Flow chemistry approach for partial deuteration of alkynes: Synthesis of deuterated taxol side chain

Article abstract of DOI:10.1016/j.tetlet.2011.05.042

The partial deuteration of alkynes proceeds via a flow chemistry approach under Lindlar's heterogeneous catalysis to provide cis-dideuterated olefins in good yields. Further, dideuterated olefin has been successfully utilized for Sharpless asymmetric dihy

Full text of DOI:10.1016/j.tetlet.2011.05.042

Tetrahedron Letters 52 (2011) 3865–3867
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Flow chemistry approach for partial deuteration of alkynes: synthesis
of deuterated taxol side chain
S. Chandrasekhar a, , B. V. D. Vijaykumar a, B. Mahesh Chandra a, Ch. Raji Reddy a, P. Naresh b
⇑
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Center for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The partial deuteration of alkynes proceeds via a flow chemistry approach under Lindlar’s heterogeneous
catalysis to provide cis-dideuterated olefins in good yields. Further, dideuterated olefin has been success-
fully utilized for Sharpless asymmetric dihydroxylation followed by Mitsunobu reaction for the synthesis
of deuterated taxol side chain.
Received 3 March 2011
Revised 10 May 2011
Accepted 11 May 2011
Available online 18 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Flow chemistry
Partial deuteration
Sharpless asymmetric dihydroxylation
Deuterated taxol side chain
5% Pd-CaCO3
(poisoned with lead)
hexanes, 50 oC
Deuterium labeled compounds possess a wide range of applica-
tions in pharmaceuticals, environmental, materials and chemical
sciences.1 Although no product containing the deuterium atom
has been found in nature, this atom constitutes important proper-
ties for the deuterated products. They are useful in studying meta-
bolic pathways of bio-active molecules, detailed mechanism of
chemical reactions etc.2 In select cases of specifically modified
molecules (by the incorporation of ‘deuterium’), can positively
impact certain drugs absorption, distribution, metabolism and
excretion (ADME) properties, creating the potential for improved
drug efficacy, safety, and tolerability. Thus, deuteration is exploited
in various sites of the rapamycin, zilascorb, atazanavir etc., mole-
cules to increase the potency of drug, reduce toxicity of the drug,
reduce the clearance of the pharmacologically active moiety and
improve the stability of the molecule.3,4 Therefore the synthesis
of deuterium labeled compounds has been receiving considerable
attention by the research groups.
Usually deuterated compounds are synthesized by H–D
exchange reaction under metal catalysis.5 Besides, D2-gas can be
used to deuterate the organic molecule analogs by hydrogenation
of olefins, acetylenes, cyanides etc. However, there is no report
on partial deuteration of alkynes in a flow chemistry approach
and further functionalization of resultant dideuterated olefins. This
prompted us to explore the partial deuteration of acetylenes (1)
using flow chemistry (H-cube) in the presence of Lindlar’s catalyst
(Scheme 1) involving a simple and inexpensive D2-gas generation.6
D
R
D
R
R1
D2O, D2 from H-Cube
50 oC, 1 bar, 1mL/min.
R1
1
2
R = aryl, alkyl
R1= alkyl, CO2Et
Scheme 1. Partial deuteration of alkynes in H-cube.
O
O
O
O
O
NH
O
D
BzHN
OH
OEt
O
D
OH
H
O
HO
HO
O
O
O
O
Dideuterated
Taxol (3)
Taxol side chain (3a)
Figure 1. Structures of taxol and dideuterated taxol side chain.
Further, we successfully achieved the synthesis of deuterated taxol
side chain 3a by utilizing dideuterated (Z)-ethylcinnamate ob-
tained via flow chemistry.
A noted example of the antitumor agent, taxol (3), contains syn-
stereoisomer phenylisoserine side chain as its key pharmacophore
⇑
Corresponding author. Tel.: +91 040 27193210; fax: +91 040 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.042

3866
S. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 3865–3867
(DHQD)IND (4 mol%),
OsO4 (0.4 mol%),
CH3SO2NH2
(Fig. 1). The approval of taxol (paclitaxel) as a therapeutic agent
against ovarian and other types of cancer has continued to elicit
interest in both the synthesis and biosynthesis of this molecule.7
As recently described by Fulop and co-workers,8 the substrates
were completely deuterated in the presence of 5% Pd/BaSO4 cata-
lyst. In our case, we have conducted the reaction using 5% Pd on
CaCO3 poisoned with lead (Lindlar’s catalyst) to obtain the partially
deuterated olefin. Ethyl 3-phenylpropiolate 1a (100 mg) was dis-
solved in 100 mL HPLC-grade hexane. 5% Pd/CaCO3 poisoned with
lead (Lindlar’s catalyst) was placed in the catalyst cartridge where
the reaction takes place. The flow of the HPLC pump was adjusted
to 1 mL/min, the temperature was set to 50 °C, and the pressure
was set to minimum (1 bar). The collected eluent was evaporated
to obtain the dideuterated olefin 2a as a Z/E (7:1) mixture (Table
1, entry 1).9
HO OH
N3H, DEAD, Ph3P
D
D
2a
CO2Et
C6H6, THF, 0 °C,
4 h, 80% (brsm)
K4[Fe(CN)6], K2CO3
t-BuOH, H2O (1:1), 0 o
4 days, 93%
C
4, (85:15er)
O
O
D
D
N3
N3
BzCl, Py, DMAP
OEt
OEt
CH2Cl2, 0 °C
83%, 6 h
OH
OBz
D
D
5
6
O
BzHN
D
H2, Pd/C
OEt
MeOH, r.t,
3 h, 87%
OH
D
Having able to partially reduce the acetylene into dideuterated
(Z)-olefin, some other alkyne substrates were subjected to the
above described protocol. Thus, alkyne 1b was reduced to obtain
exclusively cis-dideuterated olefin 2b in 99% yield (Table 1, entry
2). Similar results were observed for 1c as well as for propargylic
alcohols 1d and 1e to furnish the corresponding dideuterated ole-
fins 2c, 2d, and 2e in good yields with Z-olefin as the major product
(Table 1, entries 3, 4 and 5). The ratio of the products was deter-
mined by 1H NMR. The Z-configuration of the major product was
confirmed by the NOE studies on the reduced product of 2b as well
as on 2e.10
3a
Scheme 2. Synthesis of dideuterated taxol side chain.
tions towards taxol side chain. Thus, diol 4 was treated with hydra-
zoic acid under Mitsunobu reaction conditions to afford azide 5 in
80% yield.13 The azido alcohol 5 was treated with benzoylchloride
to azidobenzoate 6 followed by the hydrogenation reaction, where
the benzoyl group migrated from oxygen to the reduced amine
providing the desired deuterated taxol side chain 3a, in 72% yield
(for two steps). All the deuterated compounds were fully charac-
terized14 by 1H, 2H and 13C NMR, IR and mass spectra and the con-
figurations assigned are tentative.
In summary, we have demonstrated the partial deuteration of
alkynes using flow chemistry under Lindlar’s catalysis. Impor-
tantly, further asymmetric functionalization involving dihydroxy-
lation of deuterated olefin has also been demonstrated, which
presents the indirect introduction of deuterium bearing asymmet-
ric carbon. This was further converted to deuterated taxol side
chain using Mitsunobu reaction as the key step.
The (Z)-didueterated ethylcinnamate (2a) was further con-
verted to a,b-dideuterated N-benzoyl 3-phenylisoserine 3a, which
is a deuterated analog of C-13 crucial side chain present in taxol
(Scheme 2). Accordingly, deuterated olefin 2a was treated under
Sharpless asymmetric dihydroxylation (SAD) conditions using
DHQD-IND ligand to furnish the erythro diol (2R,3R)-4 in 92%
yield.11 To the best of our knowledge, this is the first example of
SAD on a deuterated olefin which provided the diol 4 with 85:15
enantiomeric ratio (by chiral HPLC analysis).12 At this stage we
have decided to use this deuterated diol 4 for further transforma-
Table 1
partial deuteration of alkynes by flow chemistry (H-cube)
Entry
Alkynea (1)
Productb (2)
Z/Ec
Yieldd (%)
98
CO2Et
D
D
1
7:1
CO2Et
1a
2a
COOEt
D
MPMO
MPMO
D
D
2
3
Z only
99
96
1b
COOEt
2b
D
OBn
20:1
OBn
1c
2c
OH
D
D
D
D
4
5
13:1
6:1
95
91
HO
2d
1d
1e
OH
OH
2e
a
b
c
All the compounds were prepared to 0.1% solutions in HPLC grade hexane.
Structure showed for major product.
All the Z/E ratios are characterized by NMR studies.
Overall yield (Z and E) based on 2.
d

S. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 3865–3867
3867
12. The enantiomeric ratio of the diol ester 4 was determined by chiral HPLC
analysis (chiral pak AD-H: 250 ꢀ 4.6 mm column, mobile phase: 12% IPA/Hex,
Flow rate: 1.0 mL/min, detection: 210 nm), er = 85:15. The ratio calculated is
only for Z-isomer.
Acknowledgments
B.V.D.V., B.M.C., and P.N. are grateful to CSIR, New Delhi for re-
search fellowship. The authors thank Dr. B. Jagadeesh, IICT for fruit-
ful discussions and Heavy Water Board, Department of Atomic
Energy for providing D2O.
13. Soo, Y. K. J. Org. Chem. 2002, 67, 2689–2691.
14. Spectral data for new compounds: (2a): IR (neat): mmax 2981, 2929, 1720, 1627,
1447, 1282, 1178, 1028, 766, 694, 667 cmꢁ1 1H NMR (CDCl3, 300 MHz): d
;
7.62–7.55 (m, 2H), 7.39–7.29 (m, 3H), 4.17 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz,
3H); 2H NMR (CHCl3, 61.3 MHz): d 6.94 (s, 1D), 5.95 (s, 1D); 13C NMR (CDCl3,
75 MHz): d 166.2, 143.0, 129.6, 128.9, 127.9, 60.3, 14.1; ESIMS (m/z): 178.
(2b): IR (neat): mmax 2935, 2857, 1715, 1614, 1513, 1464, 1365, 1249, 1136,
Supplementary data
1100, 1035, 820 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.19 (m, 2H), 6.80 (m, 2H),
;
4.39 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.71 (t,
J = 7.5 Hz, 2H), 1.72 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H); 2H NMR (CHCl3, 76.7 MHz):
d 6.28 (s, 1D), 5.80 (s, 1D); 13C NMR (CDCl3, 75 MHz): d 166.3, 159.0, 149.2,
130.2, 129.2, 119.5, 113.7, 72.5, 69.5, 59.7, 55.2, 29.1, 25.7, 14.2; ESIMS (m/z):
303 [M + Na]+; HRMS(ESI): Calcd for C16H20D2NaO4 [M+Na]+: 303.1379, found:
303.1373.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.042.
References and notes
(2b0): IR (neat): mmax 3397, 2924, 2857, 1615, 1514, 1458, 1247, 1037,
826 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.20 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4
;
1. Stovkis, E.; Rosing, H.; Beijnen, J. H. Rapid Commun. Mass Spectrom. 2005, 19,
401.
2. Baldwin, J. E.; Raghavan, A. S.; Hess, B. A.; Smentek, L. J. Am. Chem. Soc. 2006,
128, 14854.
3. Melvik, J. E.; Dornish, J. M.; Larsen, R. O.; Borretzen, B.; Oftebro, R.; Pettersen, E.
O. Anticancer Res. 1992, 12, 33.
Hz, 2H), 4.39 (s, 2H), 4.10 (s, 2H), 3.79 (s, 2H), 3.42 (t, J = 6.0 Hz, 2H), 2.18 (t, J =
6.9 Hz, 2H), 1.68 (br s, 1H), 1.65 (quin, J = 6.6 Hz, 2H); 2H NMR (CHCl3, 76.7
MHz): d 5.68 (s, 1D), 5.52 (s, 1D). 13C NMR (CDCl3, 75 MHz): d 159.1, 130.4,
129.2, 113.7, 72.4, 68.7, 58.2, 55.2, 29.1, 23.7; ESIMS (m/z): 261 [M+Na]+.
(2c): IR (neat): mmax 3399, 2925, 1711, 1620, 1454, 1274, 894, 701 cmꢁ1 1H
;
4. (a) Naicker, S.; Randall W. Yatscoff, R. W.; Foster, R. T., U.S. 6,710,053 B2, 2004.;
(b) Laissue, J. A.; Burki, H.; Berchtold, W. Cancer Res. 1982, 42, 1125.
5. (a) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmerman, J. Angew. Chem., Int. Ed. 2006, 45,
7744; (b) Hanson, S. K.; Heinekey, D. M.; Goldberg, K. I. Organometallics 2008,
27, 1454; (c) Prechtl, M. H. G.; Holscher, M.; Ben-David, Y.; Theyssen, N.;
Loschen, R.; Milstein, D.; Leitner, W. Angew. Chem., Int. Ed. 2007, 46, 2269; (d)
Erdogan, G.; Grotjahn, D. B. J. Am. Chem. Soc. 2009, 131, 10354.
6. H-CubeÒ is a commercially available continuous flow reactor, which generates
D2 from D2O in situ using an electrolytic process with a disposable catalyst
cartridge system. This method avoids the use of expensive and dangerous D2-
gas cylinders.
7. Goodman, J.; Walsh, V. The Story of Taxol: Nature and Politics in the Pursuit of an
Anti-cancer Drug; Cambridge University Press, 2000.
8. Mandity, I. M.; Martinek, T. A.; Darvas, F.; Fulop, F. Tetrahedron Lett. 2009, 50,
4372.
9. Hydrogenation of 1a using H2–Pd/C conditions gave the corresponding olefin
2a in 97% yield with E/Z > 97:3 selectivity; see Refs.: (a) Shing, T. K. M.; Luk, T.;
Lee, C. M. Tetrahedron 2006, 62, 6621; (b) Akbulut, N.; Hartsough, D.; Kim, J.-I.;
Schuster, G. B. J. Org. Chem. 1989, 54, 2549.
10. (a) Substrate 2b was subjected to DIBAL-H reduction to achieve allyl alcohol
2b0, which was used for NOE studies and observed the NOE cross peaks
between Ha and Hb as shown below.
NMR (CDCl3, 300 MHz): d 7.45–7.30 (m, 10H), 4.52 (s, 2H), 3.30 (t, J = 6.7 Hz,
2H), 2.33 (t, J = 6.7 Hz, 2H); 2H NMR (CHCl3, 61.3 MHz): d 6.21 (s, 1D), 5.69 (s,
1D); 13C NMR (CDCl3, 75 MHz): d 133.6, 133.0, 131.5, 128.4, 127.9, 127.6, 72.9,
71.0, 28.1; ESIMS (m/z): 279 [M+K]+.
(2d): IR (neat): mmax 3374, 2925, 2960, 2872, 2853, 1716, 1489, 1466, 1027,
755 cmꢁ1 1H NMR (CDCl3, 500 MHz): d 7.42–7.38 (m, 2H), 7.34–7.26 (m, 3H),
;
4.28 (d, J = 5.9 Hz, 1H), 1.96–1.76 (m, 1H), 1.80 (br s, 1H), 1.02 (d, J = 6.9 Hz,
3H), 1.00 (d, J = 6.9 Hz, 3H); 2H NMR (CHCl3, 61.3 MHz): d 6.61 (s, 1D), 5.80 (s,
1D); 13C NMR (CDCl3, 75 MHz): d 131.6, 128.7, 128.2 (2 carbons), 72.1, 34.6,
18.1, 17.4; EI-MS (m/z): 179.
(2e): IR (neat): mmax 3393, 3221, 2922, 2853, 1621, 1461, 1373, 884 cmꢁ1 1H
;
NMR (CDCl3, 300 MHz): d 7.40–7.10 (m, 5H), 4.44 (s, 2H), 2.05 (br s, 1H); 2H
NMR (CHCl3, 76.7 MHz): d 6.64 (s, 1D), 5.92 (s, 1D); 13C NMR (CDCl3, 75 MHz):
d 136.6, 128.7, 128.3, 127.2, 62.0; EIMS (m/z): 135, 119.
(4): IR (neat):
mmax 3444, 2982, 2925, 1732, 1634, 1449, 1275, 1142, 1025, 765,
;
738, 701 cmꢁ1
1H NMR (CDCl3, 300 MHz): d 7.38–7.24 (m, 5H), 4.11 (q,
J = 7.1 Hz, 2H), 3.05 (br s, 2H), 1.15 (t, J = 7.1 Hz, 3H); 2D NMR (CHCl3,
61.3 MHz): d 5.04 (s, 1D), 4.57 (s, 1D); 13C NMR (CDCl3, 75 MHz): d 171.9,
139.3, 128.2, 128.1, 126.4, 61.8, 13.9. ESIMS (m/z): 235 [M+Na]+; HRMS(ESI):
Calcd for C11H12D2NaO4 [M+Na]+: 235.0910, found: 235.0916.
(5): IR (neat): mmax 3456, 2924, 2105, 1733, 1637, 1449, 1264, 1151, 758,
700 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.54–7.32 (m, 5H), 4.29 (q, J = 7.1 Hz,
;
2H), 3.12 (br s, 1H), 1.62 (br s, 1H), 1.30 (t, J = 7.1 Hz, 3H); 2D NMR (CHCl3,
61.3 MHz): d 5.53 (s, 1D), 4.97 (s, 1D); 13C NMR (CDCl3, 75 MHz): d 171.8,
135.4, 128.8, 128.7, 127.8, 62.4, 14.0; ESIMS (m/z): 260 [M+Na]+; HRMS(ESI):
Calcd for C11H11D2N3NaO3 [M+Na]+: 260.0975, found: 260.0975.
D
MPMO
D
DIBAL-H
2b
CH2Cl2, 0 o
92%
C
H
b
H
H
a
OH
2b'
(6): IR (neat): mmax 3449, 2978, 2925, 2104, 1726, 1638, 1450, 1278, 1110,
H
1069, 755, 708 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 8.12–8.06 (m, 2H), 7.63–
;
7.56 (m, 1H), 7.51–7.31 (m, 7H), 4.13 (dq, J = 7.1, 1.5 Hz, 2H), 1.55 (br s, 1H),
1.14 (t, J = 7.1 Hz, 3H); 2D NMR (CHCl3, 61.3 MHz): d 5.44 (s, 1D), 5.16 (s, 1D);
13C NMR (CDCl3, 75 MHz): d 167.3, 165.5, 134.4, 133.6, 130.0, 129.1, 128.8,
128.5, 127.5, 61.9, 13.8; ESIMS (m/z): 364 [M+Na]+; HRMS(ESI): Calcd for
nOe correlation
(b) NOE-cross peaks observed in 2e.
D
D
C
18H15D2N3Na O4 [M+Na]+: 364.1237, found: 364.1253.
(3a): IR (neat): mmax 3422, 3353, 2977, 2929, 1717, 1624, 1523, 1489, 1276,
OH
H
1139, 1122, 718, 701, 641, 607 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.80–7.74
;
H
(m, 2H), 7.56–7.24 (m, 8H), 7.04 (br s, 1H), 4.13 (m, 2H), 3.40 (br s, 1H), 1.30
(m, 3H); 2D NMR (CHCl3, 61.3 MHz): d 5.75 (s, 1D), 4.60 (s, 1D); 13C NMR
(CDCl3, 75 MHz): d 172.9, 166.8, 134.1, 131.7, 128.7, 128.6, 127.9, 127.0, 126.9,
62.7, 14.1; ESIMS (m/z): 338 [M+Na]+; HRMS(ESI): Calcd for C18H17D2NNaO4
[M+Na]+: 338.1332, found: 378.1353.
H
nOe correlation
2e
11. (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568; (b) Xu, D.;
Sharpless, K. B. Tetrahedron Lett. 1994, 35, 4685.