Nhatrangin A: Total Syntheses of the Proposed Structure and Six of Its Diastereoisomers

Article abstract of DOI:10.1021/acs.joc.6b03060

A total synthesis of the proposed structure of nhatrangin A is described. This strategy relies on two aldol reactions to install the chiral centers at C3/C4 and C3′/C4′, a lithium-mediated coupling between an advanced intermediate alkyne and a Weinreb amide to complete the C1-C13 alkyl scaffold, and a Yamaguchi esterification to set the side chain. Discrepancies in the spectroscopic data between synthetic and natural nhatrangins led us to synthesize six more diastereoisomers of the proposed structure of nhatrangin A.

Full text of DOI:10.1021/acs.joc.6b03060

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Article
Nhatrangin A: Total Syntheses of the Proposed
Structure and Six of Its Diastereoisomers
Luiz Carlos Dias, and Ellen C. Polo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Mar 2017
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Nhatrangin A: Total Syntheses of the Proposed Structure and Six of Its
Diastereoisomers
Luiz C. Dias* and Ellen C. Polo
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Institute of Chemistry, University of Campinas, 13083-970, C.P. 6154, Campinas, SP, Brasil
*
E-mail: ldias@iqm.unicamp.br
ABSTRACT GRAPHIC
ABSTRACT
A total synthesis of the proposed structure of nhatrangin A is described. This strategy relies on
two aldol reactions to install the chiral centers at C3/C4 and C3’/C4’, a lithium-mediated coupling
between an advanced intermediate alkyne and a Weinreb amide to complete the C1−C13 alkyl
scaffold, and a Yamaguchi esterification to set the side chain. Discrepancies in the spectroscopic
data between synthetic and natural nhatrangins led us to synthesize six more diastereoisomers
of the proposed structure of nhatrangin A.
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1
. INTRODUCTION
In 2010, Orjala and co-workers reported the isolation of two polyketide metabolites from
a Vietnamese collection of Lyngbya majuscula designated as nhatrangins A and B (Figure 1).1
Nhatrangin A is a carboxylic acid containing six stereogenic centers, a di-substituted aryl ring, a
benzylic methyl ether, and a side chain connected via an ester bond. Nhatrangin B is the 9-
bromo analogue of nhatrangin A. The structure of these polyketides was assigned based on
spectrometric and spectroscopic methods, including 1D and 2D NMR experiments.
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Figure 1. Structure of Nhatrangins A and B.
The relative configurations between the carbons C2, C3, and C4 (cluster 1) and between
the carbons C3′ and C4′ (cluster 2) were determined using 3-bond coupling constants, which
included 3JH,H and 3JC,H values, and NOE correlations acquired from selective 1D ROE
2
experiments. The absolute configuration of the carbon C7 (cluster 3) was determined by
comparison of the circular dichroism spectra of nhatrangin A (1) and debromoaplysiatoxin. The
relative stereochemistry between the different clusters of nhatrangin A was determined by
comparison between the structures of nhatrangin A (1) and anhydrodebromoaplysiatoxin (3)
(Figure 2).
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Figure 2. Absolute Configuration of Nhatrangin A and Anhydrodebromoaplysiatoxin.
In 2013, Piva and Raffier reported an approach toward the total synthesis of the purported
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4
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structure of nhatrangin A. In the same year, the research groups of Kamal and Yadav
described the synthesis of the purported structure of nhatrangin A.
Herein, we describe our synthetic efforts toward the total syntheses of the proposed
structure of nhatrangin A and six of its diastereoisomers.
2
. RETROSYNTHETIC ANALYSIS OF NHATRANGIN A
Our retrosynthetic analysis is outlined in Scheme 1. The connection of both carbon chains
of nhatrangin A is installed in a late stage Yamaguchi esterification between the acid 4 and the
alcohol (7S)-5. The acid 4 is prepared by a nucleophilic substitution reaction between compound
6
and cyanide. Compound 6 can be obtained through an aldol reaction between the
oxazolidinone (S)-7 and acetaldehyde (8). The alcohol (7S)-5 is accessed through addition of
the lithium acetylide of alkyne 9 to the Weinreb amide 10. The alkyne 9 can be obtained from a
Corey−Fuchs reaction involving aldehyde 11, which can be accessed from an aldol reaction
between the aldehyde (S)-12 and the oxazolidinone (R)-13.
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Scheme 1. Retrosynthetic Analysis of Nhatrangin A.
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3. RESULTS AND DISCUSSION
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.1. Preparation of Alcohol (7S)-5. Our synthesis began with the preparation of Weinreb amide
0 (Scheme 2). The esterification of commercially available 3-hydroxybenzoic acid (14) with
1
6
7
MeOH and H
2
SO
4
(98%) followed by protection of phenol (BnBr, K
2
CO
3
, Me CO, 93%) and
2
treatment with i-PrMgCl and NH(Me)(OMe).HCl delivered the Weinreb amide 10 in 96% yield.8
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Scheme 2. Preparation of Weinreb Amide 10.
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The next step involved a protection9 of the Roche ester (S)-16 (PMB
10
trichloroacetimidate, CSA, CH
2
Cl
2
) followed by a reduction with LiAlH providing the alcohol 17
4
in 88% yield over two steps (Scheme 3). The oxidation of the alcohol 17 under Swern conditions
gave the aldehyde (S)-12 in 98% yield.11
The aldol reaction between the Z boron enolate of oxazolidinone (R)-13 (obtained from
12
the acylation of compound (R)-18) and aldehyde (S)-12 gave the Evans/1,2-syn aldol adduct
13
1
13
1
9 (74% yield, dr > 95:5). The H NMR and C NMR data spectra of aldol adduct 19 matched
the values reported in the literature for this compound.14
Scheme 3. Preparation of Aldol Adduct 19.
2 2
The protection of aldol adduct 19 (TBSOTf, 2,6-lutidine, CH Cl , 72%) followed by a
reductive cleavage of the chiral auxiliary (LiBH , MeOH, THF, 71%) yielded compound 20
4
15
(Scheme 4). A Swern oxidation of alcohol 20 followed by a Ramirez olefination delivered the
dibromoolefin 21 in 97% yield over two steps. The completion of the Corey−Fuchs protocol
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through treatment of dibromoolefin 21 with n-BuLi gave alkyne 9 in quantitative yield.15,16 The
addition of the lithium acetylide of alkyne 9 to the Weinreb amide 10 provided the compound 22
with a 71% yield.17
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Scheme 4. Preparation of Ketone 22.
The catalytic hydrogenation of 22 afforded the ketone 23 with a 98% yield, which then
underwent a Noyori asymmetric hydrogenation to produce alcohol (7S)-25 ((S,S)-24, i-PrOH,
18
94%, dr = 94:6) (Scheme 5). The methylation of alcohol (7S)-25 (Me
3
OBF , proton-sponge,
4
19
20
CH
2
Cl
2
, 90%) followed by removal of the silyl group provided the alcohol (7S)-5 with a 92%
yield.
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Scheme 5. Preparation of Alcohol (7S)-5.
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After conversion of compound (7S)-25 into esters 26a and 26b,21 the S absolute
stereochemistry of the C-7 stereogenic center was determined using Mosher ester analysis
(
Scheme 6).22
Scheme 6. Determination of Absolute Stereochemistry of the C7 Carbon of Alcohol
(7S)-25.
3.2. Preparation of Carboxylic Acid 4. The synthesis of carboxylic acid 4 began with the
preparation of the aldol adduct 30 (Scheme 7). Treatment of commercially available bromoacetic
acid (27) with NaH, BnOH, and TBAI (98%) followed by a reaction with pivaloyl chloride in the
presence of Et
3
N delivered a mixed anhydride that underwent an acylation reaction with the
lithium anion (S)-29 to give the oxazolidinone (S)-7 at 85% yield. The lithium anion (S)-29 was
23
obtained from the reaction of (S)-28 with n-BuLi. Finally, the aldol reaction between the Z boron
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enolate of oxazolidinone (S)-7 and acetaldehyde (8) provided the Evans/1,2-syn aldol adduct 30
85% yield, dr > 95:5).24
(
Scheme 7. Preparation of Aldol Adduct 30.
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After a two-step conversion of aldol adduct 30 into phenyl acetal 31 (1. LiBH
4
, H
2
O, Et O;
2
2
. PhCH(OMe)
, CSA, CH Cl
2 2 2
),25 the 1,2-syn relationship between C3’ and C4’ was determined
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using H NMR spectrum and 1D selective NOE analyses (Scheme 8).
Scheme 8. Stereochemistry Proof of Compound 31.
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The catalytic hydrogenolysis of compound 30 (H
of the hydroxyls (TBSOTf, 2,6-lutidine, THF, 87% over two steps) afforded the compound 32
(Scheme 9). The reductive removal of the chiral auxiliary of 32 (LiBH , H O, Et O, 92%) followed
2
, PdOH, EtOH) followed by a protection
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by a tosylation produced compound 6 at 94% yield.26 The nucleophilic substitution of the
compound 6 with KCN,27 followed by a reduction with DIBALH,28 and Pinnick oxidation29
provided carboxylic acid 4 (74% yield) over three steps.
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Scheme 9. Preparation of Carboxylic Acid 4.
At this point, we decided to confirm the absolute configuration of the stereogenic centers
at C3’ and C4’ (Scheme 10). The diol 33 was prepared by treatment of compound 6 with KCN
1
13
followed by removal of TBS groups (47% yield over two steps). Spectral data ( H and C NMR)
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and the optical rotation value of compound 33 matched reported values for this compound. A
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second confirmation was obtained through diol 34 (prepared from compound 6); its spectral
1
13
data ( H and C NMR) and optical rotation value also matched with the values reported in the
literature.32
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Scheme 10. Stereochemistry Proof of Compound 6.
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.2. Conclusion of the Synthesis of the Proposed Structure of Nhatrangin A. At this point,
the coupling of the advanced fragments (7S)-5 (C1−C15) and 4 (C1’−C5’) via a Yamaguchi
33
esterification provided the ester 35 at 62% yield (Scheme 11). Removal of the PMB ether of
34
compound 35 (DDQ, phosphate buffer pH7, CH
2
Cl
2
) followed by an oxidation with TEMPO and
BAIB35 gave the carboxylic acid 36 (85% yield) over two steps. Selective hydrogenolysis of
36
benzyl ether of compound 36 (H
2
, Rh/Al
2
O , MeOH, 74%) and subsequent removal of TBS
3
ethers (HF.pyridine, THF) provided the proposed structure of nhatrangin A in quantitative yield.
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Scheme 11. Completion of Synthesis of the Proposed Structure of Nhatrangin A.
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1
13
A quick comparison between the H NMR and C NMR spectra of the synthetic and the
natural nhatrangin A showed that they are similar (Table 1). However, a careful analysis of
chemical shifts of the positions C1, C2, C3, C5, C14, and C2’ showed that while these positions
37
for the reported spectra display chemical shifts of C1 = 176.5 ppm,C2 = 40.4 ppm H2 = 2.26
ppm), C3 = 78.0 ppmH3 = 4.74 ppm),C5 = 30.0 ppmH5 = 1.23 ppm), C14 = 15.1 ppm (H14
=
0.83 ppm), C2’ = 38.3 ppmH2’ = 2.05 and 2.35 ppm), for synthethic nhatrangin A these
positions display chemical shifts of C1 = 178.1 ppm,C2 = 43.1 ppmH2 = 2.42 ppm), C3 = 77.3
ppmH3 = 4.88 ppm),C5 = 29.7 ppmH5 = 1.24 ppm), C14 = 14.5 ppm (H14 = 0.92 ppm), C2’
=
37.9 ppmH2 = 2.38 and 2.14 ppm). Carbons C11 and C13 were probably misassigned in the
original paper of isolation. We believe C11 should be 114.3 ppm, and C13 should be 116.9 ppm.
Table 1. H and 13C NMR Chemical Shifts for Synthetic and Isolated Nhatrangin A in
1
DMSO-d6
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nhatrangin A synthetica
nhatrangin A isolatedb
C ppm
multipl. H
(J in Hz)
-
C ppm
multip. H
(J in Hz)
-
position
H (ppm)
position
H (ppm)
(
multipl.)
178.1 (C)
43.1 (CH)
(multipl.)
1
2
-
1
2
176.5 (C)
-
2.42
quint (7.3)
dd (7.9 and
40.4 (CH)37
2.26
dq (8.3 and 7.0)
3
77.3 (CH)
4.88
3
78.0 (CH)
4.74
dd (8.3 and 3.6)
3
.8)
4
5
33.2 (CH)
1.71
1.24
m
4
5
33.3 (CH)
1.67
1.23
qd (6.7 and 3.6)
m
29.7 (CH2)
m
30.0 (CH2)
1
.56
m
m
6
7
35.2 (CH2)
83.2 (CH)
6
7
35.2 (CH2)
83.3 (CH)
1.60
3.93
m
1.61
dd (7.9 and
3.93
dd (7.4 and 5.4)
4
.9)
s
7-OMe
56.0 (CH3)
144.0 (C)
3.06
-
7-OMe
8
56.0 (CH3)
144.0 (C)
3.07
-
s
8
9
-
-
113.1 (CH)
129.2 (CH)
114.2 (CH)
157.4 (C)
6.66
7.10
6.63
-
m
9
113.1 (CH)
129.2 (CH)
116.9 (CH)
157.5 (C)
6.65
7.10
6.63
-
m
10
t (7.8)
10
11
12
13
14
15
1’
t (7.8)
1
1
1
2
m
m
-
-
m
13
117.0 (CH)
14.5 (CH3)
14.0 (CH3)
171.1 (C)
6.65
0.92
0.76
-
m
d (7.2)
d (6.8)
-
114.3 (CH)
15.1 (CH3)
14.0 (CH3)
171.1 (C)
6.67
0.83
0.74
-
1
1
4
5
d (7.0)
d (6.7)
-
1’
dd (14.9 and
2a’
2.38
2.14
3.74
2a’
2b’
3’
2.35
2.05
3.75
dd (14.3 and 3.2)
dd (14.3 and 10.5)
3
.2)
dd (14.9 and
.8)
3
7.9 (CH2)
38.3 (CH2)
70.6 (CH)
2
b’
9
dt (9.5 and
3.8)
ddd (10.5, 4.2 and
3.2)
3
’
70.8 (CH)
qd (6.3 and
4’
5’
68.4 (CH)
3.51
0.98
4’
5’
68.4 (CH)
3.48
0.95
qd (6.4 and 4.2)
d (6.4)
4
.7)
18.0 (CH3)
d (6.4)
18.0 (CH3)
13
1
a) C NMR (125 MHz) and H NMR (600 MHz). Assignment based on COSY, HSQC and HMBC experiments. b) DEPTQ (226
1
MHz) and H NMR (900 MHz).
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As the discrepancies in the H NMR and 13C NMR spectra suggest that there is a
1
conflict in the stereochemical assignment at the carbons C2, C3, and C4, we first thought
that some epimerization could have happened either at C4 (sequence 20 -> 21 -> 9 -> 22,
Scheme 4) or at C2 (sequence 35 -> 36 -> 1, Scheme 11). Considering the high yields for
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
all of these steps and the cleanness of H NMR spectra for all the products in these
reactions we must postulate a complete inversion either at C2 or C4, something that is very
unlikely. Partial or total epimerization does not appear to be happening in any of these
steps. But, to completely refute this possibility, we prepared the C2 (2-epi-1) and C4 (4-
epi-1) epimers of proposed structure of nhatrangin A as well as the C3 epimer (3-epi-1)
(
Figure 3).
Figure 3. Epimers of the Proposed Structure of Nhatrangin A.
We also turned our attention to the configuration analysis of nhatrangin A made by Orjala
and co-workers. As already mentioned in the introduction, the relative stereochemistry between
the different clusters of nhatrangin A was determined by comparison between the structures of
nhatrangin A (1) and anhydrodebromoaplysiatoxin (3) (Figure 2). Considering that there is no
evidence that nhatrangin A (1) and anhydrodebromoaplysiatoxin (3) have the same biosynthetic
pathway, we proposed to prepare three additional diastereoisomers of the proposed structure of
nhatrangin A (Figure 4).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Isomers of the Proposed Structure of Nhatrangin A.
3
.3. Preparation of Epimer 2-epi-1. The synthesis of epimer 2-epi-1 began with preparation of
aldol adduct 2-epi-19 (Scheme 12). The protection of the Roche ester (R)-16 (PMB
trichloroacetimidate, CSA, CH Cl ) followed by a reduction with LiAlH produced the alcohol ent-
2
2
4
17 (93% yield) over two steps. The oxidation of the alcohol ent-17 under Swern conditions gave
the aldehyde (R)-12 in quantitative yield.
The aldol reaction between the Z boron enolate of oxazolidinone (R)-13 and aldehyde
1
(
R)-12 gave the Evans/1,2-syn aldol adduct 2-epi-19 (70% yield, dr > 95:5). The H NMR and
13C NMR data spectra of aldol adduct 2-epi-19 matched with the values reported in the literature
for this compound.38
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9
Scheme 12. Preparation of Aldol Adduct 2-epi-19.
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 protection of aldol adduct 2-epi-19 (TBSOTf, 2,6-lutidine, CH
2
Cl
2
, 68%) followed by
a reductive cleavage of the chiral auxiliary (LiBH , MeOH, THF, 67%) is shown in Scheme 13.
4
A Swern oxidation of alcohol 2-epi-20 followed by a Ramirez olefination delivered the
dibromoolefin 2-epi-21 (95% yield) over two steps. The completion of the Corey−Fuchs protocol
through treatment of dibromoolefin 2-epi-21 with n-BuLi gave the alkyne 2-epi-9 with a 98% yield.
The addition of the lithium acetylide of alkyne 2-epi-9 to the Weinreb amide 10 provided the
compound 2-epi-22 at a 73% yield. Next, the catalytic hydrogenation of 2-epi-22 afforded the
ketone 2-epi-23 (96% yield), which underwent a Noyori asymmetric hydrogenation to give
alcohol 2-epi-(7S)-25 ((S,S)-24, i-PrOH, 95%, dr = 93:7). The methylation of alcohol 2-epi-(7S)-
25 (Me
3
OBF
4
, proton-sponge, CH
2
Cl , 92%) followed by removal of the silyl group provided the
2
alcohol 2-epi-(7S)-5 (94% yield).
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 13. Preparation of Alcohol 2-epi-(7S)-5.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After conversion of compound 2-epi-(7S)-25 into esters 37a and 37b, the S absolute
stereochemistry of the C-7 stereogenic center was determined using Mosher ester analysis
(Scheme 14).
Scheme 14. Determination of Absolute Stereochemistry of the C7 Carbon of Alcohol
2-epi-(7S)-25.
At this point, the coupling of the advanced fragments 2-epi-(7S)-5 (C1-C15) and 4 (C1’-
C5’) via a Yamaguchi esterification provided the ester 2-epi-35 with a 99% yield (Scheme 15).
Removal of PMB ether of compound 2-epi-35 (DDQ, phosphate buffer pH7, CH
2
Cl ) followed by
2
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an oxidation with TEMPO and BAIB gave the carboxylic acid 2-epi-36 (79% yield) over two steps.
Selective hydrogenolysis of the benzyl ether of compound 2-epi-36 (H , Rh/Al , MeOH, 63%)
and subsequent removal of TBS ethers (HF.pyridine, THF) provided the epimer 2-epi-1 with a
8% yield.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
O
3
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 15. Completion of Synthesis of Epimer 2-epi-1.
1
13
Comparison of the H NMR and C NMR spectra between the epimer 2-epi-1 and the
natural nhatrangin A shows that they do not match. The main differences were observed at the
following positions: C1, C2, C3, C4, C5, C6, C7, C14, C2’, and C3’ (Table 2).
1
13
Table 2. H and C NMR Chemical Shifts for Epimer 2-epi-1 and Isolated Nhatrangin A in
DMSO-d6
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
epimer 2-epi-1a
nhatrangin A isolatedb

C ppm
multipl. H
C ppm
(multipl.)
176.5
40.437
78.0
H
(ppm)
-
multip. H
(J in Hz)
position
H (ppm)
position
(
multipl.)
175.6
41.9
(J in Hz)
1
2
3
4
5
-
-
1
2
3
4
5
-
2.54
5.00
1.61
1.19
1.51
quint (7.4)
2.26
4.74
1.67
1.23
dq (8.3 and 7.0)
dd (8.3 and 3.6)
qd (6.7 and 3.6)
m
75.6
dd (8.3 and 3.8)
34.4
m
33.3
29.4
m
30.0
m
6
34.9
6
35.2
1.60
m
1
.61
m
7
82.8
56.0
3.94
3.06
-
dd (7.7 and 5.2)
7
7-OMe
8
83.3
56.0
3.93
3.07
-
dd (7.4 and 5.4)
7
-OMe
s
s
8
9
143.9
113.0c
129.2
114.3
157.4
117.1c
13.6
-
144.0
113.1
129.2
116.9
157.5
114.3
15.1
-
6.64
7.11
6.63
-
m
9
6.65
7.10
6.63
-
m
1
1
1
1
1
1
0
1
2
3
4
5
m
10
t (7.8)
m
11
m
-
12
-
6.64
0.98
0.82
-
m
d (7.1)
13
6.67
0.83
0.74
-
m
d (7.0)
14
14.1
d (6.8)
15
14.0
d (6.7)
1
’
171.5
-
1’
171.1
-
2
a’
b’
2.44
2.22
dd (14.9 and 3.5)
dd (14.9 and 9.4)
2a’
2b’
2.35
2.05
dd (14.3 and 3.2)
dd (14.3 and 10.5)
ddd (10.5, 4.2 and
3
7.4
38.3
70.6
2
3
’
71.1
3.72
dt (9.6 and 3.7)
3’
3.75
3
.2)
4
’
’
68.5
18.1
3.51
0.98
qd (6.1 and 4.5)
d (6.3)
4’
5’
68.4
18.0
3.48
0.95
qd (6.4 and 4.2)
d (6.4)
5
13
1
a) C NMR (125 MHz) and H NMR (500 MHz). Assignment based on COSY, HSQC and HMBC experiments. b) DEPTQ (226
1
MHz) and H NMR (900 MHz). c) Can be changed.
3
.4. Preparation of Epimer 3-epi-1. The synthesis of epimer 3-epi-1 began with preparation of
aldol adduct 40 (Scheme 16). Treatment of lactate (S)-38 with i-PrMgCl and NH(Me)(OMe).HCl
followed by EtMgBr and benzoic anhydride, DIPEA, and DMAP provided the ketone (S)-39 at a
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39
5
0% yield over three steps. The aldol reaction between the E boron enolate of ketone (S)-39
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
40
1
13
and aldehyde (S)-12 gave aldol adduct 40 (67% yield, dr > 95:5). The H NMR and C NMR
data spectra of aldol adduct 40 matched with the values reported in the literature for this
compound.41
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 16. Synthesis of aldol adduct 40.
The protection of aldol adduct 40 (TBSOTf, 2,6-lutidine, CH
2
Cl
2
, 89%) followed by a
reduction (LiBH , THF), oxidative cleavage (NaIO , MeOH, H O) and subsequent Ramirez
4
4
2
olefination delivered the dibromoolefin 3-epi-21 with a 91% yield over three steps (Scheme 17).
The completion of the Corey−Fuchs protocol through treatment of dibromoolefin 3-epi-21 with
n-BuLi gave the alkyne 3-epi-9 with quantitative yield. The addition of the lithium acetylide of
alkyne 3-epi-9 to the Weinreb amide 10 provided the compound 3-epi-22 with a 35% yield (62%
brsm). Next, the catalytic hydrogenation of 3-epi-22 afforded the ketone 3-epi-23 at a 90% yield,
which underwent a Noyori asymmetric hydrogenation to give alcohol 3-epi-(7S)-25 ((S,S)-24, i-
PrOH, 94%, dr = 92:8). The methylation of alcohol 3-epi-(7S)-25 (Me
CH Cl , 86%) followed by removal of the silyl group provided the alcohol 3-epi-(7S)-5 (89%
yield).
3
OBF
4
, proton-sponge,
2
2
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 17. Preparation of Alcohol 3-epi-(7S)-5.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After conversion of compound 3-epi-(7S)-25 into esters 41a and 41b, the S absolute
stereochemistry of the C-7 stereogenic center was determined using Mosher ester analysis
(Scheme 18).
Scheme 18. Determination of Absolute Stereochemistry of the C7 Carbon of Alcohol
3
-epi-(7S)-25.
At this point, the coupling of the advanced fragments 3-epi-(7S)-5 (C1-C15) and 4 (C1’-
C5’) via a Yamaguchi esterification provided the ester 3-epi-35 with a 99% yield (Scheme 19).
Removal of the PMB ether of compound 3-epi-35 (DDQ, phosphate buffer pH7, CH
2
Cl ) followed
2
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by oxidation with TEMPO and BAIB gave the carboxylic acid 3-epi-36 (62% yield) over two steps.
Selective hydrogenolysis of the benzyl ether of compound 3-epi-36 (H , Rh/Al , MeOH, 62%)
and subsequent removal of TBS ethers (HF.pyridine, THF) produced the epimer 3-epi-1 with a
6% yield.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
O
3
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 19. Completion of Synthesis of Epimer 3-epi-1.
1
13
Comparison of the H NMR and C NMR spectra between the epimer 3-epi-1 and the
natural nhatrangin A shows that they do not match. The main differences were observed at the
following positions: C1, C2, C3, C4, C5, C6, C7, C14, C15, C2’, and C3’ (Table 3).
1
13
Table 3. H and C NMR Chemical Shifts for Epimer 3-epi-1 and Isolated Nhatrangin A in
DMSO-d6
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
epimer 3-epi-1a
nhatrangin A (isolated)b

C ppm
multipl. H
C ppm
(multipl.)
176.5
H
(ppm)
-
multip. H
(J in Hz)
position
H (ppm)
position
(multipl.)
175.8
41.4
(J in Hz)
1
2
3
4
-
-
1
2
3
4
-
2.53
4.98
1.65
quint (7.2)
40.437
2.26
4.74
1.67
dq (8.3 and 7.0)
dd (8.3 and 3.6)
qd (6.7 and 3.6)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
77.2
dd (7.8 and 4.8)
78.0
34.6
m
33.3
1
.16
m
5
26.6
35.1
5
6
30.0
35.2
1.23
1.60
m
m
1.41
m
1
1
.38
.70
m
6
7
m
82.9
55.9
3.95
3.07
-
dd (7.9 and 4.7)
7
7-OMe
8
83.3
56.0
3.93
3.07
-
dd (7.4 and 5.4)
7
-OMe
s
s
8
9
143.9
113.0
129.1
114.2
157.4
117.0
13.2
-
144.0
113.1
129.2
116.9
157.5
114.3
15.1
-
6.65
7.10
6.63
-
m
9
6.65
7.10
6.63
-
m
1
1
0
1
t (7.9)
10
t (7.8)
m
11
m
12
-
12
-
1
1
3
4
6.64
0.98
0.80
-
m
d (7.2)
13
6.67
0.83
0.74
-
m
d (7.0)
14
15
16.2
d (6.8)
15
14.0
d (6.7)
1
’
171.5
-
1’
171.1
-
2
a’
2.44
2.20
dd (14.7 and 3.6)
dd (14.8 and 9.3)
2a’
2b’
2.35
2.05
dd (14.3 and 3.2)
dd (14.3 and 10.5)
ddd (10.5, 4.2 and
3
7.5
38.3
70.6
2b’
3’
71.2
3.70
dt (9.3 and 3.9)
3’
3.75
3
.2)
4’
68.5
18.1
3.52
0.98
qd (6.4 and 4.3)
d (6.4)
4’
5’
68.4
18.0
3.48
0.95
qd (6.4 and 4.2)
d (6.4)
5
’
13
1
a) C NMR (150 MHz) and H NMR (600 MHz). Assignment based on COSY, HSQC and HMBC experiments. b) DEPTQ (226
1
MHz) and H NMR (900 MHz).
3
.5. Preparation of Epimer 4-epi-1. The synthesis of epimer 4-epi-1 began with the preparation
of aldol adduct 42 (Scheme 20). Treatment of lactate (R)-38 with i-PrMgCl and
NH(Me)(OMe).HCl followed by EtMgBr and benzoic anhydride, DIPEA, and DMAP provided the
ketone (R)-39 at a 57% yield over three steps. The aldol reaction between the E boron enolate
1
of ketone (R)-39 and aldehyde (S)-12 gave the aldol adduct 42 (73% yield, dr > 95:5). The H
13
NMR and C NMR data spectra of aldol adduct 40 matched values reported in the literature for
this compound.42
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7
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9
Scheme 20. Synthesis of aldol adduct 42.
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 protection of aldol adduct 42 (TBSOTf, 2,6-lutidine, CH
2
Cl
2
, 97%) followed by a
reduction (LiBH , THF), oxidative cleavage (NaIO , MeOH, H O) and subsequent Ramirez
4
4
2
olefination delivered the dibromoolefin 4-epi-21 at a 94% yield over three steps (Scheme 21).
The completion of the Corey−Fuchs protocol through treatment of dibromoolefin 4-epi-21 with
n-BuLi gave the alkyne 4-epi-9 with a quantitative yield. The addition of the lithium acetylide of
alkyne 4-epi-9 to the Weinreb amide 10 provided the compound 4-epi-22 with a 41% yield (68%
brsm). Next, the catalytic hydrogenation of 4-epi-22 afforded the ketone 4-epi-23 with a 88%
yield, which underwent a Noyori asymmetric hydrogenation to give alcohol 4-epi-(7S)-25 ((S,S)-
24, i-PrOH, 92%, dr = 94:6). The methylation of alcohol 4-epi-(7S)-25 (Me
CH Cl , 92%) followed by removal of the silyl group provided the alcohol 4-epi-(7S)-5 (93%
yield).
3
OBF
4
, proton-sponge,
2
2
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 21. Preparation of Alcohol 4-epi-(7S)-5.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After conversion of compound 4-epi-(7S)-25 into esters 43a and 43b, the S absolute
stereochemistry of the C-7 stereogenic center was determined using Mosher ester analysis
(
Scheme 22).
Scheme 22. Determination of Absolute Stereochemistry of the C7 Carbon of Alcohol
4
-epi-(7S)-25.
At this point, the coupling of the advanced fragments 4-epi-(7S)-5 (C1-C15) and 4 (C1’-
C5’) via a Yamaguchi esterification provided the ester 4-epi-35 with a quantitative yield (Scheme
2
3). Removal of the PMB ether of compound 4-epi-35 (DDQ, phosphate buffer pH7, CH
2
Cl )
2
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followed by oxidation with TEMPO and BAIB gave the carboxylic acid 4-epi-36 with a 74% yield
over two steps. Selective hydrogenolysis of the benzyl ether of compound 4-epi-36 (H
Rh/Al , MeOH, 56%) and subsequent removal of TBS ethers (HF.pyridine, THF) provided the
epimer 3-epi-1 with a 78% yield.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
,
2
O
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 23. Completion of Synthesis of Epimer 4-epi-1.
1
13
Comparison of the H NMR and C NMR spectra between the epimer 4-epi-1 and the
natural nhatrangin A shows that they do not match. The main differences were observed at the
following positions: C1, C2, C3, C4, C5, C6, C14, C15, C2’ and C3’. (Table 4).
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
Table 4. H and C NMR Chemical Shifts for Epimer 4-epi-1 and Isolated Nhatrangin A
in DMSO-d6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
epimer 4-epi-1a
nhatrangin A (isolated)b
C ppm
multipl.)
multipl. H
(J in Hz)
C ppm
(multipl.)
multip. H
(J in Hz)
position
H (ppm)
position
H (ppm)

(
1
2
3
4
176.1
41.9
78.1
33.5
-
-
quint (7.0)
t (6.3)
m
1
2
3
4
176.5
40.4
78.0
33.3
-
-
37
2.52
4.83
1.77
2.26
4.74
1.67
dq (8.3 and 7.0)
dd (8.3 and 3.6)
qd (6.7 and 3.6)
0
1
.91
.47
m
m
m
t (6.4)
s
-
m
m
m
5
26.8
5
30.0
1.23
m
6
7
34.6
83.3
55.9
1.56
3.95
3.06
-
6.64
7.10
6.64
-
6.65
0.95
0.81
-
6
7
35.2
83.3
56.0
144.0
113.1
129.2
116.9
157.5
114.3
15.1
1.60
3.93
3.07
-
6.65
7.10
6.63
-
6.67
0.83
0.74
-
m
dd (7.4 and 5.4)
7
-OMe
8
9
0
1
2
3
4
5
7-OMe
8
s
-
143.8
c
113.1
129.2
114.3
157.4
117.2
13.9
9
m
t (7.8)
m
-
m
d (7.0)
d (6.7)
-
1
1
1
1
1
1
10
11
12
13
14
15
1’
-
c
m
d (6.4)
d (6.7)
-
16.1
171.2
14.0
171.1
1
’
dd (15.0 and
2a’
2b’
3’
2.34
2a’
2b’
3’
2.35
2.05
3.75
dd (14.3 and 3.2)
3
.3)
dd (15.0 and
.8)
37.6
38.3
dd (14.3 and
10.5)
ddd (10.5, 4.2
and 3.2)
2.14
3.70
9
70.9
dt (9.7 and 3.8)
70.6
4
5
’
’
68.5
18.0
3.50
0.97
qd (6.3 and 4.5)
d (6.2)
4’
5’
68.4
18.0
3.48
0.95
qd (6.4 and 4.2)
d (6.4)
13
1
a) C NMR (100 MHz) and H NMR (400 MHz). Assignment based on COSY, HSQC and HMBC experiments. b) DEPTQ (226
MHz) and H NMR (900 MHz). c) Can be changed.
1
3
.6. Preparation of Isomers 2’-epi-3’-epi-1, 7-epi-1 and 2’-epi-3’-epi-7-epi-1. The isomers 2’-
epi-3’-epi-1, 7-epi-1, and 2’-epi-3’-epi-7-epi-1 were prepared using the same synthetic strategy
employed in the synthesis of compound 1.
For the change in cluster 2, the ent-4 acid was prepared from oxazolidinone (R)-28
(
Scheme 24). The reaction of carboxylic acid 44 with pivaloyl chloride in the presence of Et N
3
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delivered a mixed anhydride, which then underwent an acylation reaction with the lithium anion
R)-29 to give the oxazolidinone (R)-7 with a 94% yield. The lithium anion of (R)-29 was obtained
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
from the reaction of (R)-28 with n-BuLi. Finally, the aldol reaction between the Z boron enolate
of oxazolidinone (R)-7 and acetaldehyde (8) provided the Evans/1,2-syn aldol adduct ent-30
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
87% yield, dr > 95:5).
The catalytic hydrogenolysis of compound ent-30 (H
protection of the hydroxyls (TBSOTf, 2,6-lutidine, THF, 82% over two steps) afforded the
compound ent-32 (Scheme 24). The reductive removal of the chiral auxiliary of ent-32 (LiBH
O, Et O, 76%) followed by a tosylation gave the compound ent-6 with a 87% yield. The
2
, PdOH, EtOH) followed by a
4
,
H
2
2
nucleophilic substitution of the compound 6 with KCN, followed by a reduction with DIBALH, and
Pinnick oxidation provided the carboxylic acid 4 (41% yield) over three steps.
Scheme 24. Preparation of Carboxylic Acid 4.
The synthesis of isomer 2’-epi-3’-epi-1 is presented in Scheme 25. The coupling of the
advanced fragments (7S)-5 (C1-C15) and ent-4 (C1’-C5’) via a Yamaguchi esterification
provided the ester 2’-epi-3’-epi-35 with a quantitative yield. Removal of the PMB ether of
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
compound 2’-epi-3’-epi-35 (DDQ, phosphate buffer pH7, CH
TEMPO and BAIB gave the carboxylic acid 2’-epi-3’-epi-36 with a 79% yield over two steps.
Selective hydrogenolysis of the benzyl ether of compound 2’-epi-3’-epi-36 (H , Rh/Al , MeOH,
1%) and subsequent removal of TBS ethers (HF.pyridine, THF) provided the epimer 2’-epi-3’-
epi-1 (85% yield).
2
Cl
2
) followed by oxidation with
2
2
O
3
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 25. Completion of Synthesis of Isomer 2’-epi-3’-epi-1.
1
13
Comparison of the H NMR and C NMR spectra between the epimer 2’-epi-3’-epi-1 and
the natural nhatrangin A shows that they do not match. The main differences were observed at
the following positions: C1, C2, C3, C5, C14, C2’, and C3’ (Table 5).
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Table 5. H and 13C NMR Chemical Shifts for Isomer 2’-epi-3’-epi-1 and Isolated
1
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Nhatrangin A in DMSO-d6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
isomer 2’-epi-3’-epi-1a
nhatrangin A (isolated)b

(
C ppm
H
(ppm)
-
multipl. H
(J in Hz)
-
quint (7.5)
dd (8.2 and
C ppm
(multipl.)
H
(ppm)
-
multip. H
(J in Hz)
-
position
position
multipl.)
176.9
1
2
1
2
176.5
40.43
7
2.26
dq (8.3 and 7.0)
42.6
2.46
3
76.7
4.92
3
78.0
4.74
dd (8.3 and 3.6)
3
.4)
4
5
33.1
29.6
1.70
1.23
m
m
m
4
5
33.3
30.0
1.67
1.23
qd (6.7 and 3.6)
m
1
1
.57
.60
6
7
35.2
83.1
6
7
35.2
83.3
1.60
3.93
m
m
dd (7.4 and
3.92
dd (7.4 and 5.4)
5
.2)
s
7
-OMe
8
9
56.0
144.0
113.0
129.2
114.2
157.4
117.0
14.2
3.06
-
6.64
7.10
6.63
-
6.64
0.94
0.78
-
7-OMe
8
56.0
144.0
113.1
129.2
116.9
157.5
114.3
15.1
3.07
-
6.65
7.10
6.63
-
6.67
0.83
0.74
-
s
-
-
m
t (7.8)
m
9
m
t (7.8)
m
-
m
d (7.0)
d (6.7)
-
1
1
1
1
0
1
2
3
10
11
12
13
14
15
1’
-
m
d (7.1)
d (6.6)
-
14
15
1’
13.8
171.1
14.0
171.1
dd (14.5 and
2
a’
b’
2.38
2.15
3.70
2a’
2b’
3’
2.35
2.05
3.75
dd (14.3 and 3.2)
dd (14.3 and 10.5)
3
.6)
dd (14.5 and
.0)
dt (8.3 and
.8)
qd (6.1 and
.3)
d (6.4)
3
7.8
38.3
70.6
2
9
ddd (10.5, 4.2 and
3.2)
3’
4’
71.3
3
68.5
18.0
3.52
0.98
4’
5’
68.4
18.0
3.48
0.95
qd (6.4 and 4.2)
d (6.4)
4
5
’
1
3
1
a) C NMR (125 MHz) and H NMR (500 MHz). Assignment based on COSY, HSQC and HMBC experiments. b) DEPTQ (226
1
MHz) and H NMR (900 MHz).
For the change in cluster 3, the alcohol (7R)-25 was produced using a Noyori asymmetric
hydrogenation (Scheme 26). The treatment of ketone 23 with Noyori’s catalyst (R,R)-24 in i-
PrOH gave the alcohol (7R)-25 (99%, dr = 91:9). The methylation of alcohol (7R)-25 (Me
3
OBF ,
4
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