Route optimization and synthesis of taxadienone

Article abstract of DOI:10.1021/op500314c

Early process development toward the scalable production of taxadienone on a decagram scale is described. A continuous flow reactor was employed to safely run a potentially hazardous cyclopropane ring opening. The route featured two copper-mediated additions, a Diels-Alder reaction and a palladium-catalyzed Negishi coupling, to construct the final structure.

Full text of DOI:10.1021/op500314c

Subscriber access provided by - Access paid by the | UCSF Library
Full Paper
Route Optimization and Synthesis of Taxadienone
Sergiy Krasutsky, Sheila H Jacobo, Scott Tweedie, Ravi Krishnamoorthy, and Alexander Filatov
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500314c • Publication Date (Web): 15 Dec 2014
Downloaded from http://pubs.acs.org on December 16, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 16
1
2
3
4
5
6
7
Route Optimization and Synthesis of Taxadienone.
8
9
Sergiy G. Krasutsky,*,† Sheila H. Jacobo,† Scott R. Tweedie, † Ravi Krishnamoorthy, † and
Alexander S. Filatov‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Chemical Development Department, AMRI, 21 Corporate Circle, Albany, New York 12203,
United States
‡Xꢀray Facilities, Department of Chemistry, University at Albany, 1400 Washington Avenue,
Albany, New York, 12222, United States
Keywords: Taxadienone, continuous flow reactor, copper catalyzed addition, DielsꢀAlder
reaction, Negishi coupling.
Abstract
Early process development toward the scalable production of taxadienone on a decagram scale is
described. A continuous flow reactor was employed to safely run a potentially hazardous
cyclopropane ring opening. The route featured two copper mediated additions, a DielsꢀAlder
reaction, and a palladiumꢀcatalyzed Negishi coupling to construct the final structure.
INTRODUCTION
Paclitaxel is a promising antiꢀcancer drug with a broad range of therapeutic action.1 The
compound is produced semiꢀsynthetically and its supply relies on cell culture production.
Therefore, several synthetic routes were developed to meet the demand on scale as well as gain
access to different analogues. Recently, a promising new strategy has been described in Baran’s
group.2 The proposed route to synthetic paclitaxel relies on the stepwise oxidation of the C20ꢀ
ACS Paragon Plus Environment

Page 3 of 16
Organic Process Research & Development
1
2
3
4
5
6
structure of taxadienone which marks taxadienone as a center block intermediate in the
production of paclitaxel and analogues.
7
8
9
RESULTS AND DISCUSSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The present work describes early process development toward the production of taxadienone
(+)-16 (Schemes 1 and 2) using Baran’s route as a point of inception. The commercially
available olefin 1 served as a starting material in the preparation of bromodiene 3 via a twoꢀstep
procedure (Scheme 1), in which dibromide 2 did not have to be isolated and the reaction was
performed in a oneꢀpot fashion.
Scheme 1. Preparation of 7.
Br
Br Br
H3C
H3C
CH3
CH3
H3C
CH3
a
b
H3C
H3C
CH2
H3C
H3C
CH3
CH3
66%
98%
CH2 CH3
e
1
3
2
85%
CH3
7
O
HO
H2C
d
c
O
quant.
6
OEt
O
OEt
5
4
Reagents and Conditions: (a) CHBr3, tBuOK, heptanes, 0 °C, quant; (b) PhNMe2, 10 min, 150 °C; (c) 1 M
vinylmagnesium bromide in THF, MTBE, 0 °C to room temperature, 1 h; (d) SiO2, DCM; (e) 3, 6, secꢀBuLi,
CuBr•DMS, THF, ꢀ78 °C to ꢀ20 °C, 3 h.
Initially, the same strategy was adopted in our studies. The reaction of a carbene with the
olefin 1 was performed in heptanes at 0 ºC with the olefin 1 taken in excess as reported.3,4 The
volatiles were removed under reduced pressure and the mixture was heated to 150 °C for 1 h.
The reaction output was improved as follows:
• the level of heptanes was decreased to 3 volumes;
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 16
1
2
3
4
5
6
• the volume of N,Nꢀdimethylaniline was decreased to 1.5 volumes relative to
bromoform;
7
8
9
• the amount of olefin was decreased 1 from 2.0 to 1.5 equivalents.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to continue with the reaction scaleꢀup, a safety assessment of dibromide 2 and the
bromodiene 3 was performed (see Figure 1). The DSC analysis revealed that the second part of
the reaction is highly energetic. The dibromide 2 has an onꢀset temperature of 145 °C with
energy of 360 J/g. The bromodiene 3 has an onꢀset temperature of 226 °C with energy 500 J/g.
These results were against our standard process safety practice, which suggests at least 100 °C
margin of safety (MOS) from the operating temperature of 150 °C for a safe chemical operation
and therefore deemed unsafe for standard batch operations.5
Figure 1. DSC Data for compounds 2 and 3.
Based on these observations, we decided to isolate dibromide 2 and perform the second part
(conversion of 2 to 3) as a separate stage. Upon scaleꢀup, the exotherm was controlled by the
ACS Paragon Plus Environment

Page 5 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
slow addition of bromoform (over 4 h) to a slurry of olefin 1 and potassium tertꢀbutoxide
(tBuOK) at –9 to 0 °C. Reaction between the olefin and carbene is instantaneous, so the in situ
generated carbene was expected not to accumulate. The excess of olefin 1 was further reduced
to 10 mol %. An attempt to remove the side product, potassium bromide, by filtration was
unsuccessful even when filtration aids were employed. Hence, the salts were removed by
aqueous wash. Dibromide 2 was found to be sensitive to water at high pH. Thus, aqueous
workup conditions which properly buffer against tBuOK are important to prevent discoloration
and preserve yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
After successful scaleꢀup of 2, efforts were concentrated on a safe procedure to produce 3 due
to the high energy exhibited by DSC analysis. The conversion of 2 to 3 at a lower temperature
(100 °C) took 30 h to reach completion. A screening of reaction time (10, 20, 40 min) and the
required volume of N,Nꢀdimethylaniline (1, 2 and 3 volumes) showed that efficient conversion of
2 to 3 can be achieved in 10 min at 150 °C, and the optimum amount of N,Nꢀdimethylaniline is
2 volumes. These conditions should be amendable to the use of continuous processing.
Therefore, we employed a continuous flow reactor (CFR), which is a common solution for fast
and potentially hazardous reactions (Figure 2). The reaction occurred inside Hastelloy tubing,
which was placed in an oven. The pump speed was correlated with the reactor tube dimensions
to permit a desired residence time for the starting material inside the tube. The reaction mixture
upon leaving the oven was cooled in a separate heat exchange loop. The reaction was performed
on 490 g scale of dibromide 2 using a 125 mL reaction tube, which allowed increasing the flow
up to 10 mL/min. Processing was complete in 3.5 h. The engagement of the CFR in the
production of compound (+)ꢀ16 effectively addressed our safety concerns and minimized the
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 16
1
2
3
4
5
6
reaction time for this step. The required time from start to finish was 5 h, whereas in the batch
mode the reaction would require more than two days.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. The Flow Chemistry Setup.
The preparation of conjugated ketone 66 from commercially available compound 4 is shown in
Scheme 1. The first part is a Grignard reaction to form 5, which is followed by elimination of a
molecule of EtOH on a silica gel plug to form 6. The reaction solvent, diethyl ether, was
replaced with MTBE without any issues. The reaction time was decreased from the reported 14
h to 1 h with a quantitative yield.
Preparation of 7 (Scheme 1) in diethyl ether proceeded with 50% yield only if freshly prepared
CuBr•DMS complex was used.7 Literature suggests that THF is a good solvent for copper
mediated additions as well.8,9 Thus, when diethyl ether was replaced by THF, the reaction was
complete in 2 h. Moreover, running the reaction in THF made it possible to use commercially
available CuBr•DMS complex, which had failed earlier in our studies.
Preparation of (ꢀ)ꢀ9 is shown in Scheme 2. Although successful on small scale, the literature
conditions10 failed upon attempted scaleꢀup. It was speculated that the likely cause of this
problem was brief exposure of the highly acidic reaction mixture to atmospheric moisture during
the quench. Implementation of a reverse quench allowed the reaction to be scaled up with a
consistently quantitative yield. When the reaction was performed in an alternative solvent, such
ACS Paragon Plus Environment

Page 7 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
as THF, conversion was poor. The enantiomeric (ee) purity of compound (ꢀ)ꢀ9 was determined
by hydrolysis of the TMS ether to ketone 10 using 2 N HCl and analysis by chiral HPLC. The
observed ee varied from 92.9 to 94.2 %.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of 12 (Scheme 2) was repeated as described2 with the following modifications to
meet the scale requirements. Overall, the reaction is a twoꢀstep procedure consisting of an aldol
reaction between (-)-9 and acrolein catalyzed by gadolinium(III) triflate11 to form 11 followed
by Jones’ oxidation of the alcohol to the diketone 12 affording overall 61% yield for two steps.
In order to avoid the retro aldol reaction of 11 during the workup, the reaction was quickly
concentrated in portions, which were diluted with acetone and taken into the next oxidation step.
It is worth noting that acrolein diethoxy acetal can also be used and can be hydrolyzed in water
using camphorsulfonic acid. The product, acrolein, is distilled from the reaction as a mixture in
ethanol and water, which are the solvents used in the aldol reaction.
Modifications in the purification of (+)-13, the DielsꢀAlder reaction product,12 were critical to
obtain high quality material. The crude material after silica plug purification was contaminated
with several coꢀeluting impurities, which would not purge in the next step and were difficult to
remove by silica column chromatography. To our delight, we found that the desired product (+)-
13 can successfully be crystallized from heptanes.
13
Figure 3. Ballꢀandꢀstick views of (+)-13.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 16
1
2
3
4
Scheme 2. Preparation of taxadienone.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reagents and Conditions: (a) (i) copper (I) 2ꢀthiophenecarboxylate (CuTC), ligand 8, 2 M Me3Al in heptane, diethyl
ether, 14 h, ꢀ30 °C; (ii) TEA, TMSCl, 3 h; (b) THF, 2 N HCl; (c) acrolein, Gd(OTf)3, water, ethanol, toluene; (d)
Jones reagent, acetone, 0 °C; (e) BF3•OEt2, DCM, 0 °C; (f) PhNTf2, KHMDS, THF, 0 °C; (g) Me2Zn, Pd(PPh3)4, 0
°C to room temperature.
This crystallization step was essential to obtain taxadienone (+)-16 in high quality. Single
crystal Xꢀray data analysis confirmed the structure and the absolute stereochemistry of (+)-13
(Figure 3). Hydrogen atoms were omitted for clarity except two most stereochemically
important ones.
A Negishi coupling was employed to prepare of (+)-16 via a two step procedure.2 The triflate
15 was prepared using Nꢀphenylꢀbis(trifluoromethanesulfonimide) and potassium bis(trimethylꢀ
ACS Paragon Plus Environment

Page 9 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
silyl)amide in a quantitative yield. Azeotropic drying by distillation while adding fresh THF was
done to ensure moisture would not interfere with the next step. The Negishi reaction between
triflate 15 and dimethylzinc using tetrakis(triphenylphosphine)palladium(0) as a catalyst14
afforded the product (+)-16 in 82% yield after crystallization from methanol.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSIONS
The reported route2 to taxadienone (+)-16 was successfully optimized and scaledꢀup to
decagram quantity. Thermal hazards associated with the production of bromodiene 3 were
addressed by employing a continuous flow reactor. Two cuprate additions to form a desired
enantiomer of (-)-9 were executed in good yield. The crystallization of (+)-13 at the penultimate
step proved to be a decisive factor for obtaining taxadienone (+)-16 of high quality.
EXPERIMENTAL SECTION
Chiral analysis of ketone 8 was performed on Waters 2695 system equipped with a Daicel Chiral
OJꢀH, 4.6×250 mm, 5µm column at 25 °C with hexanes as mobile phase with the flow rate 0.5
mL/min using Waters 2487 dual wavelength detector at 220 nm.
1,1-Dibromo-2,2,3,3-tetramethylcyclopropane (2). A mixture of butene 1 (147 g, 1.75 mol,
1.10 equiv), heptanes (1.2 L), and potassium tertꢀbutoxide (196.0 g, 1.75 mol, 1.10 equiv) at –9
°C was treated with bromoform (401 g, 1.59 mol, 1.00 equiv) over 2 h at –9 to 2 °C range. The
addition funnel was rinsed with heptanes (10 mL), and the mixture was stirred at room
temperature for 2 h. After this time, 50% saturated sodium bicarbonate solution (500 mL) was
added. The mechanical stirrer was stopped and phase separation occurred. The aqueous layer
was separated and extracted with heptanes (2 × 250 mL). The organic layers were combined and
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 16
1
2
3
4
concentrated under reduced pressure to afford dibromide 2 (440 g, 98% yield) as a yellow solid.
5
6
1H NMR (500 MHz, CDCl3): 1.26 (s).
7
8
9
3-Bromo-2,4-dimethylpenta-1,3-diene (3). Continuous flow reactor (CFR) setup is shown on
Figure 1. A GC oven was equipped with a 5/16” Hastelloy tube (total volume 125 mL). A
mixture of dibromide 2 (440 g, 1.72 mol, 1.00 equiv) and N,Nꢀdimethylaniline (0.9 L) was
pumped into CFR using an HPLC pump. [The flow rate was set to 10 mL/min to achieve 12.5
min residence time in the reactor at 150 °C.] Upon exiting the CFR, the mixture was cooled to
20 °C, diluted with MTBE (2 L), and treated with HCl (4 N, 2 × 2 L). The organic layer was
separated and concentrated under reduced pressure to afford 3 (200 g, 66% yield) as a yellow oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
The material was stored over sodium hydroxide pellets. H NMR (500 MHz, CDCl3): 5.04 (m,
1H), 4.91 (m, 1H), 1.89 (m, 6H), 1.81 (s, 3H).
3-Vinylcyclohex-2-enone (6). A mixture of 4 (75 g, 0.53 mol, 1.00 equiv) and MTBE (0.5 L)
at 0 °C was treated with vinylmagnesium bromide (1 M, 0.59 L, 0.59 mol, 1.10 equiv) over 40
min at 0 °C to 10 °C range. The addition funnel was rinsed with MTBE (10 mL) and the mixture
was stirred at room temperature for 1 h. After this time, the mixture was cooled to 0 °C and
saturated ammonium chloride solution (0.2 L) was added. The mechanical stirrer was stopped
and phase separation occurred. The aqueous layer was separated, extracted with MTBE (2 × 0.1
L). The organic layers were combined, concentrated under reduced pressure, and passed through
a silica plug (500 g, eluent: dichloromethane). The fractions containing product were
1
concentrated under reduced pressure to afford 6 (65.3 g, quantitative yield) as a yellow oil. H
NMR (500 MHz, CDCl3): 6.50 (dd, J = 17.5, 10.5 Hz, 1H), 5.96 (s, 1H), 5.69 (d, J = 17.5 Hz),
5.47 (d, J = 10.5 Hz), 5.30 (s, 1H), 2.47 (m, 1H), 2.43 (m, 2H), 2.06 (m, 2H).
ACS Paragon Plus Environment

Page 11 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Preparation of CuBr•DMS complex. A suspension of Cu(0) metal powder (40 g, 0.63 mol,
1.00 equiv) and DMSO (0.6 L) at 100 °C was treated with benzyl bromide (215 g, 1.26 mol, 2.00
equiv) over 1 h at 90 to 100 °C range. The addition funnel was rinsed with DMSO (10 mL) and
the mixture was stirred at 120 °C for 5 h. After this time, the mixture was cooled to 0 °C and
water (1.2 L) was added. The suspension was stirred for 30 min and precipitate was allowed to
settle. The aqueous layer was decanted and acetone (0.6 L) was added. The suspension was
stirred for 30 min at room temperature. The precipitate was removed by filtration and dried in a
vacuum oven at room temperature to afford CuBr•DMS complex (67.3 g, 52% yield) as a white
solid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl)cyclohex-2-enone (7). A mixture of bromide 3
(127 g, 0.72 mol, 1.55 equiv) and THF (2.0 L) at –70 °C was treated with secꢀbutyllithium (1.4
M in cyclohexane, 500 mL, 0.70 mol, 1.50 equiv) over 40 min at –63 °C to –70 °C range. The
reaction was stirred for 0.5 h and was treated with CuBr•DMS complex (105 g, 0.51 mol, 1.1
equiv) over 20 min at –61 °C to –70 °C range. The reaction was stirred for 0.5 h and treated with
trimethylsilyl chloride (101 g, 0.93 mol, 2.00 equiv) over 15 min at –65 °C to –70 °C range. The
reaction was stirred for 0.5 h and was treated with a mixture of 6 (57.0 g, 0.47 mol, 1.00 equiv)
in THF (40 mL) over 15 min at –65 °C to –70 °C range. The reaction was stirred for 2 h and was
deemed complete by TLC (heptanes/ethyl acetate 3:1 (v/v)). The reaction was quenched by slow
addition of acetic acid (60 mL) followed by water (12 mL). The contents of the flask were
transferred to a 5ꢀL beaker, containing saturated sodium carbonate (2 L), and stirred for 0.5 h.
After this time, the mixture was filtered and the mother liquor was allowed to phase separate.
The aqueous layer was separated, extracted with MTBE (2 × 0.1 L). The organic layers were
combined, concentrated under reduced pressure, and passed through a silica column (570 g, 0 to
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 16
1
2
3
4
20% ethyl acetate in hexanes). The fractions containing product were concentrated under
5
6
reduced pressure to afford 7 (85.2 g, 85% yield) a yellow oil. [Care should be taken during
7
8
9
1
solvent evaporation, since 7 is volatile.] H NMR (500 MHz, CDCl3): 5.88 (t, J = 1 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.96 (dd, J = 2.5, 1 Hz, 1H), 4.57 (m, 1H), 2.35 (m, 2H), 2.30ꢀ2.23 (m, 6H), 1.98 (m, 2H), 1.76
(t, J = 1 Hz, 3H), 1.67 (s, 6H).
(S)-Trimethyl((3-methyl-3-(4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl)cyclohex-1-en-1-
yl)oxy)silane ((ꢀ)ꢀ9). A mixture of copper(I)ꢀthiopheneꢀ2ꢀcarboxylate (1.31 g, 6.9 mmol, 0.05
equiv), ligand 8 (6.81 g, 13.7 mmol, 0.1 equiv), 7 (30.0 g, 137 mmol, 1.00 equiv), and diethyl
ether (0.6 L) at –40 °C was treated with trimethylaluminum (2 M in hexanes, 96 mL, 0.19 mol,
1.40 equiv) over 40 min at –35 °C to –40 °C range and stirred for 14 h. After this time, THF (0.6
L) was added over 20 min at –35 °C to –40 °C range. The reaction was stirred for 0.5 h and was
treated with trimethylsilyl chloride (25.7 g, 0.24 mol, 1.72 equiv) over 15 min at –35 °C to –40
°C range. The reaction was stirred for 0.5 h and was treated with triethylamine (57.2 g, 0.57
mol, 4.12 equiv) over 15 min at –35 °C to –40 °C range. The reaction was stirred for 2 h
allowing the temperature to rise to room temperature and was deemed complete by TLC
(heptanes/ethyl acetate 3:1 (v/v)). The reaction was concentrated to 1/3 volume, poured into a
suspension of florisil (150 g) and heptanes (1.5 L), stirred for 0.5 h and filtered. The filtrate was
concentrated under reduced pressure and passed through a florisil plug (450 g, eluent: heptanes).
The fractions containing product were concentrated under reduced pressure to afford (-)-7 (85.2
g, quantitative yield) as a yellow oil. The product was used without additional purification.
Determination of enantiomeric purity of (-)-9. A mixture of (-)-9 (100 mg) and THF (4 mL)
was treated with 3 N HCl (2 mL) over 15 min at room temperature. The reaction was deemed
complete by TLC (heptanes/ethyl acetate 3:1 (v/v)) and ketone 10 was formed. The reaction
ACS Paragon Plus Environment

Page 13 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
mixture was portioned between ethyl acetate (20 mL) and water (2 mL). The organic layer was
separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue
was analyzed by chiral HPLC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2S,3S)-2-Acryloyl-3-methyl-3-(4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl)cyclohexanone (12).
Preparation of acrolein solution in ethanol/water. A mixture of acrolein diethyl acetal (168 g,
1.29 mol), water (48 mL), and camphorsulfonic acid (10 g) was charged to a distillation flask,
stirred for 30 min to form a homogenous solution, and was distilled under atmospheric pressure
at 65 to 70 °C. The receiving flask was charged with 60 mg of hydroquinone. The NMR assay
showed that the mixture contained 77.8 g of acrolein. The acrolein mixture at 0 °C was treated
with a solution of (-)-9 (25 g, 82 mmol, 1 equiv) in toluene (65 mL) followed by gadolinium(III)
triflate (9.86 g, 16.3 mmol, 0.2 equiv). The reaction was stirred for five days at 0 °C. After this
time, the reaction was concentrated down to 60 mL and diluted with acetone (600 mL). Jones’
reagent (100 mL, 2.1 M; made from 26.7 g CrO3, 23 mL conc. H2SO4 and 100 mL H2O) at 0 °C
was treated with the above mentioned acetone solution at 0 °C to 15 °C range. The excess of
Jones’ reagent was quenched with isopropanol (~10 mL). The flask contents were diluted with
water (100 mL) to obtain a homogenous solution and acetone was removed under reduced
pressure. (CAUTION: Acrolein is present). The product was extracted with ethyl acetate (3 ×
300 mL). The organic layers were combined, concentrated under reduced pressure, and passed
through a silica column (500 g, 0 to 20% ethyl acetate in heptanes). The fractions containing
product were concentrated under reduced pressure to afford 12 (19.0 g, 61% yield) as a yellow
oil. The material is an inseparable mixture of two diastereomers of 12 and ketone 10.
(4aS,6R,12aS)-9,12a,13,13-Tetramethyl-1,2,3,7,8,11,12,12a-octahydro-6,10-methanobenzo-
[10]annulene-4,5(4aH,6H)-dione ((+)-13). A mixture of boron trifluoride etherate (34.9 g, 0.25
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 16
1
2
3
4
5
6
7
8
9
mmol, 3.65 equiv) and dichloromethane (3 L) at 0 °C was treated with a solution of 12 (19.4 g,
67.3 mmol, 1.00 equiv) in dichloromethane (2 L) over 1.5 h using an FMI pump at 0 to 5 °C
range. The reaction was stirred for 4.5 h at 0 °C, quenched with saturated sodium carbonate
solution (1 L), and stirred for 0.5 h. The layers were separated and the aqueous layer was
extracted with dichloromethane (2 × 300 mL). The organic layers were combined, concentrated
under reduced pressure and passed through a silica column (500 g, 0 to 20% ethyl acetate in
heptanes). The product containing fractions were concentrated under reduced pressure. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
material was crystallized from heptanes to afford (+)-13 (4.3 g, 22% yield) as a white solid. H
NMR (500 MHz, CDCl3): 4.22 (s, 1H), 2.89 (m, 1H), 2.52 (m, 1H), 2.45 (d, J = 8.5 Hz, 1H),
2.34 (m, 1H), 2.22 (m, 2H), 2.04–1.90 (m, 8H), 1.75 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H),
13
1.35(m, 1H); C NMR (75 MHz, CDCl3): 209.9, 206.8, 137.1, 131.5, 64.0, 61.9, 44.0, 39.5,
39.4, 38.4, 37.5, 29.4, 28.8, 25.4, 24.9, 24.0, 22.2, 21.0, 17.8.
(4aS,6R,12aS)-9,12a,13,13-Tetramethyl-5-oxo-1,2,4a,5,6,7,8,11,12,12a-decahydro-6,10-
methanobenzo[10]annulen-4-yl trifluoromethanesulfonate (15). A mixture of (+)-13 (4.80 g,
16.6 mmol, 1.00 equiv), Nꢀphenylbis(trifluoromethanesulfonimide) (11.9 g, 33.3 mmol, 2.00
equiv), and THF (380 mL) at 0 °C was treated with 1 M solution of KHMDS in THF (25.0 mL,
25.0 mmol, 1.50 equiv) over 15 min at 0 to 5 °C range. The reaction was stirred for 1 h at 0 °C
and was quenched with saturated sodium carbonate solution (200 mL). The flask contents were
transferred into a separatory funnel containing heptanes (400 mL). The layers were separated
and the organic layer was washed with potassium hydroxide (3 N, 2 × 200 mL). The organic
layer was separated and concentrated under reduced pressure. The residual water was removed
by azeotropic coꢀdistillation with THF (2 × 200 mL). The crude material was used in the next
step.
ACS Paragon Plus Environment

Page 15 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(4aS,6R,12aS)-4,9,12a,13,13-Pentamethyl-1,4a,6,7,8,11,12,12a-octahydro-6,10-methano-
benzo[10]annulen-5(2H)-one ((+)-16). A mixture of the crude triflate 15, tetrakis(triphenylꢀ
phosphine)palladium(0) (1.92 g, 1.66 mmol, 0.1 equiv) at 0 °C was treated with 1.2 M solution
of dimethylzinc in toluene (99.9 mL, 83.2 mmol, 5.00 equiv) over 15 min at 0 to 5 °C range.
The reaction was stirred for 1 h at 0 °C and was warm up to room temperature. The reaction was
stirred for 3 days. After this time, the reaction was quenched by carefully pouring the contents
of the reaction flask to a separatory funnel containing 1 M HCl (100 mL). (CAUTION: GAS
EVOLUTION!). The product was extracted with heptanes (2 × 200 mL). The organic layers
were combined, concentrated under reduced pressure, and passed through a silica column (120 g,
0 to 20% ethyl acetate in heptanes). The fractions containing product were concentrated under
reduced pressure. The material was crystallized from methanol to afford (+)-16 (3.94 g, 82%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yield) as a white solid. H NMR (500 MHz, CDCl3): 5.55 (d, J = 6.5 Hz, 1H), 3.31 (d, J = 0.5
Hz, 1H), 2.58 (m, 1H), 2.51 (m, 2H), 2.26 (m, 1H), 2.10 (m, 2H), 2.00 (m, 2H), 1.81 (m, 5H),
13
1.48 (m, 3H), 1.32 (m, 2H), 1.21 (m, 4H), 1.09 (s, 3H), 0.92 (s, 3H); C NMR (125 MHz,
CDCl3): 218.0, 136.8, 133.35, 130.6, 124.8, 64.9, 55.9, 43.5, 40.7, 38.5, 37.3, 28.9, 28.3, 27.6,
23.7, 23.6, 22.1, 21.8, 20.6, 18.7; HRMS (ESI) m/z cald for C20H31O+ [M+H]+ 286.2375, found
287.2375; [α]D25 = + 70 ° (c 0.27, CHCl3).
ASSOCIATED CONTENT
Supporting Information.
The NMR spectra of corresponding compounds 2–7, 9–16, and Xꢀray data for 13. This material
is available free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 16
1
2
3
4
AUTHOR INFORMATION
5
6
Corresponding Author
7
8
9
*email: Sergiy.Krasutsky@amriglobal.com
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are thankful to Mr. N. C. Wilde, Dr. Yoshiro Ishihara and Prof. P. S. Baran for
insightful discussions.
REFERENCES
1 Itokawa, H; Lee, K.ꢀH. Taxus: The Genus Taxus; Taylor & Francis: London and New York, 2003.
2 Mendoza, A.; Ishihara, Y.; Baran, P. S. Nature Chem. 2012, 4, 21.
3
Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Linnane, P.; Tavares, F.; Lynch, V. Tetrahedron 1999, 55,
6435.
4 Laurent, A.; VillavaꢀSerin, N. P.; Forgione, P.; Wilson, P. D.; Smil. D. V.; Fallis, A. G. Fallis et al., Can J. Chem.
2004, 82, 215.
5 Barnhart, R.; Ironside, M. D.; Vogt, P. F. Org. Process Res. Dev. 2011, 15, 1407.
6 Petersson, M. J.; Marchal, C.; Loughlin, W. A.; Jenkins, I. D.; Healy, P. C.; Almesaker, A. Tetrahedron 2007, 63,
1395.
7 Park, IꢀH; So, M. S.; Park, K. H. Bull. Korean Chem. Soc. 2007, 28, 1515.
8 Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
9 Lipshutz, B. H.; Dimock, S. H.; James, B. J. Am. Chem. Soc. 1993, 115, 9283.
10 Vuagnouxꢀd’Augustin, M.; Alexakis, A. Chem. Eur. J. 2007, 13, 9647.
11 Kobayashi, S.; Hachiya, I.; Yamanoi, Y. Bull. Chem. Soc. Jpn. 1994, 67, 2342.
12 Funel, J. A.; Abele, S. Angew. Chem. Int. Ed. 2013, 52, 3822.
13
Color scheme: C grey, O red, H white. Hydrogen atoms were omitted for clarity except two most
stereochemically important ones.
14
Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.; Pangborn, J. J. Org. Process Res. Dev. 2003, 7,
696.
ACS Paragon Plus Environment