Chiral cyclopropanes: Asymmetric synthesis of constanolactones A and B

Article abstract of DOI:10.1016/S0040-4039(02)00699-8

The title marine eicosanoids were prepared using a novel, stereoselective bis-annulation to create the characteristic cyclopropane-δ-lactone motif.

Full text of DOI:10.1016/S0040-4039(02)00699-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3939–3941
Chiral cyclopropanes: asymmetric synthesis of
constanolactones A and B
Jurong Yu,a Jing-Yu Lai,a Jianhua Ye,a Narayanan Balu,a L. Manmohan Reddy,a Wenhu Duan,a
Elaine R. Fogel,a Jorge H. Capdevilab and J. R. Falcka,*
aDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
TX 75390, USA
bDepartments of Medicine and Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Received 8 March 2002; accepted 27 March 2002
Abstract—The title marine eicosanoids were prepared using a novel, stereoselective bis-annulation to create the characteristic
cyclopropane-d-lactone motif. © 2002 Elsevier Science Ltd. All rights reserved.
Constanolactones A (1) and B (2) were isolated1 by
Nagle and Gerwick in 1990 from the temperate red alga
Constantinea simplex where together they accounted for
3–4% of the organic extractable lipids.2 In common
with a few other marine fatty acid metabolites,3–5 1 and
2 incorporate a characteristic cyclopropane–lactone
motif as well as intriguing biological activities that have
provoked considerable synthetic interest.6–8 To expedite
current pharmaceutical evaluations of this family, we
describe herein a convergent, asymmetric total synthesis
of 1 and 2. The key transformations in our strategy
exploit (i) introduction of a one-carbon unit by dehy-
drative alkylation;9 (ii) a stereospecific, one-pot bis-
annulation to create the cyclopropane-d-lactone
substructure;10 and (iii) a b-oxido ylide homologation.11
The synthesis commenced with the addition of the
lithium salt of 6-(tert-butyldiphenylsilyloxy)hexyne12
(11) to the readily available chiral aldehyde13 3, provid-
ing a chromatographically separable mixture (45:55) of
alcohols 4 and 6 (Scheme 1).14,15 The undesired isomer,
4, was inverted to 6 via Mitsunobu adduct 5 and
saponification. Dehydrative alkylation9 of
6 with
bis(phenylsulphonyl)methane proceeded with inversion
of configuration and served to introduce the C(7)-cyclo-
propyl methylene.16 To set the stage for the bis-annula-
tion, the bis-sulphonyl adduct was uneventfully
converted to carboxylic acid 7 by sequential chromi-
um(II) reduction of the acetylene,17 fluoride mediated
desilylation, and PDC oxidation. Exposure of 7 to
iodine and NaH in refluxing THF smoothly generated
cyclopropyl-d-lactone 8 as the sole product.18
chiral pool
biomimetic
annulations
R1
R2
O
Following desulphonylation of 8 using magnesium9 in
aqueous THF, the resultant seco-acid was utilized to
adjust the C(5)-stereochemistry via intramolecular Mit-
sunobu inversion. Acetonide hydrolysis then led to
diol-9. Primary selective tosylation of 9 and displace-
ment with Ph3P furnished the corresponding b-hydroxy
phosphonium salt which was converted to its b-oxido
ylide using 2 equiv. of base at low temperature.11
Subsequent condensation with 2(S)-(4-methoxybenzyl-
oxy)-4(Z)-decenal19 (12) afforded 10 embodying the
complete carbon framework of the constanolactones.
Mild MPM cleavage of 10 using Cr(II)/LiI20 evolved
constanolactone B (2). Alternatively, 10 gave rise to
constanolactone A (1) via sequential Mitsunobu inver-
sion of the C(9)-alcohol, saponification with subsequent
re-lactonization upon acidification, and Cr(II)/LiI de-
H
O
9
8
β-oxido
ylide
H
one-carbon
unit
H
12
HO
C5H11
Constanolactones A/B
1: R1 = OH, R2 = H
2: R1 = H, R2 = OH
Keywords: annulation; eicosanoid; cyclopropanes; stereocontrol; nat-
ural products.
* Corresponding author. Tel.: 214-648-2406; fax: 214-648-6455;
e-mail: j.falck@utsouthwestern.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00699-8

3940
J. Yu et al. / Tetrahedron Letters 43 (2002) 3939–3941
O
H
a
d-g
O
H
O
OSitBuPh2
4: R1 = H, R2 = OH
84%
O
41%
CHO
R1 R2
3
b
88%
c
92%
5: R1 = PhCO2, R2 = H
6: R1 = OH, R2 = H
O
H
O
O
H
H
i,j,k
53%
O
h
80%
O
O
CO2H
H
PhO2S SO2Ph
PhO2S SO2Ph
7
8
HO
H
O
H
HO
H
O
O
H
p,q,o
57%
l,m,n
29%
HO
O
1
H
H
H
MPMO
C5H11
9
10
2
o
85%
MPM = 4-MeOC6H4CH2-
Scheme 1. Reagents and conditions: (a) acetylene 11, n-BuLi, THF, −78°C, 1 h; add 3, −78°C, 3 h, then rt, 2 h. (b) PhCO2H,
PPh3/DEAD, C6H6, 23°C, 12 h. (c) NaOH, MeOH, 23°C, 12 h. (d) (PhO2S)2CH2, PPh3/DEAD, C6H6, 23°C, 3 h. (e) CrSO4,
DMF/H2O, 23°C, 2 h. (f) n-Bu4NF, THF, 23°C, 18 h. (g) PDC, DMF, 23°C, 40 h. (h) NaH, I2, THF, 68°C, 44 h. (i) Mg, cat.
HgCl2, THF/H2O (2:1), 23°C, 12 h. (j) PPh3/DEAD, C6H6, 23°C, 7 h. (k) CF3CO2H, THF/H2O (4:1), 40°C, 10 h. (l) TsCl, py,
4°C, 36 h. (m) Ph3P, CH3CN, 80°C, 40 h. (n) Wittig salt, sec-BuLi (2 equiv.), THF, −78°C, 1.5 h; add 12, −78 to −20°C, 2 h. (o)
CrCl2/LiI, moist EtOAc, 45°C, 2 h. (p) 4-(O2N)C6H4CO2H, PPh3/DEAD, C6H6, 23°C, 10 h. (q) NaOH, THF/H2O, 23°C, 15 h;
,
PhH, 4 A mol. sieves, 80°C, 5 h.
protection. The spectral and physical data for 1 and 2
were identical with published values.
5. Hybridalactone: Higgs, M. D.; Mulheirn, L. J. Tetra-
hedron 1981, 37, 4259–4262.
6. Constanolactone A/B total syntheses: (a) White, J. D.;
Jensen, M. S. J. Am. Chem. Soc. 1995, 117, 6224–6233;
(b) Miyaoka, H.; Shigemoto, T.; Yamada, Y. Tetra-
hedron Lett. 1996, 37, 7407–7408; (c) Silva, C. B.-D.;
Benkouider, A.; Pale, P. Tetrahedron Lett. 2000, 41,
3077–3081.
7. Constanolactone E total syntheses: (a) Miyaoka, H.;
Shigemoto, T.; Yamada, Y. Tetrahedron Lett. 1996, 37,
7407–7408; (b) Miyaoka, H.; Shigemoto, T.; Yamada, Y.
Heterocycles 1998, 47, 415–428.
8. Synthetic approaches to constanolactones and related
eicosanoids: (a) Nagasawa, T.; Onoguchi, Y.; Mat-
sumoto, T.; Suzuki, K. Synlett 1995, 1023–1024; (b)
Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetra-
hedron Lett. 1998, 39, 5667–5670; (c) Baba, Y.; Saha, G.;
Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.;
Takemoto, Y. J. Org. Chem. 2001, 66, 81–88; (d) Da
Silva, C. B.; Pale, P. Tetrahedron: Asymmetry 1998, 9,
3951–3954; (e) White, J. D.; Jensen, M. S. J. Am. Chem.
Soc. 1993, 115, 2970–2971.
Acknowledgements
Professor William Gerwick (Oregon State Univ.) and
Professor James D. White (Oregon State Univ.) are
thanked for generously providing extensive spectral
data of natural and synthetic material. Financial sup-
port provided by the Robert A. Welch Foundation and
NIH (GM31278, GM37922).
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1H, J=3.3, 9.9, 9.9 Hz), 4.73 (ddd, 1H, J=9.2, 4.4, 6.0
Hz), 4.06 (dd, 1H, J=9.1, 6.0 Hz), 3.59 (dd, 1H, J=4.4,
9.1 Hz), 3.06 (dd, 1H, J=9.5, 9.5 Hz), 2.67 (dd, 1H,
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134.60, 134.37, 128.59, 128.87, 110.10, 75.83, 73.31, 68.80,
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0.75 (m, 1H), 1.60–2.08 (m, 4H), 2.25–2.36 (m, 2H), 3.19
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1
3H), 1.37 (s, 3H), 1.04 (s, 9H). 6: H NMR (250 MHz,
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4.31 (m, 1H), 4.04–4.16 (m, 2H), 3.83–3.89 (m, 1H), 3.66
(t, 2H, J=5.9 Hz), 2.31 (d, 1H, J=4.2 Hz), 2.20–2.25 (m,
2H), 1.57–1.60 (m, 4H), 1.45 (s, 3H), 1.37 (s, 3H), 1.05 (s,
9H); 13C NMR: l 135.54, 133.92, 129.56, 127.61, 110.37,
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24.93, 19.21, 18.47. 7: 1H NMR (250 MHz, CDCl3) l
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5.70 (dd, 1H, J=10.6 Hz), 5.58 (dt, 1H, J=11.1, 7.2 Hz),
4.71 (d, 1H, J=2.4 Hz), 4.56 (dt, J=6.5 Hz), 4.11 (dd,
1H, J=6.4, 8.5 Hz), 3.91 (dd, 1H, J=6.4, 8.5 Hz), 3.75
(ddd, 1H, J=2.2, 7.0, 10.8 Hz), 2.37 (t, 2H, J=7.5 Hz),
2.08 (quintet, 2H, J=7.2 Hz), 1.72 (q, 2H, J=7.4 Hz),
1.33 (s, 3H), 1.32 (s, 3H); 13C NMR: l 178.33, 140.14,
138.64, 134.85, 134.33, 129.35, 129.15, 123.50, 109.45,
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the only stereoisomer, albeit in much lower yield (40–
45%). In this case the presumed C(5)-iodo intermediate
could be isolated (80%) when the annulation was con-
ducted at room temperature. When the cyclopropyl-
iodide was warmed with base, it was completely
converted to trans-7. This suggests that cis-7 leads to an
intermediate that preferentially undergoes in situ E2-elim-
ination to trans-7 which is the ultimate source of 8.
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