Asymmetric synthesis of the stereoisomers of 11,12,15(S)-trihydroxyeicosa- 5(Z),8(Z),13(E)-trienoic acid, a potent endothelium-derived vasodilator

Article abstract of DOI:10.1016/j.bmcl.2004.07.019

The four stereoisomers 11,12,15(S)-THETA were prepared by a triply convergent, asymmetric route that exploited the stereospecific, copper mediated cross-coupling of α,β-dialkoxystannanes and the utility of dialkylthionocarbamates as orthogonal alcohol pro

Full text of DOI:10.1016/j.bmcl.2004.07.019

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4987–4990
Asymmetric synthesis of the stereoisomers of
11,12,15(S)-trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid,
a potent endothelium-derived vasodilator
a
a
a
J. R. Falck,a, Deb K. Barma, Suchismita Mohapatra, A. Bandyopadhyay,
*
Komandla Malla Reddy,a Jianjun Qia and William B. Campbellb
aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
bDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Received 19 May 2004; accepted 7 July 2004
Available online 31 July 2004
Abstract—The four stereoisomers of the endothelial-derived vasorelaxant 11,12,15(S)-trihydroxyeicosatrienoic acid [1, 11,12,15(S)-
THETA] were prepared by a triply convergent, asymmetric route that exploited the stereospecific, copper mediated cross-coupling
of a,b-dialkoxystannanes with organic electrophiles and the utility of dialkylthionocarbamates as orthogonal alcohol protective
groups. Only 11(R),12(S),15(S)-THETA was comparable to natural material by HPLC, GC/MS, and in vitro bioassay.
ꢀ 2004 Elsevier Ltd. All rights reserved.
HO
The endothelial lining of mammalian blood vessels gen-
erates1 a variety of vasoactive substances, for example,
prostacyclin (PGI2),2 nitric oxide,3 epoxyeicosatrienoic
acids,4 and endothelin.5 As a part of the intense search
for additional endogenous vasomodulators,6 our labora-
tories reported the isolation of triol 1, which is generated
by rabbit aortic endothelium from arachidonic acid via
the 15(S)-lipoxygenase pathway.7 The structure of 1
was assigned as 11,12,15(S)-trihydroxyeicosatrienoic
acid [11,12,15(S)-THETA] based upon a combination
of spectral and biochemical studies; however, the minute
amounts available from natural sources precluded a
complete stereochemical assignment.8 In the rabbit
aorta, 1 mediates acetylcholine-induced vasodilation9
and its production is stimulated by interleukin-13
treatment.10 To unambiguously establish the absolute
configuration of 1 as well as expedite additional phar-
macological evaluations, we herein report a concise,
asymmetric synthesis of all four stereoisomers of
11,12,15(S)-THETA (1) and their comparisons with
natural material. Our triply convergent strategy is
summarized in Figure 1 and highlights two synthetic
procedures recently introduced by our laboratories,
HO
OH
Cu/Tin Cross-Coupling
CO2H
S
Nozaki-Kishi Alkylation
commercial
1
S
SnBu3
CO2Me
TBDMSO
N
O
O
O
I
Br
2
3
4
Figure 1. Retrosynthetic analysis.
viz., (i) the preparation and stereospecific, copper medi-
ated cross-coupling of chiral a,b-dialkoxystannanes11
with organic electrophiles and (ii) the utility of
dialkylthionocarbamates as orthogonal protecting
groups.12
Retron 313 was conveniently accessed via diastereoselec-
tive addition11 of zinc bis-(n-tributylstannane) to
prochiral aldehyde (R)-2,3-O-isopropylidene-D-glycer-
aldehyde14 (5) (Scheme 1). Thionocarbamoylation12 of
the resultant anti-adduct 6 evolved 3 in good overall
yield. The syn-adduct 8 was obtained from 6 by a con-
ventional Mitsunobu inversion/saponification sequence
via benzoate 7.
*
Corresponding author. Tel.: +1-214-648-2406; fax: +1-214-648-
6455; e-mail: j.falck@utsouthwestern.edu
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.019

4988
J. R. Falck et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4987–4990
O
a
77%
b
87%
O
O
CO2Me
3
O
SnBu3
O
O
SnBu3
R2
Scheme 3
CHO
O
N
S
R1
5
R2
R1
19: R = H, R = OH
HO
OH
6: R1 = H, R2 = OH
7: R1 = OBz, R2 = H
8: R1 = OH, R2 = H
c (95%)
d (85%)
1
2
18
1
2
20: R = OH, R = H
Scheme 4. Synthesis of triols 19 and 20.
Scheme 1. Reagents and conditions: (a) Zn(Bu3Sn)2, THF, ꢀ78ꢁC,
4h; (b) 1,10-Im2C(S), DMAP, then pyrrolidine, CH2Cl2, 23ꢁC, 8h;
(c) DIAD, Ph3P, PhCO2H, C6H6, 23ꢁC, 24h; (d) K2CO3, MeOH,
45ꢁC, 6h.
threo, respectively, by 1H/13C analysis of the corre-
Bromo-ester 4 was readily prepared (Scheme 2) from
2-butyn-1,4-diol (9) via mono-tosylation and copper-
catalyzed alkynylation15 with commercial methyl 5-
hexynoate (11). Semi-hydrogenation of the resultant
diyne 1016 over P-217 Ni/H2 and exchange of the alcohol
for bromide using PBr3 completed the synthesis of the
C(1)–C(10) moiety.
sponding 11,12-acetonides.21
Thionocarbamoylation12 of 8 furnished chiral stannane
18, the C(1)-epimer of 3, which was then carried through
the sequence in Scheme 3 in comparable yields to give
methyl 11(R),12(S),15(S)-THETA (19) and 11(R),12(R),
15(S)-THETA (20) (Scheme 4).20
Copper mediated cross-coupling11 of chiral stannane 3
with bromide 4 smoothly generated ester 12 with reten-
tion of configuration at the C(11)-stereocenter (Scheme
3). Mild acidic hydrolysis of the acetonide and low tem-
perature sodium periodate cleavage of the liberated diol
transformed 12 into aldehyde 13. Subsequent Nozaki-
Kishi addition18 of vinyl iodide 219 provided a mixture
(7:3) of diastereomeric triols 14 and 16, which was most
conveniently separated chromatographically at a later
stage.20 Concomitant cleavage of the thionocarba-
mate,12 silyl ether, and methyl ester protecting groups
by basic hydrogen peroxide and re-esterification with
diazomethane afforded the methyl esters of 11(S),
12(R),15(S)-THETA (15) and 11(S),12(S),15(S)-THE-
TA (17), respectively, in good yield. The relative stereo-
chemistries of 15 and 17 were confirmed as erythro and
Saponification (LiOH, THF/H2O, 23ꢁC, 6–10h, 90–
95%) of 15, 17, 19, and 20 and extractive isolation fur-
nished the corresponding free acids as colorless oils.
Of the four stereoisomers, only 11(R),12(S),15(S)-THE-
TA (19) was identical with natural material by normal
and reverse-phase HPLC, GC/MS, and in vitro bio-
assay.8
In conclusion, we describe the first synthesis of all four
stereoisomers of 1 and validate novel methodology for
creating carbon–carbon bonds at heteroatom-substi-
tuted chiral centers and for the orthogonal protection/
deprotection of alcohols using thionocarbamate protec-
tive groups. The results of ongoing studies of the phys-
iological significance of this new class of vasorelaxants
will be reported elsewhere.
a,b
c,d
HO
OH
HO
CO2Me
4
76%
96%
9
10
Scheme 2. Reagents and conditions: (a) TsCl, Py, CH2Cl2, 1h, 0ꢁC, 85%; (b) 11, NaI, CuI, K2CO3, DMF, ꢀ20ꢁC, 2h; 23ꢁC, 12h, 89%; (c) Ni (P-2),
H2 (1atm), EtOH, 23ꢁC, 12h, 98%; (d) PBr3, Et2O, 0ꢁC, 1h, 95%.
CO2Me
a
b,c
+
3
4
89%
81%
O
N
O
d
O
12
S
CO2Me
CO2Me
82%
CHO
N
S
R1O
1
R3
OR4
2
R2
O
13
3
4
14: R = C H NC(S), R = OH, R = H, R = TB DMS
4
3
8
e (85%)
e (85%)
1
4
2
15: R = R = R = H, R = OH
1
2
3
4
16: R = C H NC(S), R = H, R = OH, R = TB DMS
4
2
8
1
4
3
17: R = R = R = H, R = OH
Scheme 3. Reagents and conditions: (a) CuCN (7mol%), THF, 50ꢁC, 4h; (b) 80% aq HOAc, 23ꢁC, 12h, 95%; (c) NaIO4, THF/H2O (3:1), ꢀ10ꢁC,
1h, 85%; (d) 2, NiCl2 (cat)/CrCl2, DMF, 23ꢁC, 12h, 82%; (e) H2O2, NaOH, MeOH, 23ꢁC, 10h; CH2N2, 85%.

J. R. Falck et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4987–4990
4989
for C25H42O4Sn: C, 57.16; H, 8.06. Found: C, 57.30; H,
8.29. 8: 1H NMR (CDCl3, 400MHz) d 0.89–0.97 (m, 15H),
1.30–1.36 (m, 6H), 1.37 (s, 3H), 1.44 (s, 3H), 1.48–1.55 (m,
6H), 1.82 (d, 1H, J = 6.7Hz), 3.75 (t, 1H, J = 7.30Hz),
3.91–3.96 (m, 2H), 4.39 (q, 1H, J = 6.4Hz); 13C NMR
(CDCl3, 75MHz) d 9.11, 13.84, 25.82, 26.55, 27.59, 29.26,
65.36, 65.58, 81.18, 108.89. 12: 1H NMR (CDCl3,
400MHz) d 1.36 (s, 3H), 1.46 (s, 3H), 1.61–1.73 (m, 2H),
1.90–1.98 (m, 4H), 2.05–2.12 (m, 2H), 2.28–2.34 (m, 2H),
2.38–2.61 (m, 2H), 2.79 (apparent t, 2H, J = 6.4Hz),
3.49–3.63 (m, 2H), 3.62 (s, 3H), 3.66–3.67 (m, 3H), 3.70–
3.75 (m, 2H), 3.90–4.20 (m, 2H), 4.26–4.36 (m, 1H),
5.01–5.15 (m, 1H), 5.34–5.50 (m, 2H), 5.60–5.72 (m, 1H),
5.81–5.83 (m, 1H); Anal. Calcd for C22H35NO5S: C, 62.09;
Acknowledgements
The authors express their appreciation to Dr. Raymond
E. Conrow for critically reviewing the manuscript.
Nancy Spitzbarth and Erik Edwards are thanked for
expert technical assistance. Financial support provided
by the Robert A. Welch Foundation, NIH (GM
31278, DK38226, HL-37981).
References and notes
1
1. Lind, L. Lipids 2002, 37, 1–15.
H, 8.29. Found: C, 62.16; H, 8.10. 13: H NMR (CDCl3,
2. (a) Moncada, S.; Gryglewski, R.; Bunting, S.; Vane, J. R.
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9265–9269.
4. Campbell, W. B.; Gebremedhin, D.; Pratt, P. F.; Harder,
D. R. Circ. Res. 1996, 78, 415–423.
5. Yanagisawa, M.; Kuihara, H.; Kimura, S.; Tomobe, Y.;
Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, Y. K.;
Masaki, T. Nature 1988, 332, 411–415.
6. (a) Pace-Asciak, C. R.; Reynaud, D.; Demin, P.; Nigam,
S. Adv. Exp. Med. Biol. 1999, 447, 123–132; (6) Narumiya,
S.; Salmon, J. A.; Cottee, F. H.; Weatherley, B. C.;
Flower, R. J. J. Biol. Chem. 1981, 256, 9583–9592.
7. Pfister, S. L.; Spitzbarth, N.; Zeldin, D. C.; Lafite, P.;
Mansuy, D.; Campbell, W. B. Arch. Biochem. Biophys.
2003, 420, 142–152.
8. Pfister, S. L.; Spitzbarth, N.; Nithipatikom, K.; Edge-
mond, W. S.; Falck, J. R.; Campbell, W. B. J. Biol. Chem.
1998, 273, 30879–30887.
9. Campbell, W. B.; Spitzbarth, N.; Gauthier, K. M.; Pfister,
S. L. Am. J. Physiol. 2003, 285, H2648–H2656.
10. Tang, X.; Spitzbarth, N.; Kuhn, H.; Chaitidis, P.; Camp-
bell, W. B. Arterioscler. Throm. Vasc. Biol. 2003, 23,
1768–1774.
11. Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.;
Capdevila, J. H.; Falck, J. R. Org. Lett. 2003, 5,
4759–4762.
400MHz) d 1.60–1.70 (m, 2H), 1.84–2.00 (m, 4H), 2.01–
2.10 (m, 2H), 2.20–2.32 (m, 2H), 2.50–2.65 (m, 2H), 2.78
(apparent t, 2H, J = 6.4Hz), 3.47 (t, 2H, J = 6.9Hz), 3.55–
3.62 (m, 2H), 3.81 (s, 3H), 4.04 (m, 1H), 5.33–5.55 (m,
4H), 9.67 (d, 1H, J = 1.5Hz); HRMS (CI, CH4) calcd for
C18H28NO4S: 354.1739 (M+H)+, found 354.1734. 15:
TLC: Rfꢂ0.25 (80% EtOAc/hexane); 1H NMR (CDCl3,
400MHz) d 0.89 (t, 3H, J = 6.0Hz), 1.20–1.42 (m, 6H),
1.43–1.60 (m, 2H), 1.61–1.80 (m, 2H), 2.00–2.40 (m, 6H),
2.70–2.90 (m, 2H), 3.61 (s, 3H), 3.62–3.70 (m, 1H),
4.05–4.14 (m, 2H), 5.26–5.42 (m, 3H), 5.43–5.52 (m,
1H), 5.77 (dd, J = 6, 16Hz, 1H), 5.85 (dd, J = 4.8, 16Hz,
1H); 13C NMR (CDCl3, 75MHz) d 14.25, 22,81, 24.92,
25.36, 26.03, 26.78, 31.79, 31.94, 33.61, 37.38, 51.82, 72.59,
74.16, 74.70, 125.50, 128.52, 128.75, 129.30, 131.37,
23
136.86, 174.56; ½aꢁD 2.66 (c 0.45, CHCl3); HRMS (CI,
CH4) calcd for C21H37O5: 369.2641 (M+H)+, found
369.2639. 17: TLC: Rfꢂ0.27 (80% EtOAc/hexane); 1H
NMR (CDCl3, 400MHz) d 0.89 (t, 3H, J = 8.8Hz),
1.20–1.42 (m, 6H), 1.43–1.60 (m, 2H), 1.61–1.80 (m,
2H), 2.00–2.18 (m, 2H), 2.20–2.40 (m, 4H), 2.80 (apparent
t, 2H, J = 6.4Hz), 3.53 (br s, 1H), 3.67 (s, 3H), 4.02 (br
s, 1H), 4.10–4.20 (m, 1H), 5.30–5.60 (m, 4H), 5.73 (dd,
J = 6, 16Hz, 1H), 5.85 (dd, J = 6, 16Hz, 1H); 13C NMR
(CDCl3, 75MHz) d 14.25, 22.81, 24.91, 25.30, 26.01,
26.03, 31.42, 31.95, 33.60, 37.43, 51.81, 72.32, 74.32,
74.79, 125.25, 128.78, 129.33, 129.67, 131.56, 136.71,
23
175.89; ½aꢁD ꢀ8.5 (c 0.2, CHCl3); HRMS (CI, CH4) calcd
for C21H37O5 (M+H)+ m/z 369.2641, found 369.2641. 18:
1H NMR (CDCl3, 400MHz) d 0.80–1.00 (m, 15H),
1.27–1.35 (m, 9H), 1.42 (s, 3H), 1.48–1.56 (m, 6H),
1.90–2.01 (m, 4H), 3.47–3.64 (m, 2H), 3.70–3.74 (m,
3H), 3.90–3.94 (m, 1H), 4.38–4.42 (m, 1H), 5.73–5.79 (m,
1H); 13C NMR (CDCl3, 75MHz) d 10.87, 13.78, 24.66,
25.20, 25.84, 26.64, 27.52, 29.10, 47.77, 52.13, 65.08, 76.65,
79.10, 108.13, 185.51; HRMS (CI, CH4) calcd for
C19H37NO3SSn: 479.1516 (M+HꢀBu)+, found 479.1520.
19: TLC: Rfꢂ0.20 (80% EtOAc/hexane); 1H NMR
(CDCl3, 400MHz) d 0.89 (t, 3H, J = 6.3Hz), 1.21–1.41
(m, 4H), 1.45–1.60 (m, 2H), 1.62–1.78 (m, 2H), 2.02–2.18
(m, 2H), 2.20–2.40 (m, 6H), 2.72–2.85 (m, 2H), 3.68 (s,
3H), 3.69–3.74 (m, 1H), 4.12–4.20 (m, 2H), 5.32–5.60 (m,
4H), 5.74 (dd, J = 5.6, 16Hz, 1H), 5.82 (dd, J = 5.2, 16Hz,
1H); 13C NMR (CDCl3, 75MHz) d 14.23, 22,79, 24.89,
25.33, 26.00, 26.73, 30.39, 31.95, 33.57, 37.35, 51.80, 72.18,
74.28, 74.84, 126.62, 128.26, 128.81, 129.23, 131.11,
12. Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.;
Falck, J. R. Org. Lett. 2003, 5, 4755–4757.
13. Spectral and physical data for 3: 1H NMR (CDCl3,
400MHz) d 0.80–1.00 (m, 15H), 1.27–1.35 (m, 9H), 1.42
(s, 3H), 1.48–1.56 (m, 6H), 1.90–2.01 (m, 4H), 3.47–3.64
(m, 2H), 3.70–3.74 (m, 3H), 3.90–3.94 (m, 1H), 4.38–4.42
(m, 1H), 5.73–5.79 (m, 1H); 13C NMR (CDCl3, 75MHz) d
10.87, 13.78, 24.66, 25.20, 25.84, 26.64, 27.52, 29.10, 47.77,
52.13, 65.08, 76.65, 79.10, 108.13, 185.51; HRMS (CI,
CH4) calcd for C19H37NO3SSn: 479.1516 (M+HꢀBu)+,
1
found 479.1512. 4: H NMR (CDCl3, 300MHz) d 1.60–
1.77 (m, 2H), 2.02–2.18 (m, 2H), 2.34 (t, 2H, J = 7.8Hz),
2.88 (apparent t, 2H, J = 6.4Hz), 3.67 (s, 3H), 4.02 (d,
2H, J = 9.0Hz), 5.40–5.82 (m, 4H); Anal. Calcd for
C11H17BrO2: C, 50.59; H, 6.56. Found: C, 50.68; H,
6.62. 6: 1H NMR (CDCl3, 300MHz) d 0.87–0.96 (m, 15H),
1.28–1.35 (m, 6H), 1.39 (s, 3H), 1.43 (s, 3H), 1.48–1.54 (m,
6H), 1.99–2.01 (m, 1H), 3.83–3.88 (m, 1H), 3.92–3.97 (m,
23
136.79, 174.57; ½aꢁD 7.24 (c 1.68, CHCl3); HRMS (CI,
CH4) calcd for C21H37O5: 369.2641 (M+H)+, found
369.2643. 20: TLC: Rfꢂ0.23 (80% EtOAc/hexane); 1H
NMR (CDCl3, 400MHz) d 0.89 (t, 3H, J = 8.80Hz),
1.20–1.41 (m, 6H), 1.42–1.60 (m, 2H), 1.61–1.80 (m, 2H),
2.02–2.18 (m, 2H), 2.23–2.40 (m, 4H), 2.80 (t, 2H,
J = 6.4Hz), 3.55 (m, 1H), 3.68 (s, 3H), 4.02 (br s, 1H),
4.10–4.20 (m, 1H), 5.32–5.60 (m, 4H), 5.73 (dd, J = 6,
23
1H), 4.19–4.21 (m, 1H), 4.30–4.36 (m, 1H); ½aꢁD 11.9 (c
1
1.65, CHCl3). 7: H NMR (CDCl3, 400MHz) d 0.85–0.98
(m, 15H), 1.21–1.62 (m, 18H), 3.77 (t, 1H, J = 7.9Hz), 3.97
(t, 1H, J = 6.4Hz), 4.41–4.49 (m, 1H), 5.12–5.21 (m, 1H),
7.40–7.58 (m, 3H), 8.04 (d, 2H, J = 7.6Hz); Anal. Calcd

4990
J. R. Falck et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4987–4990
16Hz, 1H), 5.85 (dd, J = 6, 16Hz, 1H); 13C NMR (CDCl3,
18. Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem.
Soc. 1986, 108, 5644–5646.
75MHz) d 14.25, 22,81, 24.93, 25.34, 25.99, 26.77, 31.37,
31.94, 33.61, 37.31, 51.81, 72.59, 74.22, 74.57, 125.33,
19. Davies, J.; Roberts, S. M.; Reynolds, D. P.; Newton, R. F.
J. Chem. Soc., Perkin Trans. 1 1981, 1317–1320.
20. In practice, the Nozaki-Kishi adducts were most conven-
iently separated after removal of the alcohol protecting
groups by NP-HPLC using Microsorb silica
23
128.80, 129.28, 130.40, 131.36, 136.39, 174.54; ½aꢁD 21.9 (c
0.8, CHCl3); HRMS (CI, CH4) calcd for C21H37O5:
369.2641 (M+H)+, found 369.2643.
14. Ermolenko, L.; Sasaki, N. A.; Potier, P. Synlett 2001,
1565–1566.
15. Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
New York, 1998; pp 203–229.
(10 · 250mm), 6%
i PrOH/0.1% HOAc/hexane, UV
215nm: Rf of 15 = 17min, Rf of 17 = 19min, Rf of
19 = 25min, Rf of 20 = 27min.
21. The spectral values for the acetonide of 15 (1H NMR:
J11,12 = 6.0Hz, 13C NMR: d 78.4, 79.0) and the acetonide
of 17 (1H NMR: J11,12 = 7.9Hz, 13C NMR: d 80.7, 81.6)
are consistent with literature erythro- and threo-diol data,
respectively. See: Kato, T.; Hirukawa, T.; Yano, M. Bull.
Chem. Soc. Jpn. 1994, 67, 839–842.
16. Dasse, O.; Mahadevan, A.; Han, L.; Martin, B. R.;
Marzo, V. D.; Razdan, R. K. Tetrahedron 2000, 56,
9195–9202.
17. Brown, C. A.; Ahuja, V. K. Chem. Commun. 1973, 15,
553–554.