ó 2007 Elsevier Ltd. All rights reserved.
2,5-Disubstituted tetrahydrofurans (THFs) constitute
important structural and functional sub-units in various
bioactive natural products including the rapidly
expanding group of cytotoxic polyethers,1a,b polyether
antibiotics,1c,d antitumour acetogenins,2 etc. As a result,
stereoselective construction of both cis- and trans-2,5-
disubstituted tetrahydrofurans has drawn considerable
attention from synthetic chemists. Several strategies
have been adopted in this pursuit, namely, cyclisation
of 4-alkenols,3a–e 3-alkenols,3f epoxy alcohols,3g Ti-medi-
ated coupling of acetylated c-lactols or lactones with
chiral enolates,4 tandem 1,3-dipolar cycloaddition/
electrophilic cyclisations supported on a polymer,5
asymmetric [3+2]-annulation of chiral b-silyloxyallyl-
silanes,6 cyclisation of 1,4-diols7a,b derived from several
chiral templates, oxidative cyclization of 1,5-dienes,7c
etc. Evidently, only a few of the reported approaches
led to the formation of either cis-3c,g,7c or trans-2,5-
disubstituted THFs.3a,b,f,4a,b In addition, it has been
observed that many of these strategies have limitations
such as moderate stereoselectivity in the crucial step
and lengthy routes. Hence, the design and development
of a simple and stereodivergent strategy to construct
both cis- and trans-2,5-disubstituted tetrahydrofurans
(THF’s) have assumed considerable importance in
organic synthesis.
During our ongoing programme on the synthesis of
bioactive molecules, we have exploited easily accessible
(R)-2,3-cyclohexylideneglyceraldehyde (1)8a to construct
several structural units, namely alkanetriols,8a–d ribo-
furanoses,8c,e–g c-lactones,8h d-lactones,8i which are
widely prevalent in bioactive natural products. We pres-
ent here another simple and efficient application of 1 as
a novel template for stereodivergent entry into both cis-
and trans-2,5-disubstituted tetrahydrofurans.
Compound 1 was treated with the Grignard reagent of
4-bromobutene to produce 2 in good yield (81%) with
anti-selectivity [syn 2a9:anti 2b10 = 9.5:90.5]. As on pre-
vious occasions,8 the diastereomers 2a,b were easily sep-
arable by column chromatography. Compound 2a could
also be prepared stereoselectively following an oxida-
tion–reduction strategy.8d Hence, PCC oxidation of a
mixture of 2a and 2b, followed by K-Selectride reduc-
tion of the resulting ketone 4 yielded 2a in excellent yield
(95%) with almost absolute syn selectivity [syn 2a:anti
2b = 99.1:0.9]. Benzoylation of 2a produced 3a, which
was subjected to Sharpless asymmetric dihydroxyl-
ation11 separately with AD-mix a and AD-mix b. Inter-
estingly, both these hydroxylations afforded only the
diastereomeric diol 5a12 with absolute stereoselectivity.
Monotosylation of 5a regioselectively at the 1° hydroxyl
produced 6 which on treatment with K2CO3 gave trans-
2,5-disubstituted tetrahydrofuran 7. Benzylation of 7
followed by deketalisation of the resulting THF 8 with
aqueous CF3COOH afforded diol 913 in good yield. This
was converted into epoxide 11 via monotosylation at
the 1° hydroxyl and base treatment of tosylate 10.
Keywords: (R)-2,3-Cyclohexylideneglyceraldehyde; Sharpless asym-
metric dihydroxylation; Absolute stereoselectivity; 2,5-Disubstituted
tetrahydrofurans; Substrate controlled addition; Stereodiversity.
*
Corresponding author. Tel.: +91 22 25595422; fax: +91 22
25505151; e-mail: achat@apsara.barc.ernet.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.093

2872
A. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 2871–2873
Cu(I)-Catalysed addition of n-nonylmagnesium bromide
to 11 afforded the known alcohol 126 (Scheme 1). The
spectral and optical data of 12 prepared by us and
its TBS derivative 12a were in good agreement with
those reported.6,14
with TBAF to afford the known cis-2,5-disubstituted-
THF 197b (Scheme 1) as verified from spectral and opti-
cal data and also from the data of its tosyl derivative 19a
which were in good agreement with the reported
data.7b,18
Next, benzoate 3b (derived from 2b) was subjected to
Sharpless dihydroxylation11 by separate treatment with
AD-mix a and AD-mix b. As with 3a, both of these
hydroxylations afforded the same diastereomeric diol
5b15 with absolute stereoselectivity. Monotosylation of
5b, regioselectively at the 1° hydroxyl, produced 13,
which on treatment with K2CO3 afforded cis-2,5-disub-
stituted tetrahydrofuran 14. Silylation of the hydroxyl
and deketalisation of the resulting THF 15 with aqueous
CF3COOH afforded diol 1616 in good yield. NaIO4
cleavage of the 1,2-diol unit of 16 yielded aldehyde 17
which was transformed into alkyne 18 following a
known procedure.17 This was desilylated on treatment
Thus, a stereodivergent and operationally simple
strategy has been established to obtain both cis- and
trans-2,5-disubstituted tetrahydrofurans starting from
the same substrate 1 employing Sharpless asymmetric
hydroxylation reactions. The formation of only one
diastereomer of diols 5a and 5b from 3a and 3b with
either of the SAH reagents suggested that unlike in liter-
ature precedence,11 in both cases, the dihydroxylation
reactions were highly substrate controlled. Furthermore,
it was evident that a-dihydroxylation took place in both
SAH reactions with the benzoates 3a,b irrespective of
their having opposite stereochemistry at C-3. This
suggested that the bulky cyclohexyl moiety, rather than
R
O
R
O
R
R
O
R
O
R
O
O
i, ii
2, R', H
3, R', Bz
+
CHO
1
2b, 3b
2a, 3a
OR'
OR'
R, R = -(CH ) -
2 5
R
O
R
O
iv
iii
2a / 2b
2a
4
O
R
O
R
O
R
O
R
O
OH
OH
va or vb
OR'
vi
vii, viii
3a
ix, vi
O
5a
6
O
O
OBz
7, R', H
8, R', Bn
OH
OBz
OTs
R
R
OBn
OBn
O
OBn
nC10H21
vii
x, xi
O
O
9, R', H
10, R', Ts
OH
OR'
12, R', H
12a , R', TBS
11
O
OR'
R
R
O
OH
va or vb
O
3b
vii, xii
OR'ix
OTPS
xiii
vi
O
O
5b, R', H
14, R', H
15 , R', TPS
O
R
O
16
13 , R', Ts
OH
OBz
OR'
OH
R
xv, vi
xiv
OTPS
OTPS
OR'
OHC
O
O
O
18
17
19, R', H
19a , R', Ts
Scheme 1. Reagents and conditions: (i) 4-butenylMgBr, 0 °C–rt, THF, 81%; (ii) BzCl, Py, 0 °C, 96%; (iii) PCC, CH2Cl2, rt, 73%; (iv) K-Selectride,
THF, ꢀ78 °C, 95%; (v) (a) ADmix-a, t-BuOH/H2O (1:1), 0 °C, 82% for 3a–5a; 86% for 3b–5b; (v) (b) ADmix-b, t-BuOH/H2O (1:1), 0 °C, 83% for
3a–5a; 80% for 3b–5b; (vi) p-TosCl, Py, 0 °C, 90% for 5a–6; 87% for 9–10; 83% for 5b–13; 91% for 19-19a; (vii) K2CO3, MeOH, rt, 92% for 6–7; 86%
for 10–11; 89% for 13–14; (viii) NaH, PhCH2Br, THF, reflux, 90%; (ix) CF3CO2H, H2O, 0 °C, 87% for 8–9; 81% for 15–16; (x) nC9H19MgBr, CuI,
THF, ꢀ50 °C, 84%; (xi) TBDMSCl, Im, rt, 88%; (xii) TBDPSCl, Im, rt, 86%; (xiii) NaIO4, CH3CN–H2O (3:2), rt, 84%; (xiv) (a) Zn, PPh3, CBr4,
CH2Cl2, rt, 83%; (b) nBuLi, THF, ꢀ 78 °C, 83%; (xv) TBAF, THF, rt, 74%.

A. Chattopadhyay et al. / Tetrahedron Letters 48 (2007) 2871–2873
2873
Tetrahedron Lett. 2005, 46, 3103–3105; (i) Dhotare, B.;
Goswami, D.; Chattopadhyay, A. Tetrahedron Lett. 2005,
46, 6219–6221.
the –OBz, might play a role in directing the site of
dihydroxylation by the AD-mix reagents at the terminal
olefins. However, with hindsight this proved advanta-
geous to attain stereodiversity in this strategy to
construct both cis- and trans-2,5-disubstituted tetra-
hydrofurans starting from two diastereomeric alcohols
originating from 1.
25
9. Compound 2a: ½aꢁD 7.2 (c 0.9, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.4–1.6 (m, 12H), 1.94 (br s, 1H),
2.0–2.3 (m, 2H), 3.4–3.5 (m, 1H), 3.75 (m, 1H), 3.9–4.0 (m,
2H), 5.0–5.1 (m, 2H), 5.7–6.0 (m, 1H). 13C NMR
(50 MHz, CDCl3): d 23.57, 23.80, 24.93, 29.50, 32.59,
34.66, 36.09, 65.54, 71.43, 78.55, 109.72, 114.79, 137.93.
Anal. Calcd for C13H22O3: C, 68.99; H, 9.79. Found: C,
68.80; H, 9.91.
References and notes
25
10. Compound 2b: ½aꢁD 13.6 (c 0.9, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.2–1.6 (m, 12H), 1.96 (br s, 1H),
2.0–2.3 (m, 2H), 3.7–3.8 (m, 1H), 3.9–4.1 (m, 3H), 5.0–5.1
(m, 2H), 5.7–6.0 (m, 1H). 13C NMR (50 MHz, CDCl3): d
23.61, 23.80, 24.97, 29.78, 31.73, 34.66, 35.9, 64.30, 70.16,
78.14, 109.39, 114.93, 137.90. Anal. Calcd for C13H22O3:
C, 68.99; H, 9.79. Found: C, 69.15; H, 9.61.
1. (a) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett.
1995, 1043–1044; (b) Kang, S. H.; Lee, S. B. Chem.
Commun. 1998, 761–762; (c) O’Hagan, D. Nat. Prod. Rep.
1989, 6, 205; (d) Bartlett, P. A. Tetrahedron 1980, 36, 3–72.
2. (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat.
Prod. 1999, 62, 504–540; (b) Keinan, E.; Sinha, A.;
Yazbak, A.; Sinha, S. C. Pure Appl. Chem. 1997, 69,
423–430; (c) Hoppe, R.; Scharf, H. D. Synthesis 1995,
1447–1464; (d) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.;
Gu, Z. M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep.
1996, 13, 275–308.
3. (a) Michael, J. P.; Ting, P. C.; Bartlett, P. A. J. Org. Chem.
1985, 50, 2416–2423, and references cited therein; (b)
Zhang, H.; Mootoo, D. R. J. Org. Chem. 1995, 60, 8134–
8135; (c) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem.
Soc. 1981, 103, 3963–3964; (d) Miura, K.; Hondo, T.;
Okajima, S.; Hosomi, A. Eur. J. Org. Chem. 2006, 3251–
3258; (e) Tanikaga, R.; Hosoya, K.; Kaji, A. J. Chem.
Soc., Perkin Trans. 1 1987, 1799–1803; (f) Kang, S. H.;
Lee, S. B. Tetrahedron Lett. 1993, 34, 1955–1958; (g)
Arista, L.; Gruttadauria, M.; Thomas, E. J. Synlett 1997,
627–628.
11. Kolb, H. C.; Van Nieuwennhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
25
12. Compound 5a: ½aꢁD 12.35 (c 1.1, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.2–1.6 (m, 12H), 1.8–1.9 (m, 2H),
2.34 (br s, 2H), 3.40 (dd, J = 7.5, 4.2 Hz, 1H), 3.5–3.9 (m,
3H), 4.03 (t, J = 6.8 Hz, 1H), 4.30 (m, 1H), 5.23 (m, 1H),
7.39–7.56 (m, 3H), 8.04 (d, J = 8.0 Hz, 2H). 13C NMR
(50 MHz, CDCl3): d 23.68, 23.78, 24.97, 27.13, 28.86,
34.72, 35.71, 65.12, 66.35, 71.86, 74.11, 77.88, 109.98,
128.29, 129.60, 129.88, 132.99, 166.36. Anal. Calcd for
C20H28O6: C, 65.91; H, 7.74. Found: C, 65.77; H, 7.90.
23
13. Compound 9: ½aꢁD ꢀ1.0 (c 0.9, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.5–1.8 (m, 2H), 1.9–2.0 (m, 2H),
2.47 (br s, 2H), 3.4–3.5 (m, 3H), 3.65 (m, 2H), 3.9–4.0 (m,
1H), 4.1–4.2 (m, 1H), 4.57 (s, 2H), 7.27 (bm, 5H). 13C
NMR (50 MHz, CDCl3): d 27.69, 28.41, 63.99, 72.53,
73.10, 73.70, 78.13, 79.85, 127.47, 127.54, 128.18, 137.86.
Anal. Calcd for C14H20O4: C, 66.64; H, 7.99. Found: C,
66.86; H, 7.78.
4. (a) Jalce, G.; Seck, M.; Franck, X.; Hocquemiller, R.;
Figadere, B. J. Org. Chem. 2004, 69, 3240–3241; (b) Pilli,
R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2, 53–56.
5. Beebe, X.; Schore, N. E.; Kurth, M. J. J. Am. Chem. Soc.
1992, 114, 10061–10062.
14. Compounds 19a and SI–V of Ref. 6.
25
15. Compound 5b: ½aꢁD 8.54 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.2–1.6 (m, 12H), 1.7–2.0 (m, 2H),
2.9 (br s, 2H), 3.35–3.45 (m, 1H), 3.56–3.69 (m, 2H), 3.89
(t, J = 6.4 Hz, 1H), 4.02–4.12 (m, 1H), 4.22 (m, 1H), 5.24
(t, J = 4.2 Hz, 1H), 7.2–7.5 (m, 3H), 8.10 (d, J = 7.8 Hz,
2H). 13C NMR (50 MHz, CDCl3): d 23.58, 24.79, 27.19,
28.47, 34.52, 35.72, 65.30, 66.30, 71.72, 73.96, 76.27,
109.98, 128.19, 129.44, 129.64, 132.95, 165.98. Anal. Calcd
for C20H28O6: C, 65.91; H, 7.74. Found: C, 66.08; H, 7.59.
6. Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem.
2005, 70, 8035–8046.
7. (a) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819–
4822; (b) Sharma, G. V. M.; Punna, S.; Prasad, T. R.;
Krishna, P. R.; Chorghade, M. S.; Ley, S. V. Tetrahedron:
Asymmetry 2005, 16, 1113–1123; (c) Goksel, H.; Stark, C.
B. W. Org. Lett. 2006, 8, 3433–3436, and references cited
therein.
8. (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem.
1995, 60, 585–587; (b) Chattopadhyay, A. J. Org. Chem.
1996, 61, 6104–6107; (c) Chattopadhyay, A.; Dhotare, B.;
Hassarajani, S. A. J. Org. Chem. 1999, 64, 6874–6878; (d)
Dhotare, B.; Salaskar, A.; Chattopadhyay, A. Synthesis
2003, 2571–2575; (e) Dhotare, B.; Chattopadhyay, A.
Synthesis 2001, 1337–1340; (f) Chattopadhyay, A.; Gos-
wami, D.; Dhotare, B. Tetrahedron Lett. 2006, 47, 4701–
4705; (g) Chattopadhyay, A. Tetrahedron: Asymmetry
1997, 8, 2727–2730; (h) Chattopadhyay, A.; Dhotare, B.
25
16. Compound 16: ½aꢁD ꢀ2.8 (c 1.9, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.04 (s, 9H), 1.8–2.0 (m, 4H), 2.90
(br s, 2H), 3.5–3.7 (m, 5H), 3.9–4.1 (m, 2H), 7.38 (m, 6H),
7.68 (m, 4H). 13C NMR (50 MHz, CDCl3): d 18.99, 26.60,
27.07, 27.22, 63.58, 65.65, 73.15, 79.41, 80.53, 127.49,
129.43, 129.51, 133.02, 133.32, 135.37. Anal. Calcd for
C20H32O6Si: C, 68.96; H, 8.05. Found: C, 68.75; H, 7.95.
17. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–
3772.
18. Compounds 49 and 50 of Ref. 7b.