Application of asymmetric ylide cyclopropanation in the total synthesis of halicholactone

Article abstract of DOI:10.1002/chem.200901685

A study was conducted to demonstrate the application of asymmetric ylide cyclopropanation in the total synthesis of halicholactone. The synthesis of the intermediate started with the enantioselective cyclopropanation of acrylate with the ylide derived fro

Full text of DOI:10.1002/chem.200901685

COMMUNICATION
DOI: 10.1002/chem.200901685
Application of Asymmetric Ylide Cyclopropanation in the Total Synthesis of
Halicholactone
Chun-Yin Zhu,[a] Xiao-Yu Cao,[b] Ben-Hu Zhu,[c] Chao Deng,[a] Xiu-Li Sun,[a]
Bi-Qin Wang,[b] Qi Shen,[c] and Yong Tang*[a]
Halicholactone belongs to a family of oxylipins that have
important and interesting biological activities, such as inhib-
iting lipoxygenase and farnesyl protein transferase. These
compounds are featured unique molecular structures con-
taining a 1,2-trans-substituted cyclopropane subunit with a
6-, 8- or 9-membered lactone (Figure 1).[1] The first total
synthesis of halicholactone 1 was accomplished by Wills et
al. using (S)-malic acid as the starting material.[2a] In their
synthesis, the cyclopropane fragment was obtained by the
reaction of the unsaturated ester with Corey ylide; the lac-
tone unit was constructed by Yamaguchiꢀs mixed anhydride
method. Later, Takemoto, Tanaka,[2c] and their co-workers
reported an asymmetric total synthesis of halicholactone 1
from chiral [(diene)Fe(CO)3], in which the cyclopropane
fragment was prepared in moderate yields with excellent
diastereoselectivity by the modified Simmons–Smith reac-
tion of a chiral allylic alcohol. Kitahara[2d] documented a
total synthesis of halicholactone by using (1S,5S,6R)-5-
isopropylidene glyceraldehyde as a chiral pool building
block.[2e] In our studies on ylide chemistry in organic synthe-
sis,[3] we developed an efficient method for the preparation
of vinylcyclopropanes from a readily available d-camphor-
derived ylide.[3c,e] In this cyclopropanation,[3c,e] excellent dia-
stereoselectivity (cis/trans) and enantioselectivity can be
achieved. Very recently, we found that this cyclopropanation
could be applied successfully to the preparation of inter-
mediate 13 in five steps to provide a formal synthesis of hal-
icholactone. In this communication, we wish to report our
results as well as the total synthesis of halicholactone in
detail.
hydroxybicycloACHTUNGTRENNUNG[4.1.0]-heptan-2-one as a chiral building
block. Dattaꢀs group[2b] described a 12-step synthesis of com-
pound 29 by employing the cyclopropanation of trans-cin-
namyl alcohol through Charetteꢀs protocol, finishing the
formal synthesis of halicholactone. Mohapatra et al. also re-
ported the total synthesis of halicholactone with (R)-2,3-O-
[a] Dr. C.-Y. Zhu, C. Deng, Dr. X.-L. Sun, Prof. Y. Tang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
345 Lingling Lu, Shanghai 200032 (PR China)
Fax : (+86)21-54925078
Figure 1. Halicholactone and related compounds (where X=CH2=CH2
the double bond has Z configuration).
E-mail: tangy@mail.sioc.ac.cn
[b] X.-Y. Cao, Prof. B.-Q. Wang
College of Chemistry and Material Sciences
Sichuan Normal University, Chengdu
Sichuan 410066 (PR China)
Our retrosynthetic approach is shown in Scheme 1. Dis-
À
connecting the C12 C13 bond will afford two fragments 13
[c] B.-H. Zhu, Prof. Q. Shen
and 14. Compound 14 is accessible from (R)-(+)-1-octyn-3-
ol.[2a] Fragment 13 can be obtained by the ring-closing meta-
thesis reaction of compound 15, which would be prepared
by the reaction of 5-hexenoic acid 16 with cyclopropane
School of Chemistry and Chemical Engineering
Suzhou University, Suzhou 215123 (PR China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901685.
Chem. Eur. J. 2009, 15, 11465 – 11468
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11465

Scheme 2. Mechanism of cyclopropanation.
Scheme 1. Retrosynthetic approach to Halicholactone.
tions within 2 h. By employing this method, the yield was
improved to 72% when the scale was increased to 4.8 mmol
at a concentration of 0.1m (entry 4, Table 1). Under the op-
timal conditions, the desired compound 19b was synthesized
in 76% yield with 97% ee and excellent diastereoselectivity
(dr >99:1) (Scheme 3).
piece 17. The trans-disubstituted cyclopropane 19 should be
synthesized by an asymmetric ylide cyclopropanation devel-
oped by our group.[3c]
The synthesis of fragment 13[2a] started with the enantiose-
lective cyclopropanation of acrylate with the ylide derived
from sulfonium salt 20.[3c] Initially, we tried the cyclopropa-
nation of methyl acrylate on a much larger scale at much
higher concentration of sulfonium salt than that in our pre-
vious reports.[3c,e] As shown in Table 1, unfortunately, only a
Table 1. Ylide cyclopropanation.[a]
Scheme 3. Synthesis of cyclopropane 18.
Entry
c of 20 [molLÀ1] ([mmol])
21a [equiv]
Yield [%]
1
2
0.21 (4.2)
0.25 (0.5)
0.01 (2)
0.1 (4.8)
0.1 (10)
4
4
8
8
8
trace[b]
31
63
72
65
3[c]
4[c]
5[c]
With the cyclopropane 19b in hand, we first tried its oxi-
dation into the corresponding aldehyde 18 with NaIO4 in
the presence of catalytic OsO4. As shown in Scheme 3, the
reaction proceeded very smoothly affording the desired al-
dehyde in up to 97% yield. The allylation of 18 was tested
with Roush reagent[4] 26, but the reaction proceeded very
slowly. Only 25% of 18 was converted even after 18 h at
À788C and a further 47 h at 08C. In addition, the diastereo-
meric ratio was 1:1, probably due to the steric hindrance of
the cyclopropane moiety. We were very pleased to find that
aldehyde 18 reacted smoothly with allyl bromide in the pres-
ence of zinc powder in a mixed solvent of saturated aqueous
ammonium chloride and THF,[5] giving alcohol 17a–b in
very high yields. Although the diastereoselectivity remained
poor, the two diastereoisomers 17a and 17b were separated
readily by flash chromatography on silica gel. In addition,
isomer 17b could easily be transformed into the desired
isomer 17a in nearly quantitative yield by the Mitsunobu
[a] Reaction conditions: À788C, KOtBu (3.0 equiv), THF as a solvent.
[b] 2,3-Sigma rearrangement product was isolated. [c] tBuOK was added
in 7–10 portions over 2 h.
trace amount of the desired product was obtained (entry 1).
In this case, the 2,3-sigma rearrangement of the ylide was
obtained as the major product. The probable reason is that
the increasing concentration of the sulfonium salt decreased
the molar ratio of acrylate 21a to ylide 22; this would favor
the rearrangement reaction (Scheme 2). On the basis of the
aforementioned analysis, we assumed that the addition of
base in portions would lower the concentration of the ylide,
thus improving the cyclopropanation. As expected, the yield
was increased to 63% when KOtBu was added in 7–10 por-
11466
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11465 – 11468

Asymmetric Ylide Cyclopropanation
COMMUNICATION
protocol.[6] Condensation of 17a with 5-hexenoic acid 16 in
CH2Cl2 in the presence of dicyclocarbodiimide (DCC) and
DMAP afforded compound 15 in 99% yield (Scheme 4).
the acid with methyl chloroformate in the presence of tri-
AHCTUNGTREGeNNNU thylamine. After removal of triethylamine hydrochloride
by filtration, the mixed anhydride was reduced with sodium
borohydride affording a primary alcohol. Aldehyde 29 was
obtained by oxidation of the alcohol with Dess–Martin per-
AHCTUNGTRENNUNG
iodinane (DMP)[9] (Scheme 6).
Scheme 6. Synthesis of aldehyde 29.
Since the diastereoselectivity of the coupling reaction of
aldehyde 30 with (3S)-(1E,5Z)-3-O-[(tert-butyldiphenylsilyl)-
oxy]-1-iodo-1,5-octadiene was poor (nearly 1:2) in the Willsꢀ
synthesis,[2a] we tried to improve the selectivity by asymmet-
ric addition of alkyne 14 with aldehyde 29, followed by re-
À
duction reaction of the carbon carbon triple bond as shown
in Scheme 7. Unfortunately, the enantioselective alkynyla-
tion of aldehyde 29 catalyzed by a chiral amino alcohol-
based ligand,[10] developed by Jiang, did not work probably
due to the steric hindrance of the cyclopropane moiety. It
was found that the coupling reaction of aldehyde 29 with
the lithium salt of alkyne 14 proceeded readily, affording al-
kynol 30 in good yields with a diastereomeric ratio of 2.6 to
1 (Scheme 7), in which the major one is the desired product.
The transformation of 30 to 31 was accomplished by a CrII-
Scheme 4. Synthesis of 17 and 15.
Using 1st generation Grubbs catalyst 27[7] as the catalyst,
ring-closing metathesis of 15 proceeded smoothly in the
presence of catalytic amount of [TiACTHNUTRGNEUNG
(OiPr)4][2c,d] giving 13 in
63% yield as shown in Scheme 5. Attempts to further im-
prove the yield by employing the second generation
Grubbsꢀ catalyst 28[8] failed and only 9% yield was obtained.
Thus, the formal synthesis of halicholactone was accom-
plished in five steps in total up to 44.5% yield, much shorter
than the 12 steps reported in the literature.[2a] The 13C and
1H NMR spectra of 13 were consistent with those reported
by Wills et al.[2a]
Scheme 5. RCM reaction of 15 to give 13.
Following Willsꢀ protocol, the transformation of 13 to al-
dehyde 29 was accomplished in a total 61% yield for four
steps.[2a] This process involved the saponification of 13 into
the corresponding carboxylic acid, followed by treatment of
Scheme 7. Total synthesis of halicholactone.
Chem. Eur. J. 2009, 15, 11465 – 11468
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11467

Y. Tang et al.
promoted reduction[11] and the desired isomer 31a was iso-
lated easily by column chromatography on silica gel. TBAF-
mediated deprotection of the TBDPS group afforded hali-
cholactone 1 in 97% yield.
In summary, an enantioselective ylide cyclopropanation
has allowed facile access to the main fragment of halicholac-
tone, 13, with excellent enantioselectivity and diastereose-
lectivity in five steps, making the synthesis much more prac-
tical than those previously reported in the literature. Thus, a
total synthesis of halicholactone has been accomplished in
11.2% overall yield, providing the shortest synthetic route
thus far.
1.08 (m, 1H), 1.06–1.00 (m, 1H), 0.89 (t, J=7.2 Hz, 3H), 0.71 (ddd, J=
5.6, 5.6, 8.8 Hz, 1H), 0.60 ppm (ddd J=5.2, 5.2, 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 174.1, 134.6, 133.9, 131.6, 124.6, 76.2, 74.1, 72.2,
37.2, 33.8, 33.5, 31.7, 26.4, 25.2, 25.0, 23.4, 22.5, 19.4, 14.0, 8.2 ppm; IR
(film): n˜ = 3410 (br), 2928 (s), 2857 (s), 1738 (s), 1712 cmÀ1 (s); MS
(ESI): m/z: 359.1 [M+Na+]; HRMS (ESI): m/z: calcd for C20H32O4Na:
359.2206, found: 359.2193 [M+Na+].
Acknowledgements
We are grateful for the financial support from the Natural Sciences Foun-
dation of China (Grant No. 20821002 and 20672131), the Major State
Basic Research Development Program (Grant No. 2009CB825300), The
Chinese Academy of Sciences, and The Science and Technology Commis-
sion of Shanghai Municipality.
Experimental Section
Cyclopropanation of tert-butyl acrylate: To a stirred suspension of sulfo-
nium salt 20 (3.5 g, 9.0 mmol) and tert-butyl acrylate (5.8 g, 45 mmol) in
THF (150 mL) at À788C was added tBuOK (3.0 g, 27 mmol) in seven
portions over 2 h. After stirring for 4 h at À788C, the reaction mixture
was passed through a short silica gel column, which was eluted with ethyl
acetate. After concentration of the combined elution, the residue was pu-
rified by flash column chromatography on silica gel (petroleum ether/
EtOAc 50:1). Yield: 1.5 g (70%); 97% ee. When 0.9 g of salt 20 was used
(THF, 100 mL), 0.35 g (76%, 97% ee) of the product was obtained. The
ee cannot be determined by chiral HPLC and was determined based on
Keywords: cyclopropanation · halicholactone · ring-closing
metathesis · total synthesis · ylides
[1] a) H. Niwa, K. Wakamatsu, K. Yamada, Tetrahedron Lett. 1989, 30,
4543–4546; b) D. G. Nagle, W. H. Gerwick, Tetrahedron Lett. 1990,
31, 2995–2998; c) D. G. Nagle, W. H. Gerwick, J. Org. Chem. 1994,
59, 7227–7237; d) Y. Seo, K. W. Cho, J.-R. Rho, J. Shin, B.-M.
Kwon, S.-H. Bok, J.-I. Song, Tetrahedron 1996, 52, 10583–10596. For
structure revision of solandelactone E, F: J. E. Davoren, S. F.
Martin, J. Am. Chem. Soc. 2007, 129, 510–511.
[2] a) D. J. Critcher, S. Connolly, M. Wills, J. Org. Chem. 1997, 62,
6638–6657; b) D. K. Mohapatra, A. Datta, J. Org. Chem. 1998, 63,
642–646; c) Y. Baba, G. Saha, S. Nakao, C. Iwata, T. Tanaka, T.
Ibuka, H. Ohishi, Y. Takemoto, J. Org. Chem. 2001, 66, 81–88; d) T.
Takahashi, H. Watanabe, T. Kitahara, Heterocycles 2002, 58, 99–
104; e) D. K. Mohapatra, K. A. Durugkar, ARKIVOC 2004, 146–
155.
[3] For reviews: a) Y. Tang, S. Ye, X.-L. Sun, Synlett 2005, 2720–2730;
b) X.-L. Sun, Y. Tang, Acc. Chem. Res. 2008, 41, 937–948. For
recent examples: c) S. Ye, Z.-Z. Huang, C.-A. Xia, Y. Tang, L.-X.
Dai, J. Am. Chem. Soc. 2002, 124, 2432–2433; d) W.-W. Liao, K. Li,
Y. Tang, J. Am. Chem. Soc. 2003, 125, 13030–13031; e) X.-M. Deng,
P. Cai, S. Ye, X.-L. Sun, W.-W. Liao, K. Li, Y. Tang, Y.-D. Wu, L.-X.
Dai, J. Am. Chem. Soc. 2006, 128, 9730–9740; f) L.-W. Ye, X.-L.
Sun, Q.-G. Wang, Y. Tang, Angew. Chem. 2007, 119, 6055–6058;
Angew. Chem. Int. Ed. 2007, 46, 5951–5954; g) Q.-G. Wang, X.-M.
Deng, B.-H. Zhu, L.-W. Ye, X.-L. Sun, Y. Tang, J. Am. Chem. Soc.
2008, 130, 5408–5409.
the ee of 18. [a]2D0
CDCl3/TMS): d
=
À157.1 (c=1.00, CHCl3). 1H NMR (400 MHz,
=
5.78 (dd, J=0.4, 18.4 Hz, 1H), 5.49 (dd, J=8.4,
18.4 Hz, 1H), 2.00–1.94 (m, 1H), 1.60–1.56 (m, 1H), 1.44 (s, 9H), 1.32–
1.27 (m, 1H), 0.94–0.87 (m, 1H), 0.03 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d = 172.4, 146.1, 129.7, 80.3, 28.1, 27.5, 23.2, 15.6, À1.3 ppm; IR
(film): n˜ = 3452 (w), 3074 (w), 2955 (m), 2911(s), 1723 (s), 1634 (m),
1461 (w), 1353 (m), 1246 (w), 910 (m), 792 cmÀ1 (s); MS (EI): m/z (%):
240 (1.35) [M+], 75 (100.00); HRMS (EI): m/z: calcd for C13H24O2Si:
240.1546, found: 240.1556 [M+].
RCM reaction for the synthesis of compound 13: A solution of 15
(154 mg, 0.5 mmol) and freshly distilled [TiACTHNUTRGEN(UNG OiPr)4] (43 mg, 0.15 mol) in
dry CH2Cl2 (500 mL) was refluxed for 1.5 h under an nitrogen atmos-
phere. After the addition of first generation Grubbsꢀ catalyst (123 mg,
0.15 mol), the resulting solution was refluxed for 60 h. The mixture was
cooled to room temperature and then exposed to air with stirring for 4 h.
Silica gel (ca. 2 g) was added and the resulting mixture was stirred at
room temperature for 1 h, passed through a short silica gel column,
which was eluted with ethyl acetate. After concentration of the elution,
the residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc 15:1). Yield: 88 mg (63%); [a]2D0 = À87.7 (c=
1
1.20, CHCl3); H NMR (400 MHz, CDCl3/TMS): d = 5.49–5.45 (m, 2H),
4.27 (ddd, J=1.6, 7.2, 10.8 Hz, 1H), 2.55–2.46 (m, 2H), 2.37–2.29 (m,
1H), 2.27–2.23 (m, 1H), 2.18–2.13 (m, 1H), 2.09–2.04 (m, 2H), 1.82–1.72
(m, 1H), 1.67–1.60 (m, 2H), 1.45 (s, 9H), 1.18–1.13 (m, 1H), 0.86–
0.81 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d = 174.0, 172.6, 134.8,
124.3, 80.4, 74.6, 33.7, 33.5, 28.1, 26.4, 25.2, 24.5, 19.5, 12.5 ppm; IR
(film): n˜ = 3081 (w), 2978 (m), 2919 (m),1719 (s), 1638 (w), 1457 (w),
1368 (m), 1151 (s), 1087 (w), 999 (w), 917 (m), 803 cmÀ1 (m); MS (ESI):
m/z (%): 303.1 [M++Na]; HRMS (EI): m/z: calcd for C16H24O4:
280.1675, found: 280.1674 [M+].
[4] W. R. Roush, K. Ando, L. K. Hoong, J. Am. Chem. Soc. 1985, 107,
8186–8190.
[5] P. Barbier, C. R. Acad. Sci. 1899, 110.
[6] O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380–
2382.
[7] a) G. C. Fu, R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 5426–5427;
b) G. C. Fu, R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 7324–7325;
c) R. H. Grubbs, J. S. Miller, G. C. Fu, Acc. Chem. Res. 1995, 28,
446–452.
Halicholactone (1): To a solution of 31a (40 mg, 0.07 mmol) in THF
(2 mL) was added TBAF (66 mg, 0.21 mmol). The solution was refluxed
for 3 h, concentrated and the residue was purified by chromatography on
silica gel (petroleum ether/EtOAc 10:3) to give the product 1 as colorless
oil (22 mg, 97%). [a]2D0 = À94.7 (c=0.61, CHCl3). 1H NMR (400 MHz,
CDCl3/TMS): d=5.80–5.71 (m, 2H), 5.51–5.43 (m, 2H), 4.22 (ddd, J=
1.6, 8.4, 10.8 Hz, 1H), 4.11 (q, J=6.4 Hz, 1H), 3.69 (dd, J=4.0, 7.6 Hz,
1H), 2.53–2.43 (m, 2H), 2.33–2.22 (m, 2H), 2.17–2.12 (m, 1H), 2.10–2.02
(m, 2H), 1.83–1.72 (m, 3H), 1.56–1.46 (m, 2H), 1.43–1.30 (m, 6H), 1.13–
[8] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–
956.
[9] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[10] B. Jiang, Z. Chen, W. Xiong, Chem. Commun. 2002, 1524–1525.
[11] a) C. E. Castro, R. D. Stephen, J. Am. Chem. Soc. 1964, 86, 4358–
4363; b) D. Brillon, D. Deslongchamps, Can. J. Chem. 1987, 65, 56–
68.
Received: June 19, 2009
Published online: September 24, 2009
11468
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11465 – 11468