Alternative synthetic approaches to rac-progesterone by way of the classic Johnson cationic polycyclization strategy

Article abstract of DOI:10.1016/j.tet.2016.03.041

Three alternative synthetic entries into Johnson's classic synthesis of rac-progesterone are presented in this manuscript. ent-Progesterone, the non-natural enantiomer of progesterone, has recently been identified as a potential alternative to progesterone for investigations into possible prevention and treatment of traumatic brain injury (TBI). Difficulties in accessing ent-progesterone in large quantities prevent it from being studied more thoroughly. Strategies for producing synthetic rac-progesterone are described and discussed herein.

Full text of DOI:10.1016/j.tet.2016.03.041

Accepted Manuscript
Alternative synthetic approaches to rac-progesterone by way of the classic Johnson
cationic polycyclization strategy
Rimantas Slegeris, Gregory B. Dudley
PII:
S0040-4020(16)30173-9
10.1016/j.tet.2016.03.041
TET 27581
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 January 2016
Revised Date: 6 March 2016
Accepted Date: 11 March 2016
Please cite this article as: Slegeris R, Dudley GB, Alternative synthetic approaches to rac-progesterone
by way of the classic Johnson cationic polycyclization strategy, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.03.041.
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Alternative synthetic approaches to rac-
progesterone by way of the classic Johnson
cationic polycyclization strategy
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Rimantas Slegeris and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Alternative synthetic approaches to rac-progesterone by way of the classic Johnson
cationic polycyclization strategy
Rimantas Slegerisa and Gregory B. Dudleya,
a Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Three alternative synthetic entries into Johnson’s classic synthesis of rac-progesterone are
presented in this manuscript. ent-Progesterone, the non-natural enantiomer of progesterone, has
recently been identified as a potential alternative to progesterone for investigations into possible
prevention and treatment of traumatic brain injury (TBI). Difficulties in accessing
ent-progesterone in large quantities prevent it from being studied more thoroughly. Strategies for
producing synthetic rac-progesterone are described and discussed herein.
Available online
Keywords:
progesterone
2009 Elsevier Ltd. All rights reserved
.
total synthesis
traumatic brain injury (TBI)
process improvement
alkene synthesis
———
Corresponding author. Tel.: +1-850-644-2333; fax: +1-850-644-8281; e-mail: gdudley@chem.fsu.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
O
O
1. Introduction
Progesterone (1) is an abundant natural hormone that has a
H
H
primary function of regulating the reproductive cycle in humans
and other species. Progesterone has recently been reported also to
reduce the negative effects associated with traumatic brain injury
(TBI) in vitro.1,2,3,4 Interactions between progesterone and
transmembrane cell receptors in damaged mice brains can reduce
swelling and inflammation,5,6 although recent clinical studies
failed to produce the corresponding positive outcomes in
humans.7 This discrepancy between rodent and human
pharmacology will have to be resolved before progesterone can
move forward as a potential therapeutic for TBI. Any potential
utility of progesterone therapy, however, would also have to be
balanced against the expected sexual side effects associated with
administration of a reproductive hormone. These are two
significant barriers to realizing the full therapeutic potential of
progesterone for TBI.
H
H
H
H
O
O
progesterone (1a)
ent-progesterone (1b)
O
O
O
O
Figure 1. Skeletal stuctures and conformational drawings,
showing the relative distance between the terminal oxygen atoms
bridged by a hydrocarbon spacer, for natural progesterone (left)
and ent-progesterone (right).
However, difficulties in accessing ent-progesterone prevent it
from being studied more thoroughly as a potential drug
candidate. ent-Steroids are only available through total chemical
synthesis. Current access to ent-progesterone can be secured by
leveraging an asymmetric synthesis of ent-testosterone,10,11,12 or
by resolution of rac-progesterone13,14 by chiral preparative
HPLC.15 We decided to investigate alternative entries into the
classic synthesis of rac-progesterone and aim to reduce the
number of synthetic steps and increase the overall efficiency of
the synthesis.
An
intriguing
proposition
for
overcoming
both
pharmacological barriers is to explore the therapeutic potential of
ent-progesterone, which displays superior activity to that of
natural progesterone in vitro8,9 against TBI. One can rationalize
this unusual result by considering that both enantiomers of
progesterone present peripheral carbonyl functionality bridged by
a rigid hydrocarbon spacer (Figure 1). This topographical
similarity seems to be sufficient for the molecular recognition
events associated with TBI but not for reproductive cycle
modulation. Therefore, there is reason to be optimistic that
ent-progesterone can duplicate or enhance the TBI potential
without the same degree of concern for sexual side effects.
O
2
O
O
1. MeLi, Et2O
2. TFA, DCE,
ethylene carbonate
4
1
1. O3, AcOH, Zn
2. KOH, H2O
C17
K2CO3
H
H
45 %, 2 steps,
85 : 15 d.r,
17α / 17β
H
H
H
H
MeOH, 71 %
3
O
O
O
O
rac-progesterone
Scheme 1. Final steps in the classic Johnson synthesis of rac-progesterone. Trienyne 2 is converted into tetracycle 4 via key cation-π
cyclization, which is followed by ozonolysis and aldol condensation to give rac-progesterone (1).
1. NaI,
2-butanone, 99 %
5
a) BuLi, THF
Br
7
O
O
6
O
O
O
b)
, 75 %
PPh3I
Br
2. PPh3, C6H6, 94 %
Br
2. 1. pTsOH,
HOCH2CH2OH
O
O
O
O
71 % (88 % BRSM)
8
1. CH3C(OEt)3, CH3CH2COOH
55 % overall
Mg, then
methacrolein
OH
9
O
10
Br
H
2. LiAlH4, Et2O
3. CrO3*2py, 77 %, 2 steps
7
O
11
1. PhLi, THF
2. MeOH, HCl
2
O
EtOH, NaOH
40 %, 3 steps
+
10
O
Scheme 2. Johnson’s synthesis of trienyne 2. top: Preparation of the olefination reagent. middle: Synthesis of aldehyde 10 by
Johnson ortho-ester Claisen rearrangement. bottom: E-Selective Wittig–Schlosser olefination, followed by deprotection and aldol
condensation to produce trienyne 2.

3
Johnson’s bio-inspired synthesis of rac-progesterone13,14 is
2. Results and Discussion
ACCEPTED MANUSCRIPT
widely recognized as a landmark achievement in total synthesis.16
Most significantly, it features a key cationic π-cyclization
process, which is still a most attractive strategy for preparing
synthetic progesterone (Scheme 1). Toward the end goal of
making ent-progesterone more available, we endeavored to
develop alternative processes for the synthesis of trienyne 2, the
substrate for Johnson’s key cation-π cyclization event.
The synthesis of trienyne 2 was initially envisioned to involve
parallel preparations of aldehyde 10 (cf. Scheme 2) and a pro-
nucleophile partner exemplified by 15 (Scheme 3, bottom),
which would be capable of delivering the cyclopentenone moiety
and creating the central trans-alkene. We envisioned preparation
of aldehyde 10 by the oxidative cleavage of epoxide 17, which
could be prepared from readily available geranyl halides (18a,b).
We later investigated the conversion of homoallylic bromide 12
(Scheme 3, top) to the trienyne 2, which proved advantageous.
Johnson originally prepared trienyne 2 in 13 steps total, with a
longest linear sequence of 9 steps,17 for which we calculated an
overall yield of up to 17%18 (Scheme 2). A pivotal step in the
sequence is an E-selective Wittig–Schlosser olefination of
aldehyde 10. The stereoselective formation of this trans-alkene is
one of the central challenges in the synthesis of trienyne 2. We
initially conceived of exploiting sulfone-mediated olefination
technology (i.e., Julia–Kocienski and related reactions) to craft
this alkene. As discussed herein, we ultimately expanded our
investigations to develop three alternative approaches to trienyne
2. We also converted trienyne 2 to rac-progesterone according to
the four-step sequence pioneered by Johnson.
2.1. Synthesis of aldehyde 10
We started by devising an alternative route to known aldehyde
10.13,14,15,19 Epoxidation of geranyl bromide, followed by one-pot
propargylation / deprotection20 using lithiated TMS-propyne,
gave terminal alkyne 19 in 52% yield over 2 steps (Scheme 4,
top). Methylation followed by periodate cleavage of the epoxide
then gave the desired aldehyde in 4 steps. However, this route is
compromised by the relatively high cost of trimethylsilylpropyne
and relative instability of the epoxidation product of geranyl
bromide.
cyclopentenone
O
2
O
O
13
moiety
14
Br
+
or
Br
O
O
12
central trans
alkene
10
2
O
OTBS
15
16
10
SO2PT
+
O
OTBS
17
O
OH
18a, X = Br
18b, X = Cl
OH
X
Scheme 3. Retrosyntheses of trienyne 2. top: strategic disconnections involving homoallylic bromide 12 (prepared from aldehyde 10)
and either a pre-formed cyclopentenone (14) or a cyclopentenone precursor (13). bottom: first-generation approach featuring Julia–
Kocienski olefination of aldehyde 10, to be prepared from geranyl halides 18a or 18b.
1. m-CPBA, CHCl3
18a
19
Br
O
2. a) BuLi, THF,
b) TBAF, THF
52 % (two steps)
TMS
BuLi, MeI, THF
17
O
quantitative recovery
(not purified)
20
18b
O
m-CPBA, CHCl3
Cl
Cl
1. a) propargyl-Br, BuLi, TMEDA, Et2O
b) 20, TBAI
c) Me2SO4, DMPU, THF / Et2O
67 % overall from 18b
10
H
17
HIO4, NaIO4 THF : H2O
O
O
quantitative recovery
(used without purification)
Scheme 4. Alternative syntheses of aldehyde 10, featuring epoxidation, homologation, and oxidative cleavage. top: Three-step
homologation using lithiated TMS-propyne as a propyne dianion equivalent. bottom: One-pot homologation by double-lithiation of
propargyl bromide, as outlined in Table 1.

4
Tetrahedron
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Table 1. Optimization of the one-pot sequential double alkylation of dilithiopropyne (C3H2Li2) depicted in Scheme 4
Entry
C3H2Li2
Additive(s)
Methylating agent
Time and temperaturea
Ratio 20:19:17b
only 20
Yield %c
N.D.
1
1.2 equiv
—
2.0 equiv MeI
Stage 1: –78 °C, 20 min
Stage 2: –78 °C, 20 min
2
3
1.2 equiv
1.2 equiv
—
—
2.0 equiv MeI
3.0 equiv MeI
Stage 1: 0 °C, 20 min
Stage 2: 0 °C, 60 min
40:38:22
60:32:8
N.D.
N.D.
Stage 1: rt, 30 min
Stage 2: 0 °C, 60 min
4
5
6
1.5 equiv
2.2 equiv
2.2 equiv
10mol% TBAI
10mol% TBAI
—
Stage 1: 0 °C, 30 min
Stage 1: 0 °C, 30 min
32:68:—
only 19
7:33:60
N.D.
—
81 (19)
N.D.
10mol% TBAI
5.0 equiv DMPU
5.0 equiv MeI
Stage 1: 0 °C, 30 min
Stage 2: rt, 60 min
7
2.2 equiv
2.2 equiv
2.2 equiv
2.4 equiv
10mol% TBAI
5.0 equiv DMPU
5.0 equiv Me2SO4
5.0 equiv Me2SO4
5.0 equiv Me2SO4
6.0 equiv Me2SO4
Stage 1: 0 °C, 30 min
Stage 2: rt, 60 min
only 17
only 17
74 (17)
76 (17)
≤73 (17)
67 (17)
8d
10mol% TBAI
5.0 equiv DMPU
Stage 1: 0 °C, 30 min
Stage 2: rt, 60 min
9d,e,f
10d,e,g
10mol% TBAI
5.0 equiv DMPU
Stage 1: 0 °C, 30 min
Stage 2: rt, 60 min
complex and
variable mixture
10mol% TBAI
6.0 equiv DMPU
Stage 1: 0 °C, 30 min
Stage 2: rt, 60 min
only 17
aStage 1: reaction of C3H2Li2 with 12; Stage 2: addition of methylating agent to the reaction mixture
bEstimated by 1H NMR analysis of the crude product mixture.
cIsolated yield of the major product.
dReaction mixture was quenched with 5% NH3(aq) solution.
e8.33-mmol scale
fStirring was compromised by formation of an insoluble sludge.
gTHF was added as a co-solvent prior to Stage 2.
reaction was diluted with dry THF after the first stage, and the
reaction time was extended to ensure completion. The epoxide of
17 was then cleaved with periodic acid / sodium periodate to give
the desired aldehyde (10). In this manner, we were able to
complete a concise and efficient synthesis of Johnson’s aldehyde
(10) in 3 steps and 67% overall yield from geranyl chloride
(Scheme 4).
We therefore refined our approach and switched to geranyl
chloride as a starting material. Both the epoxidation (with
mCPBA) and the epoxide cleavage (with HIO4) produced the
expected products in the theoretically expected yields. The
homologation of the allylic chloride to install the methylated
alkyne (20 → 17) received the bulk of our attention.
We then turned our attention to identifying and preparing
appropriate coupling partners for homologating aldehyde 10 into
the key cyclization substrate, 2.
TMS-propyne (cf. Scheme 4, top) was in effect being
employed here as a propyne dianion equivalent. Formally
identifying lithiated TMS-propyne as a propyne dianion synthon
inspired us to consider other possible options. Propargyl bromide
(cf. Scheme 4, bottom) has been used to generate a propyne
dianion suitable for one-pot sequential addition to a pair of
aldehydes.21 If this sequential addition strategy could be extended
to sp3-hybridized electrophiles (i.e., sequential substitution), then
we could streamline this homologation process. Propargyl
bromide is also cheaper than TMS-propyne.
2.2. Julia–Kocienski approach to trienynone 2
We investigated the possibility of preparing 2 via Julia-
Kocienski olefination (Scheme 5) as an alternative to the
Schlosser–Wittig protocol previously employed by Johnson for
installing the central trans-alkene. First, sulfone 22 was prepared
in 4 steps from known diol 16.22 The diol was protected using
TBSCl / imidazole in DMF. Hydroboration followed by
Mitsunobu reaction and oxidation of the resulting sulfide using
hydrogen peroxide / ammonium molybdate afforded 22 in 34%
overall yield. E-selective Julia-Kocienski olefination23 with
aldehyde 10 then provided the desired olefination product in 67%
yield and 7 : 1 E : Z ratio (as estimated by 1H NMR). From here,
intermediate 23 was converted to the desired 2 in 3 steps — TBS
deprotection with TBAF, Swern oxidation of the resulting diol,
and aldol condensation (61% yield over 3 steps). Attempts to
make this route more convergent — namely, to olefinate the
aldehyde using sulfone 24 — were unsuccessful, however, and
the route from 16 was deemed too long (too many steps) for our
prescribed objectives. Therefore, we abandoned the Julia-
Kocienski strategy in favor of efforts to prepare the central trans-
alkene by a cyclopropyl-homoallyl rearrangement.24,25,26
We optimized for one-pot sequential alkylation of the C3H2Li2
synthon as outlined in Table 1. During optimization, it was found
that 2.2 equivalents of the propyne dianion (generated from
propargyl bromide using n-butyllithium) and TBAI as an additive
were necessary for complete conversion in the first stage of
alkylation (entry 5). When methyl iodide was used as an
alkylating agent, the second stage of the reaction was sluggish,
giving mixtures of terminal and methylated alkyne. However,
when 5 equivalents of dimethyl sulfate with DMPU as an
additive was used, the reaction proceeded efficiently to
completion on the exploratory scale (entry 8). Problems of
solubility arose on larger scales (e.g., 8.33 mmol), with the
formation of solid sludge on the bottom of the flask that
complicated stirring and resulted in significantly decreased yields
of the desired product (17). To avoid the insoluble sludge, the

5
OTBS
16
21
OH
1. TBSCl, im, DCM
ACCEPTED MANUSCRIPT
OH
2. BH3*THF; H2O2 / NaOH
OTBS
OH
1. PTSH, DEAD, PPh3, THF
2. (NH4)6Mo7O24, H2O2 EtOH
34 %, 4 steps
23
22
OTBS
OTBS
KHMDS, 7, 18-crown-6
THF, 67 %, 7 : 1 E : Z
O
S
PT
OTBS
OTBS
O
1. TBAF, THF
2. DMSO, COCl2, Et3N, DCM
3. NaOH, H2O, 61 %, 3 steps
24
O
O
O
2
S
N
N
N
O
N
Ph
Scheme 5. Synthesis of 2 via Julia-Kocienski route.
One-Pot
MgBr, Et2O
12
10 (from 17)
O
a)
Br
H
b) MgBr2, Et2O, 1 % H2O
45-62 % from 17
central trans alkene
> 20 : 1 E : Z
Scheme 6. Synthesis of homoallylic bromide 12 by one-pot Grignard addition and SN1-type substitution with stereoselective
cyclopropyl→homoallyl rearrangement.
2.3. Approaches to trienynone 2 via homoallyl bromide 12
2.4. Completion of the synthesis
Cyclopropyl carbinols can be converted into homoallyl
bromides stereoselectively and in good yield.25,26 Cyclopropyl
carbinols, in turn, can be prepared by addition of cyclopropyl
Grignard reagents to aldehydes. Consequently, the conversion of
aldehyde to homoallyl halide can be achieved in a two-step
process comprising Grignard addition and subsequent
rearrangement. We aimed to develop a one-pot protocol.
Having developed a new route to 2, we then finished the
synthesis of rac-progesterone using chemistry originally
published by Johnson.13 The overall efficiency of this 4-step
transformation was similar to what was reported by Johnson; our
yield for the MeLi addition and cation-π cascade sequence was
slightly lower than originally reported, whereas our yield for the
ozonoloysis and aldol condensation sequence was slightly higher
than originally reported.
Addition of cyclopropylmagnesium bromide solution in
diethyl ether to aldehyde 10, followed by the dilution with
diethyl ether and addition of magnesium bromide and small
amounts of water (0.5–1%), gave satisfactory results (Scheme 6).
The small amount of water was optimal: byproducts were
observed in TLC analysis of reactions conducted under
anhydrous conditions, and the rearrangement became sluggish
with increasing concentrations of water. Thus, Grignard addition
was followed by dilution with ether and addition of magnesium
bromide and water. Heating this mixture overnight resulted in the
desired one-pot transformation in 45-62% yield and high E : Z
ratio (no Z isomer observed by 1H NMR).
3. Conclusion
In conclusion, we report three alternative ways to access
cation-π cyclization substrate 2 en route to rac-progesterone.
These new methods may be viable for accessing larger amounts
of rac-progesterone . During the course of our endeavors, we
developed a straightforward process for converting a linear
aliphatic aldehyde into a homoallylic bromide, which proved to
be a good choice for preparing the isolated and unbranched
central trans-alkene of 2 with high stereocontrol. The optimal
route produces 2 in up to 21% overall yield for the seven-step
longest linear sequence (LLS).
A convergent means of converting homoallylic bromide 12 to
the desired ketone (2) would be by coupling 12 with bromo-
cyclopentenone 14 (Scheme 7). However, we were unable to
develop a satisfactory and reproducible protocol. Our best efforts
involved borylation of 12 via the corresponding Grignard
reagent, followed by Suzuki coupling with 14. This sequence
provided 2 in up to 46% yield, but it was capricious.
4. Experimental section
All reagents were purchased from commercial suppliers and used
without further purification. NMR spectra were recorded on a
Bruker Ultrashield spectrometer operating at 400 MHz for H
1
NMR and at 100 MHz for 13C NMR. The spectra were measured
in CDCl3 and are given as δ values (in ppm) relative to TMS.
Column chromatography was carried out using compressed air,
Silica Gel 60 (230– 400 mesh, Merck), and mixtures of ethyl
acetate / hexanes. Mass spectra were recorded using electrospray
ionization (ESI+) or atmospheric pressure chemical ionization
(APCI). All reactions were run under inert atmosphere unless
otherwise indicated in the text. All solvents were purified using a
Waters SG SiO2 column based solvent purification system.
A more robust protocol for completing the route to 2 makes
use of the classic tactic of alkylation and decarboxylation of β-
keto esters, followed by aldol condensation.27,28,29,30 β-Keto ester
25 was prepared according to the procedure reported by Crabbe
et. al.31 and alkylated with 12. Saponification followed by one-
pot decarboxylation, deprotection, and aldol condensation then
gave the desired intermediate 2.

6
Tetrahedron
2
1. a) Mg, THF
ACCEPTED MANUSCRIPT
12
b) B(OMe)3
c) KHF2
O
Br
2. Pd(OAc)2, RuPhos, 14
K3PO4, tol : H2O 3 : 1
9-46 %
O
1. KOH, THF, H2O
2. a) HCl, MeOH
b) KOH, MeOH, THF
71 %
Br
14
O
O
O
25
26
Cs2CO3, 12
O
O
O
acetone, 8 h.
67-73 %
O
O
O
O
Scheme 7. Synthesis of trienynone 2 via Suzuki reaction and the alkylation route. The Suzuki coupling of 14 with boronates derived
from 12 proved capricious and unreliable on small-scale, so we alternatively crafted the cyclopentenone moiety by aldol condensation
after alkylation of β-keto ester 25 with bromide 12.
2
O
1. MeLi, Et2O
2. a) TFA, DCE, ethylene
carbonate
4
O
H
b) K2CO3, MeOH, H2O
38 - 55 % (71 %)
H
H
O3, Me2S,
DCM
O
1
O
KOH, H2O , heat, 1h
C17
27
H
57 % (trace 17β)
O
H
(45 % 5.6 : 1, 17α / 17β)
H
H
H
H
O
O
rac-PROGESTERONE
Scheme 8. Completion of the synthesis of rac-progesterone (originally reported yields by Johnson in red in parentheses).
Yields refer to isolated yields of material judged to be ≥95% pure
6.0 equic.) of dimethyl sulfate. The 0 °C bath was then removed
and the reaction stirred for 1 h at r.t. Reaction was then cooled to
0 C and 25 mL of 5% NH3 solution was added to quench the
by 1H NMR spectroscopy.
o
4.1. (E)-4-methyldec-4-en-8-ynal (10)
unreacted dimethyl sulfate. The reaction mixture was stirred for 1
h at r.t., then diluted with water, and extracted 3 times with ethyl
acetate. Organic extracts were washed twice ammonium chloride,
twice with water, and once with brine, and then dried over
Na2SO4, concentrated under rotary evaporator and subjected to
column chromatography using 3 % ethyl acetate / hexanes to
Geranyl chloride (5.8 g, 33.6 mmol, 1.0 equiv.) was dissolved
o
in 336 mL of chloroform. Solution was then cooled to 0 C and
then mCPBA (77 % purity) (7.9 g, 35.3 mmol, 1.05 equiv.) was
added in small portions over 30 min. After addition, solution was
o
stirred for additional 30 minutes at 0 C. Solution was then
1
afford 1.14 g (67 % yield) of 17 as a colorless liquid: H NMR
extracted 5 times with 1M NaHCO3. Organic layer was washed
with water, brine, dried over Na2SO4 and concentrated to give
(400 MHz, CDCl3) δ 5.21 (t, 1H, J=5.6), 2.71 (t, 1H. J=6.3),
2.25-2.05 (m, 6H), 1.77 (t, 3H), 1.72-1.56 (m, 5H), 1.31 (s, 3H),
1.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.4, 123.6, 79.1,
75.4, 64.1, 58.4, 36.3, 27.7, 27.4, 24.9, 19.1, 18.7, 16.1, 3.5.
HRMS (APCI) Calcd. for C14H23O [M+H]: 207.1743, found:
207.1746. A cold (0 °C) solution of 17 (540 mg, 2.62 mmol, 1.0
equiv., prepared as described above) in 10.5 mL of 1 : 1 THF :
H2O was then treated with sodium periodate (1.35 g, 6.28 mmol,
2.4 equiv.), followed by the addition of periodic acid (59.7 mg,
0.262 mmol, 0.1 equiv.). The resulting mixture was stirred for 3 h
at 0oC and 1 h at r.t. and then partitioned between cold (0 °C) 1
M NaHCO3 and EtOAc. The aqueous layer was extracted with 3
portions of ethyl acetate. Organic layers were then combined and
washed twice with water, brine and dried over sodium sulfate.
Reaction mixture was then concentrated using rotary evaporator
to give a quantitative recovery of crude aldehyde 10 (67% overall
from geranyl chloride) as a colorless oil, which was used without
purification in the next step. Characterization data for aldehyde
10 matched literature data:14 1H NMR (400 MHz, CDCl3) δ 9.80-
9.74 (t, 1H, J=1.2), 5.21 (t, 1H, J=5.7), 2.52 (tq, 2H, J=8, 1.2),
2.33 (t, 2H, J=8), 2.2-2.07 (m, 4H), 1.76 (t, 3H, J=2.4), 1.62 (s,
1
6.34 g (100 % yield, ca. 90-95 % pure by H NMR) of epoxide
20 as a colorless liquid, which was used in the next step without
further purification and for which the characterization data
matched literature values:32 1H NMR (400 MHz, CDCl3) δ 5.50
(td, 1H, J=7.9, 1.1), 4.10 (d, 2H. J=8.0), 2.69 (t, 1H, J=6.2), 2.29-
2.11 (m, 2H), 1.74 (s, 3H), 1.66 (m, 2H), 1.30 (s, 3H), 1.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 141.7, 120.8, 63.8, 58.4,
40.8, 36.1, 26.9, 24.8, 18.7, 16.0. Propargyl bromide (2.97 g, 80
wt % in toluene, 20 mmol, 2.15 mL, 2.4 equiv.) was added
dropwise to a cold (–78 °C) solution of BuLi (25 mL, 1.6 M in
hexanes, 40 mmol, 4.8 equiv.) and TMEDA (1.162 g, 10 mmol,
1.5 mL, 1.2 equiv.) in 25 mL of ether. The resulting solution was
stirred for 20 min at –78 °C, and then a mixture of epoxide 20
(1.572 g, 8.33 mmol, 1.0 equiv.) and TBAI (303 mg, 0.833
mmol, 0.1 equiv.) in 5 mL of ether was then added by cannula,
followed by rinsing with two additional 5-mL portions of ether.
The reaction mixture was then switched to a 0 °C bath and stirred
for 1h, and then the cloudy mixture was diluted with 50 mL of
THF and 6.41 g (50 mmol, 6.03 mL, 6.0 equiv) of DMPU,
followed by the dropwise addition of 6.30 g (50 mmol, 4.78 mL,

7
3H). 13C NMR (100 MHz, CDCl3) δ 202.6, 134.3, 124.1, 78.9,
75.6, 42.1, 31.8, 27.6, 19.0, 16.2, 3.4. Aldehyde 10 has strong
irritating odor, which is felt even when the sample is in the fume
hood.
mixture was then dissolved in 3.0 mL of methanol and treated
ACCEPTED MANUSCRIPT
with 0.5 mL of 2 M HCl. This mixture was stirred for 3 h then
diluted with 2.5 mL of 2M KOH and 3 mL of THF. The resulting
mixture was heated at reflux overnight, then allowed to cool to rt
and partitioned between satd. ammonium chloride and ethyl
acetate. The aqueous layer was extracted 3 times with ethyl
acetate, and the organics were washed with water, brine, dried
over sodium sulfate, and concentrated using a rotary evaporator.
The crude material was purified using column chromatography
(10 % ethyl acetate / hexanes) to give 155 mg (71%) of trienyne
2 as a colorless oil. Characterization data for trienyne 2 matched
literature data:14 1H NMR (400 MHz, CDCl3) δ 5.47-5.30 (m,
2H), 5.16 (t, 1H, J=6.1), 2.48 (d, 2H, J=4.2), 2.36 (t, 2H, J=4.2),
2.32-1.92 (m, 15 H), 1.78 (t, J=2.3), 1.60 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 209.6, 170.6, 140.0, 136.0, 130.7, 129.4, 123.1,
79.2, 75.4, 29.6, 34.3, 31.5, 31.2, 31.1, 27.7, 23.2, 19.2, 17.3,
16.1, 3.5. HRMS (ESI+) Calcd. for C20H28ONa: 307.2038, found:
307.2030.
4.2. (6E,10E)-13-bromo-6-methyltrideca-6,10-dien-2-yne (12)
Cyclopropylmagnesium bromide (7.82 mL, 0.5 M solution in
Et2O, 3.91 mmol, 1.5 equiv.) was added dropwise to a cold (0 °C)
solution of aldehyde 10 (prepared as described above from 540
mg of epoxide 17) in 10 mL of ether, and the resulting mixture
o
was stirred for 30 min at 0 C, then 30 min at r.t., and then
recooled to 0 °C. Water (0.29 mL) was then added slowly. After
an additional 5 min of stirring, the reaction mixture was diluted
with 12 mL of Et2O, and MgBr2•Et2O (3.35 g, 13.1 mmol, 5.0
equiv.) was added. The reaction mixture was then heated to
reflux and stirred overnight. The reaction mixture was then
cooled and partitioned between ethyl acetate and 1.0 M solution
of NaHCO3. The aqueous layer was extracted 2 times with
EtOAc. Organic layer was then washed with NaHCO3 (1.0 M),
water, and brine, and dried over sodium sulfate and concentrated
using rotary evaporator. The crude material was purified using
column chromatography (gradient elution using hexanes to 1 %
ethyl acetate / hexanes) to give 435 mg of homoallyl bromide 12
(62% yield from 17, 42% over four steps from geranyl chloride)
Acknowledgments
This work was supported by an FSU GAP Award. The authors
thank Prof Jacob Vanlandingham (FSU College of Medicine) for
stimulating discussions and support of this research.
1
as a colorless oil: H NMR (400 MHz, CDCl3) δ 5.53 (dt, 1H,
References and notes
J=14.8, 8), 5.40 (dt, 1H. J=14.8, 8), 5.18 (t, 1H, J=5.2), 3.36 (t,
2H, J=8), 2.54 (q, 2H, J=8), 2.23-2.00 (m, 8H), 1.78 (t, 3H,
J=2.8), 1.6 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.6, 133.4,
126.5, 123.3, 79.1, 75.4, 39.3, 36.0, 32.8, 30.9, 27.7, 19.2, 16.0,
3.45. HRMS (APCI) Calcd. for C14H20Br [M–H]: 269.0722,
found: 269.0718.
1. Wei, J.; Xiao, G. Acta Pharm. Sinica 2013, 34, 1485-1490.
2. Cooke, P. S.; Nanjappa, M. K.; Yang, Z.; Wang, K. K. W. Front.
Neurosci. 2013, 7, 108.
3. Deutsch, E. R.; Espinoza, T. R.; Atif, F.; Woodall, E. K. J.;
Wright, D. W. Brain Res. 2013, 1530, 82-105.
4. Kaore, S. N.; Langade, D. K.; Yadav, V. K.; Sharma, P. T.; Vijay,
R.; Sharma, R. J. Pharm. Pharmacol. 2012, 64, 1040-1062.
5. Guennouna, R.; Meffrea, D.; Labombarda, S. L.; Gonzalez, M. C;
Gonzalez, D.; Stein, D. G.; De Nicola, A. F.; Schumacher, M.
Brain Res. Rev., 2008, 493-505.
6. Meffre, D.; Labombarda, F.; Delespierre, B.; Chastre, A.; De
Nicola, A. F.; Stein, D. G.; Schumacher, M.; Guennoun, R.
Neuroscience, 2013, 231, 111-124.
7. Wright, D. W.; Yeatts, S. D.; Silbergleit, R.; Palesch, Y.Y.;
Hertzberg, V. S.; Frankel M.; Goldstein, F. C.; Caveney, A. F.;
Howlett-Smith, H.; Bengelink, E. N.; Manley, G. T.; Merck L. H.;
Janis, L. S.; Barsan, W. G.; N. Engl. J. Med. 2014, 371, 2457-
2466.
8. VanLandingham, J. W.; Cutler, S. M.; Virmani, S. H.; Covey, S.
W.; Krishnan, D. F. K.; Hammes, S. R.; Jamnongjit, M.; Stein, D.
G. Neuropharmacology 2006, 51, 1078-1085.
9. Vanlandingham, J. W.; Suber, J.; Marin, V.; Lewandowski, M.
Prophylactic and post-acute use of progesterone to better
outcomes associated with traumatic brain injury and concussion.
PCT Int. Appl., WO 2013052849 A2, April 11, 2013.
10. Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem. 1992, 57, 2732-
2736.
11. Auchus, R. J.; Sampath, K. A.; Andrew, B. C.; Gupta, M. K.;
Bruce, K. R.; Nigam P.; Covey, D. F. Arch. Biochem. Biophys.
2002, 409, 134-144.
4.3. (5E,9E)-methyl 9-methyl-2-(3-(2-methyl-1,3-dioxolan-2-
yl)propanoyl)pentadeca-5,9-dien-13-ynoate (26)
Homoallyl bromide 12 (357 mg, 1.33 mmol, 1.0 equiv.,
prepared as described above) was added to a solution of β-keto
ester 2531 (430 mg, 1.99 mmol, 1.5 equiv) and cesium carbonate
(562 mg, 1.73 mmol, 1.3 equiv) in acetone. The reaction vessel
was then sealed and heated at 70 °C for 8 h, then cooled to rt and
partitioned between ethyl acetate and half-saturated aqueous
ammonium chloride. The aqueous layer was then extracted 3
times with ethyl acetate, and the combined organics were washed
with water, brine, dried over sodium sulfate and concentrated
using a rotary evaporator. The crude material was then purified
using column chromatography with 15% ethyl acetate / hexanes
to give 357 mg (73% yield) of β-keto ester 26 as a colorless
liquid: 1H NMR (400 MHz, CDCl3) δ 5.48-5.26 (m, 2H), 5.16 (t,
1H, J=6.5), 3.97-3.86 (m, 4H), 3.71 (s, 3H), 3.49 (t, 3H, J=7.2),
2.68-2.62 (m, 2H), 2.22-1.84 (m, 14H), 1.77 (t, 3H, J=2.9), 1.59
(s, 3H), 1.30 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 204.7,
170.3, 135.89, 131.8, 128.4, 123.2, 109.1, 79.2, 75.4, 64.7, 64.6,
58.0, 52.3, 39.5, 36.7, 32.5, 31.1, 30.3, 28.0, 27.7, 23.9, 19.2,
16.0, 3.5 HRMS (ESI+) Calcd. for C24H36O5Na: 427.2460, found:
427.2457.
12. Levy, D. E.; Zhang, F.; Zhan, X. Synthesis of ent-progesterone
and intermediates thereof. PCT Int. Appl., WO 2015095339 A1,
June 25, 2015.
13. Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am. Chem.
Soc. 1971, 93, 4332-4334.
4.4. 3-Methyl-2-((3E,7E)-7-methyltrideca-3,7-dien-11-yn-1-
yl)cyclopent-2-enone (2)
14. Gravestock, M. B.; Johnson, W. S.; McCarry, B. E.; Parry, R. J.;
Ratcliffe, B. E. J. Am. Chem. Soc. 1978, 100, 4274-4282.
15. Cran, J. W.; Han, Y.; Zhang, F. Synthesis of ent-progesterone and
intermediates thereof. PCT Int. Appl., WO 2014145302 A2,
September 18, 2014.
16. Nicolaou K. C.; Sorensen, E. J. Classics in Total Synthesis:
Targets, Strategies, Methods, VCH: Weinheim, 1996.
17. Although bromide 8 is now commercially available, in the original
publication by Johnson it was prepared in 2 steps – an addition of
propyne to ethylene oxide and subsequent exchange of alcohol to
bromide. The most cost-effective way to access 8 today, however
A solution of β-keto ester 26 (310 mg, 0.77 mmol, 1.0 equiv.),
2 mL of methanol, 2 mL of THF, and 2 mL of 2M KOH was
heated at reflux for 3 h in a 75 °C oil bath and then allowed to
cool to rt. The resulting mixture was partitioned between ethyl
acetate and satd. ammonium chloride. The aqueous layer was
extracted with 3 portions of ethyl acetate, and the combined
organics were washed with water and brine, dried over sodium
sulfate, and concentrated using a rotary evaporator. The crude

8
Tetrahedron
ACCEPTED MANUSCRIPT
is from the corresponding alcohol according to Fuchs, M.;
Fürstner, A. Angew. Chem. Int. Ed. 2015, 54, 3978–3982.
26. Moiseenkov, A. M.; Czeskis, B. A.; Ivanova, N. M.; Nefedov, O.
M. J. Chem. Soc. Perkin 1 1991, 2639 – 2649.
27. Johnson, W. S.; William, D. G.; Lyle, T. A.; Mineo, N. J. Am.
Chem. Soc. 1980, 102, 7800 – 7802.
28. Fish, P. V.; Johnson, W. S.; Jones, G. S.; Tham, F. S.; Kullnig, R.
K. J. Org. Chem. 1994, 59, 6150 – 6152.
29. Johnson, W. S.; Buchanan, R. A.; Bartlett, W. R.; Tham, F. S.;
Kullnig, R. K. J. Am. Chem. Soc. 1993, 115, 504 – 515.
30. Johnson W. S.; Bartlett W. R.; Czeskis, B. A.; Gautier, A.; Lee, C.
H.; Lemoine, R.; Leopold, E. J.; Luedtke G. R.; Bancroft, K. J.; J.
Org. Chem. 1999, 64, 9587 – 9595.
18. The overall yield for a linear sequence is calculated by assuming
no loss of material between steps (e.g., consumed by analytical
methods) and, when a range of yields is provided for a particular
step, using the high end of the yield range. The calculated overall
yield thus represents a high-end estimate of what might be
observed in practice and is therefore qualified as “up to” the
calculated value. The yield of steps to prepare 8 is not included
due to the lack of details in original publication.
19. Van Tamelen, E. E.; Hwu, J. R. J. Am. Chem. Soc. 1983, 105,
2490–2491.
20. Clausen, D. J.; Wan, S.; Floreancig, P. E. Angew. Chem. Int. Ed.
2011, 50, 5178 – 5181.
31. Bahman, N.; Elmer, O. S.; Crabbe, P. J. Chem. Soc. Perkin 1
1983, 2337 – 2347.
32. Zheng Y. F.; Dharmpal, S. D.; Allan, C. O. Tetrahedron, 1995, 18,
5255–5276.
21. Cabezas J. A.; Pereira, A. R.; Amey, A. A. Tetrahedron Lett.
2001, 42, 6819–6822.
22. Nagano, H.; Sugihara, H.; Harada, N.; Fukuchi, N.; Yamada, K.;
Izawa, H.; Shiota, M. Bull. Chem. Soc. Jpn. 1990, 63, 3560-3565.
23. Pospíšil, J. Tetrahedron Lett. 2011, 52, 2348–2352.
24. Julia, M. Bull. Soc. Chim. Fr. 1961, 1849–1853.
25. McCormick, J. P.; Barton, D. L. J. Org. Chem. 1980, 45, 2566-
2570.
Supplementary Material
Experimental procedures for alternative processes and 1H
NMR and 13C NMR spectra.
1 Wei, J.; Xiao, G. Acta Pharmacologica Sinica, 2013, 34 (12), 1485-1490.
2 Cooke, P. S.; Nanjappa, M. K.; Yang, Z.; Wang, K. K. W. Frontiers in Neuroendocrine Science, 2013, 4, 108.
3 Deutsch, E. R.; Espinoza, T. R.; Atif, F.; Woodall, E. K. J.; Wright, D. W. Brain Research, 2013, 1530, 82-105.
4 Kaore, S. N.; Langade, D. K.; Yadav, V. K.; Sharma, P. T.; Vijay, R.; Sharma, R. Journal of Pharmacy and Pharmacology, 2012, 64 (8), 1040-1062.
5 Guennouna, R.; Meffrea, D.; Labombarda, S. L.; Gonzalez, M. C; Gonzalez, D.; Stein, D. G.; De Nicola, A. F.; Schumacher, M. Brain Research Reviews, 2008,
493-505.
6 Meffre, D.; Labombarda, F.; Delespierre, B.; Chastre, A.; De Nicola, A. F.; Stein, D. G.; Schumacher, M.; Guennoun, R. Neuroscience, 2013, 231, 111-124.
7 Wright, D. W.; Yeatts, S. D.; Silbergleit, R.; Palesch, Y.Y.; Hertzberg, V. S.; Frankel M.; Goldstein, F. C.; Caveney, A. F.; Howlett-Smith, H.; Bengelink, E.
N.; Manley, G. T.; Merck L. H.; Janis, L. S.; Barsan, W. G.; N. Engl. J. Med., 2014, 371, 2457-2466.
8 VanLandingham, J. W.; Cutler, S. M.; Virmani, S. H.; Covey, S. W.; Krishnan, D. F. K.; Hammes, S. R.; Jamnongjit, M.; Stein, D. G. Neuropharmacology,
2006, 51(6), 1078-1085.
9 Vanlandingham, J. W.; Suber, J.; Marin, V.; Lewandowski, M. Prophylactic and post-acute use of progesterone to better outcomes associated with traumatic
brain injury and concussion. PCT Int. Appl., WO 2013052849 A2, April 11, 2013.
10 Rychnovsky, S. D.; Mickus, D. E. Journal of Organic Chemistry, 1992, 57 (9), 2732-2736.
11 Auchus, R. J.; Sampath, K. A.; Andrew, B. C.; Gupta, M. K.; Bruce, K. R.; Nigam P.; Covey, D. F. Archives of Biochemistry and Biophysics, 2002, 409 (1),
134-144.
12 Levy, D. E.; Zhang, F.; Zhan, X. Synthesis of ent-progesterone and intermediates thereof. PCT Int. Appl., WO 2015095339 A1, June 25, 2015.
13 Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. Journal of the American Chemical Society, 1971, 93(17), 4332-4334.
14 Gravestock, M. B.; Johnson, W. S.; McCarry, B. E.; Parry, R. J.; Ratcliffe, B. E. Journal of the American Chemical Society, 1978, 100(13), 4274-4282.
15 Cran, J. W.; Han, Y.; Zhang, F. Synthesis of ent-progesterone and intermediates thereof. PCT Int. Appl., WO 2014145302 A2, September 18, 2014.
16 Nicolaou K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods.; VCH Verlagsgesellschaft mbH, D-69451 Weinheim (Federal
Republic of Germany), 1996.
17 Although bromide 8 is now commercially available, in the original publication by Johnson it was prepared in 2 steps – an addition of propyne to ethylene oxide
and subsequent exchange of alcohol to bromide. The most cost-effective way to access 10 today, however is from the corresponding alcohol according to Fuchs,
M.; Fürstner, A. ACIEE, 2015, 54 (13), 3978–3982.
18 The overall yield for a linear sequence is calculated by assuming no loss of material between steps (e.g., consumed by analytical methods) and, when a range of
yields is provided for a particular step, using the high end of the yield range. The calculated overall yield thus represents a high-end estimate of what might be
observed in practice and is therefore qualified as “up to” the calculated value. The yield of steps to prepare 8 is not included due to the lack of details in original
publication.
19 Van Tamelen, E. E.; Hwu, J. R. J. Am. Chem. Soc., 1983, 105 (8), 2490–2491.
20 Clausen, D. J.; Wan, S.; Floreancig, P. E. Angewandte Chemie - International Edition, 2011, 50 (22), 5178 – 5181.
21 Cabezas J. A.; Pereira, A. R.; Amey, A. A. Tetrahedron Letters, 42(39), 2001, 6819–6822.
22 Nagano, H.; Sugihara, H.; Harada, N.; Fukuchi, N.; Yamada, K.; Izawa, H.; Shiota, M. Bulletin of the Chemical Society of Japan, 1990, 63 (12), 3560 – 3565.
23 Pospíšil, J. Tetrahedron Letters, 2011, 52(18), 2348 – 2352.
24 Julia, M. Bulletin de la Societe Chimique de France, 1961 , 1849 – 1853
25 McCormick, J. P.; Barton, D. L. Journal of Organic Chemistry, 1980, 45(13), 2566 – 2570.
26 Moiseenkov, A. M.; Czeskis, B. A.; Ivanova, N. M.; Nefedov, O. M. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic
Chemistry, 1991, 2639 – 2649.
27 Johnson, W. S.; William, D. G.; Lyle, T. A.; Mineo, N. Journal of the American Chemical Society, 1980, 102, 26, 7800 – 7802.
28 Fish, P. V.; Johnson, W. S.; Jones, G. S.; Tham, F. S.; Kullnig, R. K. Journal of Organic Chemistry, 1994, 59(21), 6150 – 6152.
29 Johnson, W. S.; Buchanan, R. A.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K. Journal of the American Chemical Society, 1993, 115(2), 504 – 515
30 Johnson W. S.; Bartlett W. R.; Czeskis, B. A.; Gautier, A.; Lee, C. H.; Lemoine, R.; Leopold, E. J.; Luedtke G. R.; Bancroft, K. J.; Journal of Organic
Chemistry, 1999, 64(26), 9587 – 9595.
31 Bahman, N.; Elmer, O. S.; Crabbe, P. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, 10,
2337 – 2347.
32 Zheng Y. F.; Dharmpal, S. D.; Allan, C. O. Tetrahedron, 1995, 18, 5255–5276