Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N′-protected piperazines via organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2011.12.063

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic c

Full text of DOI:10.1016/j.tetlet.2011.12.063

Tetrahedron Letters 53 (2012) 1539–1542
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of C2-functionalized, N-protected morpholines
and orthogonally N,N0-protected piperazines via organocatalysis
Matthew C. O’Reilly a, Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN),
Vanderbilt University Medical Center, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-
benzyl protected morpholines and orthogonally N,N0-protected piperazines with chiral alkyl groups
installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for
the rapid preparation of functionalized morpholines and piperazines that are not readily accessible
through any other chemistry in good to excellent % ee (55–98% ee).
Received 6 December 2011
Revised 15 December 2011
Accepted 16 December 2011
Available online 29 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Morpholine
Piperazine
Enantioselective
Organocatalysis
Cyclization
Both morpholines (1) and piperazines (2) are widely used aza-
heterocyclic bases in organic synthesis;1 furthermore, they are a fre-
quently found component in both natural products and pharmaceu-
tical compositions,1–3 finding applications as key pharmacophores
in antidepressants (3),4 antibiotics (4),5 antipsychotics (5),6 antican-
cer agents (6)7 and antihypertensive agents (7)8 (Fig. 1). Many of the
pharmacologically relevant congeners possess chiral C-functionali-
zation, frequently at C2.1 Importantly, synthetic chemistry to access
enantiomerically pure C2-functionalized morpholines and pipera-
zines is limited.1 The majority of synthetic efforts rely either on
the resolution of racemic mixtures, or employ enantiopure amino
alcohols and amino acids accessible from the chiral pool.1,9 Alas, reli-
ance on the chiral pool limits the structural diversity of C2-function-
alized congeners, decreasing the synthetic versatility of these
methods.1 Recently, alternative approaches to these scaffolds are
beginning to appear.10–13 With our NIH sponsored Molecular Probe
Center Network (MLPCN) efforts,14 many screening hits are based on
these motifs, and we required new synthetic methods to enable ra-
pid lead optimization campaigns. In this Letter, we describe a novel
three-step, one-pot procedure for the enantioselective synthesis of
N-benzyl protected morpholines and orthogonally N,N0-protected
piperazines with chiral alkyl groups installed at the C2 position of
each heterocyclic core via organocatalysis.
cation of organocatalysis to access chiral b-fluoroamines,15,16 which
in turn, led us to develop a one-pot protocol for the enantioselective
synthesis of N-alkyl terminal aziridines (Scheme 1).17 Here, com-
mercial aldehydes 8 are subjected to an organocatalytic, enantiose-
lective
a
-chlorination to produce 9,18 which then undergoes a
reductive amination reaction with a primary amine, followed by
base induced cyclization to deliver N-alkyl terminal aziridines 10
in good yields (40–65% for the one-pot, three step sequence) and
good to excellent enantioselectivity (55–96% ee).17
Based on the precedent, we hypothesized that we should be able
to employ an amine in the reductive amination step containing an
embedded nucleophile (11 or 12), such that after based-induced
cyclization of either 13 or 14, N-benzyl protected morpholines 15
and orthogonally N,N0-protected piperazines 16, respectively, with
chiral alkyl groups (with inversion of stereochemistry) at the C2 po-
sition could be obtained (Scheme 2). Here, we recount our efforts
toward the realization of this hypothesis.
We initially proceeded with a racemic chlorination employing
10 mol % D,L-proline as catalyst to validate the approach, and to
provide access to racemic analogs to optimize separation of the
enantiomers via chiral supercritical fluid chromatography (SFC)
to determine % ee.15–17 Dodecanal 17 smoothly underwent the
desired racemic a-chlorination to provide 18 after a quick pentane
Our approach for the enantioselective synthesis of C2-function-
alized morpholines and piperazines is based upon our recent appli-
work-up. Reductive amination with 11 and NaB(OAc)3H at ꢀ78 °C,
followed by KOtBu-induced cyclization in CH3CN at ꢀ10 °C
provided racemic C2-functionalized, benzyl-protected morpholine
19 (Scheme 3). While we were thrilled to see the approach success-
ful, the overall yield for the three step, one-pot process was low
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 345 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.063

1540
M. C. O’Reilly, C. W. Lindsley / Tetrahedron Letters 53 (2012) 1539–1542
1) 11, NaBH(OAc)3
4Å M. S., DCM
-78 °C
1
10 mol%
H
N
1
O
O
O
D,L-proline
NBn
2
3
6
5
2
3
6
5
8
H
H
O
8
4
4
8
NCS, DCM, rt
2)
KOtBu, MeCN
Cl
N
N
-10 °C
H
H
17
18
19
11% over 3 steps
1
2
Scheme 3. Three step, one-pot synthesis of C2-functionalized, N-benzyl protected
morpholine 19.
O
N
O
N
F
CO2H
H
H
N
O
N
O
iminium ion 20 could either be reduced by the hydride to provide
the desired 13, or the free hydroxyl could attack 20 producing an
oxazolidine 21, which could be hydrolyzed back to 18 upon aqueous
work-up and/or chromatography (Scheme 4). To explore this possi-
bility, an NMR study was conducted and confirmed that a stereoiso-
meric mixture of oxazolidines 21 was being formed, as shown by the
shift and coupling of the two characteristic downfield diastereotopic
protons indicated below. To improve the yield of the three step, one-
pot process, we would need to prevent this undesired oxazolidine
pathway.
H
O
F
OEt
N
N
H
NMe2
3
4
5
OH
O
N
NH
N
N
N
O
NH
O
N
S
N
NBn
Two approaches were pursued to prevent the formation of 21.
First, we protected the hydroxyl moiety as a TBDMS ether such that
the silyl analog of 13 was generated without the ability to produce
21. A subsequent TBAF deprotection and cyclization afforded race-
mic morpholine 19 in 35% overall yield, a notable improvement;
however, this route added an additional protection/deprotection se-
quence. Alternatively, we focused on the reducing agent. Simply
replacing NaB(OAc)3H/DCM with NaCNBH3/5% HOAc/THF provided
morpholine 19 once again in 35% overall yield for the three steps
(ꢁ70%/step); therefore, these latter conditions were employed to
generate the racemic examples for SFC separation and % ee determi-
nation. The enantioselective congeners utilized the same protocol,
6
7
Figure 1. Structures of morpholine (1), piperazine (2) and pharmaceutical compo-
sitions 3–7, possessing C2-functionalization of these aza-heterocycles.
1. Reductive
O
O
Enantioselective
amination
N
R1
R1
R1
H
H
R2
α-chlorination
2. Base-induced
cyclization
Cl
8
9
10
except the D,L-proline catalyst was replaced with 10 mol % (2R,5R)-
40-65% yield
56-96% ee
diphenylpyrrolidine.18,19 This proved to be the optimal catalyst/
chlorination system, as it proceeds in DCM; the majority of other
organocatalysts/chlorination systems require acetone as solvent,
which is not compatible with our one-pot reductive amination se-
quence, as described in our earlier aziridine work.17 Therefore,
Scheme 1. Organocatalytic approach to chiral N-alkyl terminal aziridines 10.
(11% overall, or ꢁ48% yield per step). Of note, the reductive amina-
tion step required low temperature, ꢀ78 °C. Above ꢀ78 °C, we ob-
asymmetric
a-chlorination, reductive amination and cyclization
afforded enantioenriched C2-functionalized morpholines 19, 22
and 23 in 76–98% ee (Fig. 2).20 Interestingly, the one-pot, three step
yields for the racemic analogs were higher (35–40% overall or
70–75% per step) than for the enantioenriched congeners (13–19%
overall or 50–58% per step).
served severe racemization of the
a-stereocenter, elimination,
alkylation and other by-products, while at ꢀ78 °C, reductive amin-
ations proceeded smoothly with amines such as 11 and 12.
Efforts now focused on optimization of the reaction sequence.
The racemic a-chlorination was a robust step, affording 18 and re-
We next explored the synthesis of orthogonally N,N0-protected
piperazines 16. Here, we did not need to worry about the unde-
sired oxazolidine pathway, so we piloted our initial morpholine
conditions. To our surprise, the one-pot protocol afforded 24 in
good yield, with very little of the desired 25 (Scheme 5), suggesting
the cyclization conditions required optimization. After surveying a
number of solvents (THF, CH3CN and DMF), bases (NaH, KOtBu,
KHMDS) and temperatures, we found that simply replacing the
CH3CN with DMF and employing KOtBu at ꢀ20 °C enabled the for-
mation of 25 from 24 in 98% conversion. Application of this modi-
fication to the one-pot, three step protocol (Scheme 6) delivered
racemic 25 in 47% overall yield (78% per step).
lated congeners in yields of >90% routinely; thus, the low yields
had to be the result of either the reductive amination and/or the
base-induced cyclization step. In addition to 19, the major isolated
by-product from the one-pot process was the
a-chloroaldehyde
18; however, by TLC, LCMS, and NMR analysis of the crude reactions,
18 was consumed. This led us to speculate that the incipient
OH
BnHN
O
O
11
Enantioselective
or
R1
R1
H
H
NHBoc
α-chlorination
BnHN
Cl
12
As shown in Table 1, the three step, one-pot yields for orthogo-
reductive amination
8
9
nally N,N0-protected piperazines were uniformly better (15–50%
Base-induced
cylcization
R1
R1
R1
NBn
NBn
N
Bn
Ph
8
N+
or
Ph
8
N
H
BocN
O
Cl
X
oxygen
hydride
N
OH
8
O
H
Cl
OH
Ph
Cl
Cl
H-
13 X = OH
14 X = NHBoc
15
16
δ1=4.47 ppm
δ2=4.41 ppm
13
20
21
Scheme 2. Proposed organocatalytic approach to C-functionalized, N-protected
morpholines 15 and orthogonally N,N0-protected piperazine 16.
Scheme 4. Competing pathways: undesired oxazolidine 21 formation.

M. C. O’Reilly, C. W. Lindsley / Tetrahedron Letters 53 (2012) 1539–1542
1541
1)
2)
10 mol%
N
Ph
N
Ph
N
Ph
8
3
D,L-proline
O
O
O
Ph
KOtBu, DMF
-20 o
N
Ph
NCS, DCM, rt
17
8
19
22
23
Cl
C
BocHN
NHBn
18% (35% racemic)
94% ee
13% (42% racemic)
76% ee
19% ( 40% racemic)
98% ee
3
65%
BocHN
NaBH(OAc)3
4Å M. S., DCM
-78 °C
Figure 2. Structures and yields for the one-pot, three step synthesis of racemic and
enantioenriched C2-functionalized, N-benzyl protected morpholines.
29
55% over 2 steps
1) 10 mol%
BocHN
N
Ph
KOtBu
D,L-proline
8
8
N
Ph
MeCN
NCS, DCM, rt
NBn
+
BocN
17
N
8
8
2) 12, NaBH(OAc)3
BocN
-20 °C
BocHN
Cl
24
Ph
4Å M.S., DCM
-78 °C
25
30
4:1
31
Scheme 7. Three step, one-pot synthesis of C2-functionalized, orthogonally N,N0-
protected homopiperazine 30.
Scheme 5. First attempt at a three step, one-pot synthesis of a C2 functionalized,
orthogonally N,N0-protected piperazine 25.
1) 12, NaBH(OAc)3
In summary, we have developed a novel three-step, one-pot
procedure for the enantioselective synthesis of N-benzyl protected
morpholines and orthogonally N,N0-protected piperazines with
chiral alkly groups installed at the C2 position of each heterocyclic
core via organocatalysis. Notably, this methodology does not rely
on the chiral pool; instead we can employ simple aldehydes and
commercial organocatalysts. Thus, either enantiomer of the corre-
sponding morpholines and piperazines can be arrived at by
employing either the (R)- or (S)-organocatalyst. This methodology
allows for the rapid preparation of functionalized, pharmaceuti-
cally relevant morpholines and piperazines in 13–50% overall yield
(50–79% per step) that are not readily accessible through any other
chemistry in good to excellent % ee (55–98% ee). Further refine-
ments and improvements are under development and will be
reported in due course.
10 mol%
O
O
4Å M. S., DCM
-78 °C
D,L-proline
NBn
8
H
H
BocN
8
8
NCS, DCM, rt
2)
KOtBu, DMF
-20 oC
Cl
17
18
25
47% over 3 steps
Scheme 6. Three step, one-pot synthesis of C2-functionalized, orthogonally N,N0-
protected piperazine 25.
Table 1
Structures and yields for enantioenriched C2-functionalized, orthogonally N,N0-
protected piperazines
Compd
Piperazine
3-Step, one-pot yield
% (racemic)
% eea
50
(47)
NBn
8
25
96
BocN
Acknowledgments
NBn
NBn
3
45
(55)
26
27
28
92
55
70
The authors gratefully acknowledge funding from the Depart-
ment of Pharmacology, Vanderbilt University Medical Center and
the NIH/Molecular Libraries Production Center Network (MLPCN)
(U54MH084659). M.C.O. acknowledges a predoctoral fellowship
(2009–2010) from the Vanderbilt Institute of Chemical Biology
(VICB) and an ACS Division of Medicinal Chemistry Predoctoral Fel-
lowship (2011–2012) for support.
BocN
Ph
21
(31)
BocN
NBn
15
(21)
BocN
a
% ee determined by chiral SFC.
References and notes
1. Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.
Synthesis 2004, 5, 641–662. and references therein.
2. Elliott, S. Drug Test. Anal. 2011, 3, 430–438.
3. Loeber, S.; Heubner, H.; Tschammer, N.; Gmeiner, P. Trends Pharmacol. Sci.
2011, 32, 148–157.
4. Hajos, M.; Fleishaker, J. C.; Filipak-Reisner, J. K.; Brown, M. T.; Wong, E. H. F. CNS
Drug Rev. 2004, 10, 23–44.
5. Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.; Moriguchi, A.;
Yamamoto, K.; Ikeda, Y.; Kawakita, T. Bioorg. Med. Chem. Lett. 1998, 8, 2185–
2190.
overall or 53–79% per step) than for the analogous morpholines,
and % ee, obtained by chiral SFC analysis, remained good to excel-
lent (55–96% ee).21
Finally, since the piperazines worked well, we elected to see if
this approach would allow entry into enantioenriched homopiper-
azines, the seven-membered ring congeners of 16. Beginning with
17, racemic organocatalytic
a-chlorination, followed by reductive
amination with the N-benzyl-N-Boc protected diaminopropane
delivered 29 in 55% overall yield for the two steps. Our standard
base-induced cyclization conditions for piperazines (KOtBu, DMF,
ꢀ20 °C) did deliver the desired C2-functionalized, orthogonally
N,N0-protected homopiperazine 30, but as a 4:1 mixture with the
elimination product 31 in 65% yield (Scheme 7). This was not
totally unexpected, as the cyclization to produce the seven
-membered ring was anticipated to be slow, allowing the compet-
ing elimination pathway to the alkene to compete. All attempts to
modify the reaction conditions to increase the rate of cyclization
leading to 30 and diminish the production of 31 were unsuccess-
ful; therefore we did not produce an enantioselective variant of 30.
6. Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.; Mawer, I. M.; Ridgill, M. P.;
Baker, R.; Emms, F.; Freedman, S. B.; Marwood, R.; Patel, S.; Ragan, C. I.; Leeson,
P. D. J. Med. Chem. 1996, 39, 1941–1942.
7. Lawrence, N.J.; Pireddu, R.S.; Sebti, S.M. WO 130740, 2011.
8. Scheiper, B.; Matter, H.; Steinhagen, H.; Bocskei, Z.; Fleury, V.; McCort, G.
Bioorg. Med. Chem. Lett. 2011, 21, 5480–5486.
9. Otto, W. G. Angew. Chem. 1956, 68, 181–183.
10. Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47,
3784–3786.
11. Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257–260.
12. Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6, 1045–1047.
13. Bornholdt, J.; Felding, J.; Kristensen, J. L. J. Org. Chem. 2010, 75, 7454–7457.
14. For information on the MLPCN see: http://mli.nih.gov/mli/mlpcn.
15. Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 943–946.
16. Schulte, M. L.; Lindsley, C. W. Org. Lett. 2011, 13, 5684–5687.

1542
M. C. O’Reilly, C. W. Lindsley / Tetrahedron Letters 53 (2012) 1539–1542
17. Fadeyi, O. O.; Schulte, M. L.; Lindsley, C. W. Org. Lett. 2010, 12, 3276–3278.
18. Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790–4791.
19. Marigo, M.; Bachmann, S.; Halland, N.; Braunton, A.; Jørgensen, K. A. Angew
Chem., Int. Ed. 2004, 43, 5507–5510.
29.51, 29.45, 29.24, 25.33, 22.60, 14.04. Specific rotation ½a D22
ꢃ = +13.04° (c 100,
MeOH).
21. Representative experimental for the synthesis of enantioenriched C2-
functionalized orthogonally N,N0-protected piperazines: To
a
solution of
aldehyde (1 mmol, 1 equiv) and (2R,5R)-2,5-diphenylpyrrolidine (22.3 mg,
0.1 mmol, 0.1 equiv) in DCM (2.0 mL) was added N-chlorosuccinimide
(173 mg, 1.3 mmol, 1.3 equiv) at 0 °C. The reaction was kept at 0 °C for 1 h at
which point it was allowed to warm to ambient temperature. It was then
stirred until the aldehyde was completely consumed as determined by 1H NMR
spectroscopy of the reaction mixture. Pentane was added to the reaction
mixture at ꢀ78 °C and the precipitated NCS, succinimide, and catalyst were
filtered off. After removal of the solvent at 0 °C, the filtration process was
repeated one time. The crude oil was redissolved in DCM (3 mL) and 4 Å
molecular sieves (500 mg) were added. The reaction was cooled to ꢀ78 °C and
a solution of amine (1.5 mmol, 1.5 equiv) in DCM (2 mL) was added followed
by the addition of NaBH(OAc)3 (339 mg, 1.6 mmol, 1.6 equiv). The reaction
vessel was purged and left to stir at ꢀ78 °C for greater than 16 h at which time
it was filtered through a pad of celite eluting with ethyl acetate. It was
extracted with ethyl acetate and washed with saturated NaHCO3 and brine,
and the organic layer was dried over MgSO4 followed by concentration in
vacuo resulting in a crude oil, which was then redissolved in DMF (50 mL). The
solution was cooled to ꢀ20 °C followed by the addition of KOtBu (560 mg,
5 mmol, 5 equiv). It was then stirred until the b-chlorodiamine was completely
consumed as determined by thin layer chromatography. The reaction was
extracted with diethyl ether (3 ꢂ ) and washed with brine. The crude oil was
concentrated and purified by flash column chromatography (9:1 Hexanes/
Ethyl Acetate) to afford the product. Enantiomeric Excess was determined via
chiral SFC analysis.
20. Representative experimental for the synthesis of enantioenriched C2-
functionalized morpholines: To a solution of aldehyde (1 mmol, 1 equiv) and
(2R,5R)-2,5-diphenylpyrrolidine (22.3 mg, 0.1 mmol, 0.1 equiv) in DCM
(2.0 mL) was added N-chlorosuccinimide (173 mg, 1.3 mmol, 1.3 equiv) at
0 °C. The reaction was kept at 0 °C for 1 h at which point it was allowed to
warm to ambient temperature. It was then stirred until the aldehyde was
completely consumed as determined by 1H NMR spectroscopy of the reaction
mixture. Pentane was added to the reaction mixture at ꢀ78 °C and the
precipitated NCS, succinimide, and catalyst were filtered off. After removal of
the solvent at 0 °C, the filtration process was repeated one time. The crude oil
was redissolved in THF (3 mL) and 4 Å molecular sieves (500 mg) were added.
The reaction was cooled to ꢀ78 °C and
a solution of amine (1.5 mmol,
1.5 equiv) in THF (2 mL) was added followed by the addition of NaBH3CN
(100.5 mg, 1.6 mmol, 1.6 equiv) and acetic acid (120.1 mg, 2 mmol, 2 equiv).
The reaction vessel was purged and left to stir at ꢀ78 °C for greater than 16 h at
which time it was filtered through a pad of celite eluting with ethyl acetate. It
was extracted with ethyl acetate and washed with saturated NaHCO3 and
brine, and the organic layer was dried over MgSO4 followed by concentration in
vacuo resulting in a crude oil, which was then redissolved in acetonitrile
(50 mL). The solution was cooled to ꢀ20 °C followed by the addition of KOtBu
(560 mg, 5 mmol, 5 equiv). It was then stirred until the b-chloroaminoalcohol
was completely consumed as determined by thin layer chromatography. The
reaction was extracted with diethyl ether (3ꢂ) and washed with brine. The
crude oil was concentrated and purified by flash column chromatography
(Hexanes/Ethyl Acetate) to afford the product. Enantiomeric Excess was
determined via chiral SFC analysis.
NBn
BocN
NBn
O
(R)-tert-butyl4-benzyl-2-decylpiperazine-1-carboxylate
(R)-4-benzyl-2-decylmorpholine
The product was prepared according to the above description and was purified
by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear
oil (208 mg, 50%). 1H NMR (400.1 MHz, CDCl3) d (ppm): 1HNMR (400.1 MHz,
CDCl3) d (ppm): 7.32–7.21 (m, 5H); 3.99 (s, br r, 1H); 3.90–3.82 (m, 1H); 3.53
(d, J = 13.2, 1H); 3.37 (d, J = 13.3, 1H); 3.05 (t, J = 12.5, 1H); 2.75–2.65 (m, 2H);
2.06–2.00 (m, 2H); 1.78–1.73 (m, 1H); 1.66–1.61 (m, 1H); 1.45 (s, 9H); 1.30–
1.15 (m, 16H); 0.88 (t, J = 7.5, 3H). 13C NMR (100.6 MHz, CDCl3) d (ppm):
154.81, 138.39, 128.68, 128.12, 126.93, 79.18, 62.80, 55.39, 53.29, 51.37, 39.24,
31.84, 29.74, 29.59, 29.56, 29.53, 29.50, 29.27, 28.38, 26.20, 22.52, 14.04.
The product was prepared according to the above description and was purified
by silica chromatography (9:1 Hexanes/EtOAc) to afford the product as a clear
oil (57 mg, 18%). 1H NMR (400.1 MHz, CDCl3) d (ppm): 1HNMR (400.1 MHz,
CDCl3) d (ppm): 7.32–7.24 (m, 5H); 3.84 (dq, J1 = 11.5 Hz, J2 = 1.8, 1H); 3.65 (td,
J1 = 11.5, J2 = 2.5, 1H); 3.52–3.45 (m, 3H), 2.74–2.71, (m, 1H), 2.65 (dq, J1 = 11.4,
J2 = 1.8, 1H), 2.14 (td, J1 = 11.4, J2 = 3.3, 1H), 1.87–1.82 (m, 1H), 1.5–1.25 (m,
18H), 0.87 (t, J = 7.1, 3H). 13C NMR (100.6 MHz, CDCl3) d (ppm): 137.76, 129.11,
128.17, 127.03, 75.76, 66.73, 63.29, 58.80, 53.12, 33.67, 31.83, 29.60, 29.52,
Specific rotation ½a D22
ꢃ = ꢀ34.68° (c 100, MeOH).