Synthetic studies of stereocalpin A and its C5-epimer: Total synthesis of 11-epi- and 5,11-diepi-stereocalpin A

Article abstract of DOI:10.1016/j.tetlet.2011.08.158

This Letter describes the synthetic studies of stereocalpin A and its C5-epimer. After various cyclization attempts, successful macrolactamization at 9-10 position was tried inorder to obtain stereocalpin A and its C5-epimer, which were accompanied by complete racemization and resulted in the synthesis of 11-epi- and 5,11-diepi-stereocalpin A. Highly functionalized octanoic acid motif of the depsipeptide was constructed by applying Paterson's aldol methodology, owing to its diversity in synthesizing various analogs of aliphatic acid.

Full text of DOI:10.1016/j.tetlet.2011.08.158

Tetrahedron Letters 52 (2011) 5987–5991
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies of stereocalpin A and its C5-epimer: total synthesis
of 11-epi- and 5,11-diepi-stereocalpin A
⇑
K. Mahender Reddy, J. Shashidhar, Gurava Reddy Pottireddygari, Subhash Ghosh
CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the synthetic studies of stereocalpin A and its C5-epimer. After various cyclization
attempts, successful macrolactamization at 9-10 position was tried inorder to obtain stereocalpin A and
its C5-epimer, which were accompanied by complete racemization and resulted in the synthesis of 11-
epi- and 5,11-diepi-stereocalpin A. Highly functionalized octanoic acid motif of the depsipeptide was con-
structed by applying Paterson’s aldol methodology, owing to its diversity in synthesizing various analogs
of aliphatic acid.
Received 25 July 2011
Revised 25 August 2011
Accepted 27 August 2011
Available online 6 September 2011
Keywords:
Stereocalpin A
Antitumor
Ó 2011 Elsevier Ltd. All rights reserved.
Antidiabetic
Paterson’s aldol
Macrolactamization
Secondary metabolites produced by cyanobacteria are an
important source of biologically active compounds. Many of these
secondary metabolites are cyclic peptides and depsipeptides. Ste-
reocalpin A is one such a depsipeptide, isolated by Oh et al. from
the dry lichen Ramalina terebrata of Antarctica in 2008.1 They pro-
posed the structure of stereocalpin A to be 1 (Fig. 1), with the help
of a detailed spectroscopic analysis. Initial biological studies
against various solid tumor cell lines showed promising results.
for making the macrocycles of target molecules, while the cycliza-
tion precursors could be obtained from the highly substituted octa-
noic acid moieties (4 and 5) and the dipeptide unit 9 simply via
coupling protocols. For the synthesis of poly propionate units 4
and 5 we envisaged that the use of Paterson’s anti-aldol reaction,4
would provide all the possible diastereoisomers of the acid frag-
ment 4 required for the structural reassignment and analogs
preparation.
Stereocalpin
A
inhibits the protein tyrosine phosphatase 1B
M), thereby
Thus our synthesis commenced from the known keto com-
pound 85 (Scheme 2), which was subjected to substrate-controlled
and reagent-controlled Paterson’s aldol reaction conditions,4 con-
secutively with butyraldehyde. Thus compound 8 on condensation
with butyraldehyde under substrate control Paterson’s aldol condi-
tions4a,b using dicyclohexyl boran chloride afforded b-keto alchol,
which was reduced in situ with LiBH4 to give the diol compound
10 in good yield and diastereoselectivity. Likewise, reagent-con-
trolled Paterson aldol reaction4c of compound 8 with butyralde-
hyde using (ꢀ)-Ipc2BOTf followed by hydroxyl directed keto
reduction6 furnished 1,3-anti diol compound 11 in 70% yield (dr
4:1). Subsequently benzylidene rearrangement7 with DDQ affor-
ded compounds 12 and 13, which on protection with TBSCl fur-
nished fully protected compounds 14 and 15, respectively.
Finally opening of the benzylidene with DIBAL-H gave the primary
alcohols 6 and 7.8
(PTP1B) in a dose-dependent manner (IC50 = 40
l
exhibiting cytotoxic and antidiabetic activities.2 However, exten-
sive biological studies were hampered by the limited availability
of the natural product. Ghosh and Xu3a reported the first total syn-
thesis of the proposed structure of stereocalpin A (1) and pointed
the incorrect structural assignment of the original molecule. Very
recently Huang et al. reported the synthetic studies of stereocalpin
A.3b High biological importance and our desire to assign the correct
structure of stereocalpin A led us to plan and devise a rationalized
strategy for the synthesis of all its possible stereoisomers. As a
manifestation of our strategy, we initially aimed at the synthesis
of the proposed structure of stereocalpin A and its C5-epimer that
eventually led to the synthesis of 11-epi-stereocalpin A (2) and
5,11-di-epi-stereocalpin A (3). The present communication de-
scribes our efforts in this direction.
Retrosynthetically (Scheme 1), we envisaged that either a mac-
rolactonization or macrolactamization strategy could be adopted
After synthesizing the alcohols 6 and 7, we decided first to syn-
thesize the C5-epimer of the proposed structure of stereocalpin A,
as it might help us to assign the correct structure of stereocalpin
and we thought of using a macrolactonization strategy for the tar-
get molecule. Accordingly alcohol 7 was oxidized with DMP9 to
⇑
Corresponding author. Fax: +91 40 27193108.
E-mail addresses: subhashbolorg3@yahoo.com, subhash@iict.res.in (S. Ghosh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.158

5988
K. M. Reddy et al. / Tetrahedron Letters 52 (2011) 5987–5991
O
O
O
O
O
O
1
O
O
O
Me
Me
Me
NH
NH
NH
Me
Me
Me
5
O
O
Me
O
8
N
N
N
O
O
O
Me
Me
Stereocalpin A (1)
11-epi-Stereocalpin A (2)
5,11-diepi-Stereocalpin A (3)
(proposed structure)
Figure 1.
O
O
O
Me Me
Me
5
5
NH
4
2
COOH
O
N
Me
TBSO
OPMB
O
NHBoc
OPMB
O
N
4: 5S
9
O
O
Me
5: 5R
Me Me
OH
Proposed structure of stereocalpin A (1): 5S
5-epi-stereocalpin A: 5R
8
TBSO
OPMB
6: 5S
7: 5R
O
Scheme 1. Retrosynthetic analysis.
OPMB
OH OH
10
i
OH
O
O
iii
OPMB
ii
8
12: 5S
13: 5R
O
iv
OPMB
OH OH
O
11
OH
v
TBSO
O
O
TBSO
OPMB
14: 5S
15: 5R
6: 5S
7: 5R
O
Scheme 2. Reagents and conditions: (i) (c-C6H11)2BCl, Et3N, Et2O, 0 °C, 2 h, then buteraldehyde, ꢀ78 °C to ꢀ20 °C, 14 h, LiBH4, THF ꢀ78 °C, NaOH, H2O2, 75%, dr (85:15); (ii) (a)
(ꢀ)-Ipc2BOTf, iPr2NEt, CH2Cl2, buteraldehyde, ꢀ78 °C to 0 °C; (b) Me4NBH(OAc)3 AcOH–CH3CN (1:1), ꢀ20 oC, 19 h, 70%, dr (80:20); (iii) DDQ, 4 Å MS, ꢀ10 °C, 2 h, CH2Cl2, 85%;
(iv) TBSOTf, 2,6 lutidine, CH2Cl2, rt, 45 min 96% (v) DIBAL-H, CH2Cl2, ꢀ40 °C to ꢀ10 °C, 2 h, 90%.
give an aldehyde, which on further oxidation with NaClO2 afforded
acid 5 in good yield. Coupling of the acid with dipeptide (S)-
HClꢁNH2-Phe-(S)-MePhe-Oallyl using HATU as a coupling agent
afforded compound 16 in 75% yield over three steps.10 TBS depro-
tection of 16 with catalytic amount of CSA afforded the secondary
alcohol, which on treatment with Pd[PPh3]4 furnished seco-acid,
the macrolactonization precursor in good yield (Scheme 3). Seco-
acid was then subjected to macrolactonization reaction under
Yamaguchi conditions.11 Unfortunately the Yamaguchi cyclization
was not successful.
steps. Acylation of secondary hydroxyl group of compound 20 with
the acid Cbz-(S)-Phe-(S)-Me Phe-OH under Yamaguchi esterifica-
tion11 protocol afforded compound 21, which on detritylation with
a catalytic amount of PTSA in MeOH furnished primary alcohol 22
in good yield. Two-step oxidation of primary alcohol 22 gave an
acid, which on hydrogenolysis in the presence of catalytic amount
of CH3COONH4 afforded amino acid 23. The stage was set for the
crucial macrolactamization, but unfortunately the macrolactami-
zation reaction under various reagents and conditions again failed
to provide the desired cyclized product.
As an alternative, we surmised that a macrolactamization strat-
egy between Phe-NH2 and –COOH of the polypropionate unit (for-
mation of N12–C1 bond) might provide the cyclized product
(Scheme 4). To perform this primary alcohol 7 was protected as tri-
tyl ether to give fully protected compound 19, which was desilylat-
ed with TBAF in THF to give compound 20 in 85% yield over two
As a final resort we decided to perform the macrolactamization
via Phe–Phe bond formation. Although Ghosh and Xu3a observed
that the exclusive racemization had taken place at the C11-center
during the cyclization for their substrate, we felt that by keeping
C3–OH free, the steric hindrance can be reduced and racemization
can be minimized. Accordingly acylation of the secondary hydroxyl

K. M. Reddy et al. / Tetrahedron Letters 52 (2011) 5987–5991
5989
PMB
O
O
Me
Me Me
NH
Me Me
i
ii
OH
Me
OR
COOH
OPMB
O
O
O
TBSO
OPMB
N
7
TBSO
Me
5
16: R = TBS
PMB
O
PMB
O
O
O
Me
Me
NH
NH
v
iii
iv
Me
OH
Me
OH
O
O
O
O
O
N
N
Me
HO
Me
17
18
t
Scheme 3. Reagents and conditions: (i) (a) DMP, CH2Cl2, 0 °C to rt, 1 h; (b) NaH2PO4ꢁ2H2O, NaClO2, H2O, 2-methyl-2-butene, BuOH, 1 h; (ii) HATU, N-ethyl piperidine, (S)-
HClꢁNH2-Phe-(S)-Me Phe-Oallyl, CH3CN, 0 °C to rt, 12 h, 75%; (iii) CSA, MeOH–CH2Cl2 (1:4), 0 °C, 1 h, 90%; (iv) Pd[PPh3]4, morpholine, THF, rt, overnight, 85%; (v) 2,4,6-
trichlorobenzoyl chloride, DMAP, toluene, reflux, overnight.
PMB
O
PMB
O
OR
NHCbz
Ph
Me Me
OTr
i
iii
ii
Me
OTr
7
Me
Me
TBSO
OPMB
Me
OH
19
O
O
20
N
PMB
O
O
Me
21: R = Tr
22: R = H
Me
COOH
iv
NH2
vi
v
Me
Ph
O
O
N
O
Me
23
Scheme 4. Reagents and conditions: (i) TrCl, Et3N, CH2Cl2, 0 °C to rt, 95%; (ii) TBAF, THF, 0 °C to rt, 12 h, 90%; (iii) Cbz-(S)-Phe-(S)-Me Phe-OH, 2,4,6 Trichloro benzoyl chloride,
Et3N, DMAP, CH2Cl2, 0 °C to rt, 7 h, 85%; (iv) PTSA, MeOH, rt, 30 min, 88%; (v) (a) DMP, CH2Cl2, 0 °C to rt, 45 min; (b) NaH2PO4ꢁ2H2O, NaClO2, 1 h, H2O, 2-methyl-2-butene,
tBuOH; (c) H2, Pd(OH)2, CH3COONH4, MeOH, rt, 1h.
OPMB
OPMB
Me
Me
OTr
Me Me
OH
i
ii
iii
Me
O
OTr
Me
O
NBoc
OH OPMB
NBoc
O
O
20
24
25
Ph
OH
Ph
O
O
N
PMB
O
O
O
Me
NH
O
NH
Me
Ph
v
iv
Ph
Me
NH
Ph
O
O
O
Me
NBoc
26
O
N
27
COOMe
O
O
O
Ph
Ph
3
Ph
Scheme 5. Reagents and conditions: (i) Boc-(S)-Me Phe-OH, 2,4,6 Tri chloro benzoyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to rt, 7 h, 75%; (ii) PTSA, MeOH, rt, 30 min, 88%; (iii) (a)
DMP, CH2Cl2, 0 °C to rt, 1 h; (b) NaH2PO4ꢁ2H2O, NaClO2, 1 h, H2O, 2-methyl-2-butene, tBuOH; (c) (S)-HClꢁNH2-Phe-OMe, HATU, N-ethyl piperidine, CH3CN, 0 °C to rt, 12 h, 75%;
(iv) (a) LiOH, tBuOH–H2O (2:1); (b) 50% TFA in CH2Cl2, 0 °C to rt, 2 h; (c) HATU, HOAt, DMF–CH2Cl2 (1.5: 7), DIPEA, 0 °C to rt 3 days, 40%; (v) DMP, CH2Cl2, 0 °C to rt, 1 h, 90%.

5990
K. M. Reddy et al. / Tetrahedron Letters 52 (2011) 5987–5991
oxidation gave a compound whose detailed NMR studies revealed
that it is 5,11-di-epi-stereocalpin A,15 but not the C5-epimer of the
stereocalpin A.
Detailed 1D and 2D NMR experiments, using Double Quantum
Filtered Correlation Spectroscopy (DQFCOSY) and Nuclear Overha-
user Effect Spectroscopy (NOESY) techniques were carried out to
confirm the structure of 3. It was interesting to note from the cou-
pling constants, that the side chains are rather rigid and contain
predominance of single conformation around the C–C single bonds.
3
For phenylalanine side chain at C8, the values of JC8H–C8aH and 3J
C8H–8aH0
are 11.0 and 5.8 Hz, respectively, implying predominance
of a structure with anti arrangement of C8H and C8aH. Using the
reported procedure,16 the major rotamer about C8–C8a was found
to be ‘gꢀ’ (N9-C8-C8a-C8aPh;
v
ꢂꢀ60°), with a population of about
72%. Similarly for the phenylalanine side chain at C11, the cou-
3
3
0
plings JC11H–C11aH and JC11H–C11aH
, have values of 5.0 and
10.0 Hz, which correspond to a major rotamer with an anti confor-
mation for C11H–C11aH0. The major isomer is ‘t’ (N12-C11-C11a-
C11aPh;
v
ꢂ180°), with a population of about 63%. This results
in the two phenyl rings having a distance between the centroids
0
of about 4.9 ÅA (Fig. 2) of each other, thus stabilizing the structure
through
p–p
interactions.17 Even the n-propyl side chain at the
Figure 2. The energy minimized structure of ‘5,11-diepi-stereocalpin A(3)’. The
arrows (M) represent the important nOe correlations. The dotted line (- -) represent
the spatial distance 4.9 Å between two phenyl groups.
C5, interestingly show restrained C–C single bond rotations. The
couplings, 3JC5H–C5aH = 3.5 Hz; 3J
= 10.0 Hz; 3JC5aH–
C5H–C5aH0
3
3
3
0
0
0
C5bH = 6.2 Hz; JC5aH–C5bH = 10.4 Hz; JC5aH –C5bH = 10.0 Hz; JC5aH –
C5bH0
group of 20 with Boc-(S)-Me Phe-OH under Yamaguchi conditions
gave compound 24 (Scheme 5), which on detritylation with a cat-
alytic amount PTSA in MeOH furnished primary alcohol 25 in 66%
over two steps. Primary alcohol 25 was then oxidized to aldehyde
with DMP to give an aldehyde, which on further oxidation followed
by coupling of the resultant acid with (S)-HClꢁNH2-Phe-OMe using
HATU gave compound 26 in 75% yield over three steps. Selective
hydrolysis of the methyl ester with 1 N LiOH followed by Boc
and PMB deprotection with TFA afforded amino acid with free hy-
droxyl group at C3 position. At this juncture we attempted BOP-Cl
mediated cyclization as per the reported literature,12 where it has
been suggested that favored cyclizations with BOP-Cl occur when
N-methyl aminoacid is present at the cyclization site. But even this
attempt was unsuccessful. However, treatment of the amino acid
with HATU and HOAt13 under high dilution in CH2Cl2–DMF
(7:1.5) afforded the cyclized compound 27,14 which on DMP
= 5.0 Hz; clearly bring out this aspect. The major rotamer
about C5–C5a is ‘g+’ (O6-C5-C5a-C5b;
v
1 ꢂ60°), with a population
of ꢂ63% and about C5a–C5b is ‘t’ (C5-C5a-C5b-C5c;
v
2 ꢂ180°),
with a population of ꢂ68%. It is evident from these NMR spectral
studies that during the cyclization complete racemization had ta-
ken place at C11 center, which resulted in the formation of 5,11
diepi-stereocalpin(3).
Similarly when we attempted the synthesis of the proposed
structure of stereocalpin A from compound 6 following the same
set of reaction sequence as mentioned above, we ended up with
11-epi-stereocalpin A (2) (Scheme 6), whose spectral data18 were
in good agreement with the data reported by Ghosh and Xu.3a
In conclusion we have reported the synthetic studies of
reported structure of stereocalpin A and its C5-epimer, which
eventually resulted in the total synthesis of 11-epi- and 5,11-di-
epi-stereocalpin A. We have observed that during cyclization
Me Me
Me Me
iii
ii
i
OTr
OTr
6
TBSO
iv
OPMB
28
OH OPMB
29
PMB
O
O
OPMB
OPMB
Me
Ph
Me
NH
Me
OTr
OH
v
Me
Me
O
O
Me
O
COOMe
NBoc
NBoc
O
NBoc
O
O
32
30
31
Ph
Ph
Ph
OH
O
Me
NH
vi
Me
Ph
vii
O
2
O
N
O
33
Ph
Scheme 6. Reagents and conditions: (i) TrCl, Et3N, CH2Cl2, 0 °C to rt, 95%; (ii) TBAF, THF, 0 °C to rt, 12 h, 90%; (iii) Boc-(S)-Me Phe-OH, 2,4,6 tri chloro benzoyl chloride, Et3N,
DMAP, CH2Cl2, 0 °C to rt, 7 h, 75%; (iv) PTSA, MeOH, rt, 30 min, 88%; (v) (a) DMP, CH2Cl2, 0 °C to rt, 1 h; (b)NaH2PO4ꢁ2H2O, NaClO2, 1 h, H2O, 2-methyl-2-butene, tBuOH; (c) (S)-
HClꢁNH2-Phe-OMe, HATU, N-ethyl piperidine, CH3CN, 0 °C to rt, 12 h, 75%; (vi) (a) LiOH, tBuOH–H2O (2:1); (b) 50% TFA in CH2Cl2, 0 oC to rt, 2 h; (c) HATU, HOAt, DMF–CH2Cl2
(1.5:7), DIPEA, 0 °C to rt 3 days, 40%; (vii) DMP, CH2Cl2, 0 °C to rt, 1 h, 90%.

K. M. Reddy et al. / Tetrahedron Letters 52 (2011) 5987–5991
5991
13. Carpiono, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
racemization had taken place at the C11 position of the molecule,
14. Spectral data for compound 27: Rf = 0.4 (SiO2, 5% MeOH in chloroform). ½a D29
ꢃ
which supports the observation of Ghosh and Xu. Here we have
developed a simple and straight forward strategy for the synthesis
of various stereoisomers of stereocalpin A by applying switchable
Paterson aldol reaction. Currently we are trying to develop a differ-
ent strategy to overcome the racemization, which might help us to
assign the correct structure of stereocalpin A. We are also making
various analogs of stereocalpin A by using present strategy for bio-
logical screening.
ꢀ24.0 (c 0.55, CHCl3);IR (neat):
tmax 3385, 2922, 2853, 1643, 1562, 1459, 1414,
1316, 1260, 1089, 1020, 799 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.25–6.92 (m,
;
10H), 6.60 (d, J = 10.2 Hz, 1H), 5.81 (dd, J = 9.8, 6.6 Hz, 1H), 5.23 (dt, J = 15.1,
4.9 Hz, 1H), 4.87 (d, J = 10.3 Hz, 1H), 3.66 (m, 1H), 3.32–2.98 (m, 4H), 2.82 (s,
3H), 2.71 (m, 1H), 2.35(m, 1H), 2.20–1.97 (m, 2H), 1.70–1.54 (m, 2H), 1.10 (d,
J = 7.1 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 174.8, 173.9, 168.5, 136.3, 135.8, 129.5, 129.0, 128.8, 128.5, 126.7,
126.6, 80.0, 78.8, 55.5, 50.0, 48.0, 37.2, 36.8, 32.6, 30.5, 30.1, 19.8, 18.2, 13.7,
13.4; HRMS (ESIMS): calcd for
517.2679.
C
29H38N205Na [M+Na]+:517.2678, found:
15. Spectral data of 5,11-diepi-stereocalpin A: Rf = 0.5 (SiO2, 30% EtOAc in
petroleum ether). ½a D29
ꢃ
ꢀ60.5 (c 0.5, CH2Cl2); IR (neat): tmax 3310, 2925,
Acknowledgments
2860, 1750, 1670, 1625, 1450, 1250, 1226, 1178, 960, 750, 699 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 7.23–6.95 (m, 10H), 6.50 (d, J = 10.2 Hz, 1H), 5.72 (dd,
J = 10.7, 5.6 Hz,1H), 5.21(dt, J = 10.2, 5.2 Hz, 1H), 4.92 (dt, J = 9.0, 3.7 Hz, 1H),
3.34–3.18 (m, 4H), 2.89 (dd, J = 15.4, 10.9 Hz, 1H), 2.82 (s, 3H), 2.77 (d,
J = 5.3 Hz, 1H), 1.87–1.64 (m, 4H), 1.38 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 7.3 Hz,
3H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,75 MHz): d 209.2, 172.6, 169.6,
167.6, 136.4, 136.0, 128.6, 128.5, 128.46, 128.41, 126.5, 126.4, 57.7, 56.1, 50.1,
42.4, 36.4, 32.6, 32.0, 30.4, 20.0, 16.4,14.0, 13.8, 13.7; HRMS (ESIMS): calcd for
We are thankful to CSIR (K.M, G.R.) and UGC (J.S.), New Delhi for
research fellowships. We are also thankful to Dr. A.C. Kunwar for
the useful discussion.
References and notes
C
29H37N2O5 [M+H]+: 493.2702, found: 493.2708.
16. Cung, M. T.; Marrraud, M. Biopolymers 1982, 21, 953.
1. Seo, C.; Yim, J. H.; Lee, H. K.; Park, S. M.; Sohn, J.-H.; Oh, H. Tetrahedron Lett.
2008, 49, 29.
2. Korea Ocean Res & Dev Inst, KOOC-2007.11.04
3. (a) Ghosh, A. K.; Xu, C.-X. Org. Lett. 2009, 11, 1963; (b) Yixian, H.; Yikang, W.
Chin. J. Chem. 2011, 29, 1185–1191.
17. Chourasia, M.; Sastry, G. M.; Sastry, G. N. Int. J. Biol. Macromol. 2011, 48, 540.
18. Spectral data of 11-epi-stereocalpin A: Rf = 0.45 (SiO2, 30% EtOAc in petroleum
ether). ½a 2D9
ꢃ
ꢀ67.0 (c 0.25, CH2Cl2); IR (neat): tmax 3300, 2924, 2854, 1737,
1677, 1624, 1457, 1260, 1226, 1172, 962, 752, 698 cmꢀ1
;
1H NMR (CDCl3,
500 MHz): Contains two rotamers. d 7.34–6.87 (m, 10H), 6.34 (d, J = 10.5 Hz,
0.6H), 5.64 (dd, J = 12.8, 4.4 Hz, 0.7H), 5.46 (d, J = 3.4 Hz, 0.3H), 5.22 (td, J = 10.5,
4.6 Hz, 0.7H), 5.15 (m, 0.2H), 4.99 (m, 0.7H), 4.60 (m, 0.4H), 3.40–3.49 (m,
2.5H), 3.29 (q, J = 7.0 Hz, 0.8H), 3.20 (dd, J = 14.0, 10.5 Hz, 0.7H), 2.99 (m, 0.5H),
2.93 (s, 0.8H), 2.77–2.83 (m, 1.4H), 2.76 (s, 2.4H), 2.31 (m, 0.5H), 1.88–2.04 (m,
1.1H), 1.53 (m, 1H), 1.46 (d, J = 7.0 Hz, 2H), 1.28 (d, J = 6.8 Hz, 0.8H), 1.22–1.4
(m, 3H), 1.05 (d, J = 7.0 Hz, 2.4H), 1.03 (d, J = 6.8 Hz, 0.8H), 0.93 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz): M for major rotamer, m for minor rotamer, d
211.1 (m), 207.6(M), 173.9(M), 171.1(m), 170.2(M), 169.0(m),167.7(m),
167.6(M), 136.4(M), 136.0(M), 135.8(m), 77.8(m), 76.9(M), 62.2(m), 58.9(m),
58.3(M), 58.0(m), 56.9(M), 50.6(M), 42.6(m), 41.7(M), 36.7(M), 34.6(m),
34.4(m), 34.1(M), 33.4(M), 31.9(M), 31.7(m), 31.1(m), 17.8(m), 16.5(M),
15.0(M), 14.8(m), 14.4(M), 14.0(m), 12.8(M), 12.5(m).HRMS (ESIMS): calcd
for C29H37N2O5 [M+H]+: 493.2702, found: 493.2706.
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