Total synthesis of a cuticular hydrocarbon from the cane beetle Antitrogus parvulus: Confirmation of the relative stereochemistry

Article abstract of DOI:10.1039/c2ob06906g

The stereoselective reaction of an allyl bromide with an aldehyde mediated by a low valency bismuth species was the key reaction in stereoselective syntheses of (4S,6R,8R,10S,16S)- and (4S,6R,8R,10S,16R)-4,6,8,10,16- pentamethyldocosanes. ¹³C N

Full text of DOI:10.1039/c2ob06906g

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Total synthesis of a cuticular hydrocarbon from the cane beetle Antitrogus
parvulus: confirmation of the relative stereochemistry†
Norazah B. Basar,a Hao Liu,b Devendra Negi,c Hasnah M. Sirat,a Gareth A. Morrisb and Eric J. Thomas*b
Received 11th November 2011, Accepted 16th December 2011
DOI: 10.1039/c2ob06906g
Bismuth(0) mediated reactions of 1-bromo-5-benzyloxy-2,4-
dimethylpent-2-ene 3 with aldehydes give the 1,5-anti-(E)-hex-3-
enols 4.3–5 Using stereoselective hydrogenation and cuprate
based methylation with inversion, the butanal derived product
The stereoselective reaction of an allyl bromide with an alde-
hyde mediated by a low valency bismuth species was the key
reaction in stereoselective syntheses of (4S,6R,8R,10S,16S)-
and (4S,6R,8R,10S,16R)-4,6,8,10,16-pentamethyldocosanes.
13C NMR data for these compounds confirmed that the
cuticular hydrocarbon isolated from the cane beetle Antitro-
gus parvulus was the (4S,6R,8R,10S,16S)-stereoisomer.
n
(4, R = Pr) was converted into the all-syn- or anti,anti-2,4,6-tri-
methylnonan-1-ols 5 and 6 with useful overall stereoselectivity.6
We now report the stereoselective synthesis of the pentamethyldo-
cosanes (16S)- and (16R)-2 using this chemistry and confirmation
that the natural product corresponds to the (16S)-diastereoisomer.
Two hydrocarbons isolated from the cuticular extract of the cane
beetle Antitrogus parvulus were identified as 4,6,8,10,16,18-hex-
amethyl- and 4,6,8,10,16-pentamethyl-docosanes.1 Synthesis
established the anti,anti,anti-configuration for the methyl
bearing stereogenic centres at the 4-, 6-, 8- and 10-positions for
both compounds and the syn-configuration for the methyl groups
at the 16- and 18-positions in the hexamethyl analogue.1 Further
synthetic studies subsequently established the structure of the
natural hexamethyldocosane as the (4S,6R,8R,10S,16R,18S)-
stereoisomer 1.2 However, the configuration of the pentamethyl-
docosane at C(16) relative to its other stereogenic centres was
not confirmed, i.e. it was not established whether the natural pen-
tamethyldocosane is the (4S,6R,8R,10S,16S)- or the
(4S,6R,8R,10S,16R)-stereoisomer (16S)-2 or (16R)-2.
A synthesis of the anti,anti,anti-1-iodo-2,4,6,8-tetramethylun-
decane 16 using the organobismuth chemistry is outlined in
Scheme 1. Reaction of (S)-3-methylhexanal 77 and (4R,2E)-5-
aUniversiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
bSchool of Chemistry, University of Manchester, Manchester, UK, M13
9PL. E-mail: e.j.thomas@manchester.ac.uk; Fax: +44 (0)161 275 4939;
Tel: +44 (0)161 275 4614
Scheme 1 Reagents and conditions: i, BiI3, Zn powder, THF, r.t., 2 h,
then add 3 and 7, reflux, 2 h (60%); ii, Li, naph., THF, r.t., 8, −25 °C,
2 h (78%); iii, TIPSCl, imid., THF, 0 °C to r.t., 16 h (94%); iv,
[Rh(NBD)diphos-4]BF4, H2, DCM, 950 psi, 5 h (11, 68%; 12, 22%); v,
TsCl, DMAP, DCM, r.t., 16 h (93%); vi, CuI, MeLi. LiI, 0 °C, add 13,
0 °C to r.t., 16 h (21%); vii, aq. HCl, dioxane, r.t., 16 h (91%); viii, (a)
TsCl, DMAP, DCM, r.t., 16 h (85%) (b) NaI, acetone.
cDepartment of Chemistry, HNB Garhwal University (A Central
University), Srinagar (Garhwal), Uttarakhand, 246 174, India
†Electronic supplementary information (ESI) available: Experimental
details and full spectroscopic data for key compounds. See DOI:
10.1039/c2ob06906g
This journal is © The Royal Society of Chemistry 2012
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n
n
Scheme 2 Reagents and conditions: i, TsCl, DMAP, DCM, r.t., 16 h (96%); ii, NaI, acetone, reflux, 16 h (90%); iii, BuS(O)2Ph, BuLi, DMPU,
THF, −40 °C, 30 min, (R)-21, THF, −40 °C to r.t., 16 h (95%); iv, O3, DCM, MeOH, −78 °C, then NaBH4, r.t., 16 h (85%); v, Na/Hg, MeOH, r.t.,
16 h (73%); vi, TsCl, DMAP, DCM, r.t., 16 h (99%); vii, NaI, acetone, reflux, 2 h (90%); viii, MeS(O)2Ph, THF, DMPU, nBuLi, −40 °C, 30 min, then
(S)-26, −40 °C to r.t., 16 h (73%); ix, (S)-27, nBuLi, DMPU, THF, −40 °C, 30 min, then 16, −40 °C to r.t., 16 h (45%); x, Na/Hg, 10 equiv., MeOH,
r.t., 24 h (83%).
benzyloxy-1-bromo-2,4-dimethylpent-2-ene (3)6 with the low
valency bismuth species prepared by treatment of bismuth(III)
iodide with activated zinc in tetrahydrofuran9 gave the 2,6-anti-
(3E)-1-benzyloxy-2,4,8-trimethylundec-3-en-6-ol 8 containing
only small amounts of other diastereoisomers (<10% in total).
Reductive removal of the benzyl group gave the diol 9 that was
protected as its monotri-iso-propylsilyl ether 10. Hydroxyl
directed hydrogenation using [Rh(NBD)diphos-4]BF4 as the cat-
alyst10 then gave the (4R)- and (4S)-2,4,8-trimethyl-1-(tri-iso-
propylsilyloxy)undecan-6-ols 11 and 12, ratio ca. 75 : 25, which
were separated by chromatography. Unfortunately, in this case,
preliminary studies gave only a low yield of the 1-tri-iso-propyl-
silyloxy-2,4,6,8-tetramethylundecane 14 from the reaction of the
tosylate 13 with lithium dimethylcuprate, perhaps because of
Scheme 3 Reagents and conditions: i, (R)-27, nBuLi, THF, DMPU,
−40 °C, 30 min, then 16, −40 °C–r.t., 16 h (34%); ii, Na/Hg, MeOH, r.
t., 6 h (85%).
steric hindrance, but rather than optimise this reaction, the silyl
ether 14 that was obtained was taken through to the iodide 16
via the alcohol 1511 to complete the synthesis.
The structure of the major product 8 from the bismuth(0)
mediated reaction between the aldehyde 7 and allyl bromide 3
was assigned by analogy with earlier work and was confirmed
later in the synthesis. A sample of this alcohol 8 was also con-
verted into its 2,6-syn-(E)-epimer 18 via a Mitsunobu reaction
using 4-nitrobenzoic acid and triphenylphosphine followed by
saponification of the resulting 4-nitrobenzoate 17. The 2,6-anti-
and -syn-alcohols 8 and 18 could be distinguished by 13C NMR
and the 2,6-syn-epimer 18 shown to be only a minor product
(ca. 5%) of the organobismuth reaction.12
(R)-2014 followed by ozonolysis of the resulting sulfone (7R)-22
with a reductive work-up, gave the alcohol (4R)-23. Reductive
removal of the phenylsulfonyl group, conversion of the primary
alcohol (S)-2415 into the iodide (S)-2616 via toluene p-sulfonate
(S)-25, and alkylation of methyl phenyl sulfone using this iodide
gave (S)-5-methyl-1-phenylsulfonylundecane (S)-27. Alkylation
of this sulfone using the tetramethylundecanyl iodide 16 then
gave the long-chain sulfone 28 that was converted into
(4S,6R,8R,10S,16S)-4,6,8,10,16-pentamethyldocosane [(16S)-2]
by reductive removal of the phenylsulfonyl group.
(S)-Citronellol [(S)-19] was converted into (R)-5-methyl-1-
phenylsulfonylundecane (R)-27 via (S)-3,7-dimethyloct-6-enyl
iodide (S)-21.17,18 Alkylation of this sulfone using the iodide 16
gave the 11-phenylsulfonyldocosane 29 that was reduced to give
(4S,6R,8R,10S,16R)-4,6,8,10,16-pentamethyldocosane [(16R)-2],
see Scheme 3.
The completion of
a synthesis of (4S,6R,8R,10S,16S)-
4,6,8,10,16-pentamethyldocosane [(16S)-2] is outlined in
Scheme 2. Alkylation of n-butyl phenyl sulfone using the iodide
(R)-2113 prepared from (R)-citronellol [(R)-19] via the tosylate
1744 | Org. Biomol. Chem., 2012, 10, 1743–1745
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product and the synthetic (16S)-epimer were, with the one excep-
tion noted, remarkably consistent.
Acknowledgements
We thank UTM Skudai for support to N.B. and Novartis for
support to H. L. We are grateful for a Commonwealth Fellowship
to D. S. N. and we would like to thank Professor W. Kitching for
exchange of 13C NMR data.
Fig. 1 Chemical shift differences in parts per billion between (16S)-2
and the natural product.
Notes and references
1 (a) M. T. Fletcher, S. Chow, L. K. Lambert, O. P. Gallagher, B. W. Cribb,
P. G. Allsopp, C. J. Moore and W. Kitching, Org. Lett., 2003, 5, 5083;
(b) S. Chow, M. T. Fletcher, L. K. Lambert, O. P. Gallagher, C. J. Moore,
B. W. Cribb, P. G. Allsopp and W. Kitching, J. Org. Chem., 2005, 70,
1808.
2 (a) C. Herber and B. Breit, Angew. Chem., Int. Ed., 2005, 44, 5267;
(b) C. Herber and B. Breit, Eur. J. Org. Chem., 2007, 3512; (c) J. Zhou,
Y. Zhu and K. Burgess, Org. Lett., 2007, 9, 1391; (d) G. Zhu, B. Liang
and E.-i. Negishi, Org. Lett., 2008, 10, 1099.
3 S. Donnelly, E. J. Thomas and E. A. Arnott, Chem. Commun., 2003,
1460.
4 S. Donnelly, M. Fielding and E. J. Thomas, Tetrahedron Lett., 2004, 45,
6779.
Fig. 2 Chemical shift differences in parts per billion between (16R)-2
and the natural product.
5 E. J. Thomas, Chem. Rec., 2007, 7, 115.
Having prepared the pentamethyldocosanes (16S)- and (16R)-
2, it remained to establish which diastereoisomer corresponded
to the natural product. Unfortunately, no sample of the natural
product was available and its optical rotation was unknown, and
so it was necessary to compare the 13C NMR data of the two
epimers (16S)-2 and (16R)-2 with the data available for the
natural product. As the 13C NMR spectra of the two epimers
were very similar indeed,1 a quantitative comparison was used.
Fortunately the original data were measured at high field (17.6
T) and reported to 1 ppb precision, so spectra measured at 9.4 T
were processed with Gaussian weighting and extensive zero
filling to allow detailed comparison.
6 N. Basar, S. Donnelly, H. Liu and E. J. Thomas, Synlett, 2010, 575.
7 Synthesized from (S)-citronellol, for an alternative route see ref. 8.
8 D. R. Williams, A. L. Nold and R. J. Mullins, J. Org. Chem., 2004, 69,
5374.
9 M. Wada, H. Ohki and K.-Y. Akiba, Bull. Chem. Soc. Jpn., 1990, 63,
1738.
10 (a) D. A. Evans and M. M. Morrissey, J. Am. Chem. Soc., 1984, 106,
3866; (b) D. A. Evans, M. M. Morrissey and R. L. Dow, Tetrahedron
Lett., 1985, 26, 6005.
11 Spectroscopic data, in particular its 13C NMR spectrum, of alcohol 15
corresponded to those in the literature (ref. 2).
12 As the bromide 3 had an e.e. of ca. 90% (Mosher’s on the corresponding
alcohol), another minor impurity at the 5% level was the diastereoisomer
resulting from the reaction of the enantiomer of bromide 3 with the alde-
hyde 7.
Fig. 1 shows the differences in the chemical shifts between
those listed1 for the natural product and our data for the (16S)-
epimer (16S)-2. Apart from the peak assigned to C(19),19 all the
peaks correspond to within less 5 ppb once the small difference
in referencing is corrected for, with an rms error of 1.4 ppb (less
than the instrumental linewidth).
In contrast, the differences between the chemical shifts listed
for the natural product and our data for the (16R)-epimer (16R)-
2, are much larger, with an rms error of 10 ppb (see Fig. 2).
Based on this comparison, the natural product was identified as
(4S,6R,8R,10S,16S)-4,6,8,10,16-pentamethyldocosane (16S)-2.20
Of interest in this work is the use of the allyl organobismuth
chemistry for the stereoselective synthesis of the undecenol 8,
the confirmation of the relative stereochemistry of the
naturally occurring 4,6,8,10,16-pentamethyldocosane as the
(4S,6R,8R,10S,16S)-epimer (16S)-2, and the unusually detailed
numerical comparison of the 13C spectra of the natural product
and the (16S)- and (16R)-epimers which allowed the assignment
of stereochemistry to be made. Indeed the spectra of the natural
13 K. Mori, Tetrahedron, 2008, 64, 4060.
14 S. E. Denmark, C. S. Regens and T. Kobayashi, J. Am. Chem. Soc., 2007,
129, 2774.
15 D. Raederstorff, A. Y. L. Shu, J. E. Thompson and C. Djerassi, J. Org.
Chem., 1987, 52, 2337.
16 E. Hedenström, H. Edlund, S. Lund, M. Abersten and D. Persson,
J. Chem. Soc., Perkin Trans. 1, 2002, 15, 1810.
17 Y. S. Chow, J. H. Williams, Q. Huang, S. Nanda and I. A. Scott, J. Org.
Chem., 2005, 70, 9997.
18 E. Hedenström, B. V. Nguyen and L. A. Silks, Tetrahedron: Asymmetry,
2002, 13, 835.
19 In the 13C NMR spectrum of the natural product, the peak at δ 29.712
was originally assigned to both C(4) and C(19) but C(19) has since been
reassigned to a peak at δ 29.697 although this peak was partly obscured
by an impurity in the natural product. (Personal communication from Pro-
fessor W. Kitching.) However, it remains slightly more than 5 ppb differ-
ent from the peak at δ 29.6987 assigned to C(19) in (16S)-2 and from the
peak at δ 29.6951 assigned to C(19) in the 13C NMR spectrum of (16R)-
2.
20 This work establishes the relative configuration of the natural 4,6,8,10,16-
pentamethyldocosane. As the optical rotation of the natural hydrocarbon
is unknown, the absolute configuration shown was provisionally assigned
by analogy with that of the naturally occurring 4,6,8,10,16,18-hexam-
ethyldocosane 1 (see ref. 2).
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