A highly diastereoselective synthesis of (1R)-(+)-camphor-based chiral allenes and their asymmetric hydroboration-oxidation reactions

Article abstract of DOI:10.1021/jo016201i

Synthesis of camphor derived chiral allenes and their hydroboration-oxidation reactions are described. Reaction of (1R)-(+)-camphor with alkynyllithium followed by the reduction of the resulted propargyl alcohol derivatives using AlH₃ furnished chiral allenes 2a-g in excellent yields with high diastereoselectivity. Reduction of the propargyl alcohols with aluminum hydride proceeded through selective intermolecular anti-addition of hydride ion. The stereochemistry of the chiral allenes 2 was assigned based on lanthanide shift studies and chemical correlations. Diastereoselectivity was observed in the hydroboration-oxidation of 2 which produced a mixture of (E,R) and (E,S) stereoisomers in a ratio of 6:1 to 18:1.

Full text of DOI:10.1021/jo016201i

1308
J . Org. Chem. 2002, 67, 1308-1313
A High ly Dia ster eoselective Syn th esis of (1R)-(+)-Ca m p h or -Ba sed
Ch ir a l Allen es a n d Th eir Asym m etr ic Hyd r obor a tion -Oxid a tion
Rea ction s†
Shang-Cheng Hung, Yen-Fang Wen, J ia-Wen Chang, Chun-Chen Liao, and Biing-J iun Uang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, Republic of China
bjuang@mx.nthu.edu.tw
Received October 16, 2001
Synthesis of camphor derived chiral allenes and their hydroboration-oxidation reactions are
described. Reaction of (1R)-(+)-camphor with alkynyllithium followed by the reduction of the resulted
propargyl alcohol derivatives using AlH3 furnished chiral allenes 2a -g in excellent yields with
high diastereoselectivity. Reduction of the propargyl alcohols with aluminum hydride proceeded
through selective intermolecular anti-addition of hydride ion. The stereochemistry of the chiral
allenes 2 was assigned based on lanthanide shift studies and chemical correlations. Diastereo-
selectivity was observed in the hydroboration-oxidation of 2 which produced a mixture of (E,R)
and (E,S) stereoisomers in a ratio of 6:1 to 18:1.
In tr od u ction
a general, simple and efficient means of synthesizing
chiral allenes for further usage in organic synthesis, we
report herein a substrate-controlled asymmetric synthe-
sis of camphor-derived chiral allenes and the stereochem-
ical course of their hydroboration-oxidation reactions.
Chiral allenes gained significant importance as versa-
tile intermediates for asymmetric synthesis via the axial
to centered chirality transfer.1 Recently chiral allenes are
explored as potential chiral synthons in the synthesis of
bioactive molecules and natural products.1n,s,2 The SN2′
addition of nucleophiles to suitably derivatized, optically
active propargyl derivatives is one of the most widely
used routes for the asymmetric synthesis of chiral
allenes.1e,3,4 In conjunction with our program to develop
Resu lts a n d Discu ssion
Most of the reported synthetic procedures for the chiral
allenes made use of enantiomerically enriched chiral
compounds either as substrates5 or as reagents.6 We have
envisaged the synthesis of chiral allenes through chiral
propargyl alcohols. Reaction of (1R)-(+)-camphor and
lithium acetylides in THF gave the corresponding chiral
alcohols 1a -g with >95% diastereoselectivity (Table 1)
† A preliminary result was reported: Uang, B.-J .; Po, S.-C.; Hung,
S.-C.; Liu, H.-H.; Hsu, C.-Y.; Lin, Y.-S.; Chang, J .-W. Pure Appl. Chem.
1997, 69, 615.
(1) (a) Taylor, D. R. Chem. Rev. 1967, 67, 317. (b) Smadja, W. Chem.
Rev. 1983, 83, 263. (c) Coppola, G. M.; Schuster, H. F. Allenes in
Organic Synthesis; Wiley: New York, 1984. (d) Patai, S. The Chemistry
of Ketenes, Allenes, and related Compounds; J ohn Wiley & Sons: New
York, 1984; parts 1 and 2. (e) Pasto, D. J . Tetrahedron 1984, 40, 2805.
(f) Danheiser, R. L.; Stoner, E. J .; Koyama, H.; Yamashita, D. S.; Klade,
C. A. J . Am. Chem. Soc. 1989, 111, 4407. (g) Alexakis, A.; Marek, I.;
Mangeney, P.; Normant, J . F. J . Am. Chem. Soc. 1990, 112, 8042. (h)
Marshall, J . A.; Tang, Y. J . Org. Chem. 1993, 58, 3233. (i) Buynak, J .
D.; Borate, H. B.; Lamb, G. W.; Khasnis, D. D.; Husting, C.; Isom, H.;
Siriwardane, U. J . Org. Chem. 1993, 58, 1325. (j) Masse, C. E.; Panek,
J . S. Chem. Rev. 1995, 95, 1293. (k) Ikeda, I.; Kanematsu, K. J . Chem.
Soc., Chem. Commun. 1995, 453. (l) Koop, U.; Handke, G.; Krause, N.
Liebigs Ann. 1996, 1487. (m) Myers, A. G.; Zheng, B. J . Am. Chem.
Soc. 1996, 118, 4492. (n) Shepard, M. S.; Carreira, E. M. J . Am. Chem.
Soc. 1997, 119, 2597. (o) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F.
J . Am. Chem. Soc. 1997, 119, 11295. and references therein. (p) J ung,
M. E.; Pontillo, J . Org. Lett. 1999, 1, 367. (q) Parsons, P. J .; Gold, H.;
Semple, G.; Montagnon, T. Synlett 2000. 1184. (r) J onasson, C.;
Horvath, A.; Backvall, J .-E. J . Am. Chem. Soc. 2000, 122, 9600. (s)
Wan, Z.; Nelson, S. G. J . Am. Chem. Soc. 2000, 122, 10470.
(2) (a) Marshall, J . A. Chem. Rev. 1996, 96, 31 and references
therein. (b) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J . Am. Chem.
Soc. 1997, 119, 11295. (c) Marshal, J . A.; J ohns, B. A. J . Org. Chem,
1998, 63, 7885. (d) Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf,
E.; Love, J . A. J . Am. Chem. Soc. 1999, 121, 5348. (e) Arredondo, V.
M.; Tian, S.; McDonald, F. E.; Marks, T. J . J . Am. Chem. Soc. 1999,
121, 3633.
1
as judged from their H NMR spectra. The major product
presumably arose from the endo addition of the alkynyl-
lithium to the carbonyl group as the exo face in hindered
by C8 protons.7 Earlier, Mattay8 and co-workers have
reported two approaches for the preparation of allenic
compounds from optically pure propargyl derivatives, but
inseparable mixtures of allenic products were obtained
in these reactions. We found that reduction of propargyl
1c
alcohols 1 with AlH3 afforded the corresponding opti-
cally active allenes 2 stereospecifically except in the case
of propargyl alcohol 1g (R ) CH2CH2OH) which gave a
chromatographically inseparable mixture of diastereo-
mers 2g and 3g in a 5:1 ratio (66% de).
The stereochemistry of allenes 2 was determined by
means of lanthanide shift studies9 employing Eu(fod)3 as
(5) (a) Rossi, R.; Diversi, P. Synthesis 1973, 25. (b) Elsevier: C. J .
In Houben-Weyl, series Methods of Organic Chemistry; Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
1995; Vol. E21a, p 537.
(6) (a) Nishibayashi, Y.; Singh, J . D.; Fukuzawa, S.; Uemura, S. J .
Org. Chem. 1995, 60, 4114. (b) Naruse, Y.; Watanabe, H.; Ishiyama,
Y.; Yoshida, T. J . Org. Chem. 1997, 62, 3862. (c) Mikami, K.; Yoshida,
A. Angew. Chem., Int. Ed. Engl. 1997, 36, 858. (d) Node, M.; Nishide,
K.; Fujiwara, T.; Ichihashi, S. Chem. Commun. 1998, 2363.
(7) Brittelli, D. R.; Boswell, G. A. J . Org. Chem. 1981, 46, 312.
(8) Mattay, J .; Conrads, M.; Runsink, J . Synthesis 1988, 595.
(9) Morrill, T. C. Lanthanide Shift Reagents in Stereochemical
Analysis; VCH: New York, 1986.
(3) (a) Rona, P.; Crabbe, P. J . Am. Chem. Soc. 1969, 91, 3289. (b)
Bruneau, C.; Dixneuf, P. H. In Comprehensive Organic Functional
Group Transformations; Katritzky, A. P., Meth-Cohn, O., Rees, C. W.,
Eds.: Pergamon Press: New York, 1997; Vol. 1, Ch. 1.20, pp 953-
995.
(4) (a) Mori, K.; Nukada, T.; Ebata, T. Tetrahedron 1981, 37, 1343.
(b) Cooper, G. F.; Wren, D. L.; J ackson D. Y.; Beard C. C.; Galeazzi,
E.; Van Horn, A. R.; Li, T. T. J . Org. Chem. 1993, 58, 4280.
10.1021/jo016201i CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/25/2002

Synthesis of (1R)-(+)-Camphor-Based Chiral Allenes
J . Org. Chem., Vol. 67, No. 4, 2002 1309
Ta ble 1. Yield s of P r op a r gyl Alcoh ols 1, Allen es (2 a n d
3), a n d Allylic Alcoh ols 4/5
allylic
allenes
alcohol 1 (2+3)
alcohol
(4+5)
yield
(%)
ratio
(2:3)
(% de)
ratio
(4:5)
yield
(%)
yield
(%)
R
(% de)
a : CH3
b: C2H5
c: C3H7
d : C4H9
92
89
80
83
83
76
65
72
84
85
88
90
86
51
43
87
>50:1 (>95)
>50:1 (>95)
>50:1 (>95)
>50:1 (>95)
>50:1 (>95)
>50:1 (>95)
5:1 (66%)
66
6:1 (72)
80
82
77
15:1 (88)
15:1 (88)
18:1 (89)
e: C5H11
f: CH2OBn
g: CH2CH2OH
h : CH2CH2OBn
>50:1 (>95)
71
15:1 (88)
a
F igu r e 2. The ∆δ of 3-exo and 3-endo protons of 2g vs the
equivalents of Eu(fod)3.
Proportions of EA/hexanes used as eluent in the purification
of products by column chromatography: 1a , 1b (1:30); 1c, 1d , 1e
(1:15); 1f (1:8); 1g, 1h (1:2); 2a , 2b, 2c, 2d , 2e (0:100); 2f, 2h (1:
30); 2g and 3g (1:10); 4a and 5a , 4h and 5h (1:4); 4c and 5c, 4d
and 5d , 4e and 5e (1:6).
F igu r e 3. The ∆δ of C8, C9, and C10 protons of 2g vs the
equivalents of Eu(fod)3.
Figure 2 shows the variation of chemical shifts of 3-exo
and 3-endo protons with the amount of shift reagent.
Shift in the signal position of 3-exo proton with the
increase in the concentration of shift reagent is more
significant when compared to that of 3-endo proton,
indicating that the former proton is spatially closer to
the hydroxyl group. In other words, the CH2CH2OH
group and the 3-exo proton of the major product 2g must
be syn to each other. The C8 and C10 protons being
spatially closer to the hydroxyl group, a similar shift in
their signal positions should be observed when the shift
reagent is used. Plots on the variation of chemical shift
values of C8, C9, and C10 protons with the concentration
of the shift reagent are shown in Figure 3. As expected,
the chemical shifts of C8 and C10 protons were shifted
substantially upon the addition of shift reagent. This
further corroborates the stereochemical assignment of 2g.
Stereochemistry of the minor diastereomer 3g was
established in a similar manner from Figure 4 in which
plots on the variation of chemical shift positions of 3-exo
and 3-endo protons of 3g with the concentration of the
shift reagent are shown. Relatively larger shift in the
signal position of 3-endo proton when compared to that
of 3-exo proton strongly suggests the proximity of 3-endo
proton and hydroxyl group. Obviously CH2CH2OH group
and 3-exo proton in 3g must be anti to each other. This
postulation was confirmed by Figure 5 in which plots
on the change in the chemical shift of three methyl
groups of 3g with the concentration of shift reagent are
shown. As expected, only the signal position of C10
protons was shifted substantially upon the addition of
shift reagent.
F igu r e 1. 1H NMR spectra of the mixture 2g/3g (5:1) in the
presence and absence of Eu(fod)3.
the shift reagent and by chemical correlations. Dia-
stereomeric mixture of 2g and 3g was used for such
purpose. In the 1H NMR spectrum of the mixture, almost
all the signals of 2g and 3g except those of allenic protons
have similar chemical shift values and overlap with each
other. When Eu(fod)3 was added to a solution of this
mixture in CDCl3, significant shifts were observed in the
signal positions and the resolution increased with the
amount of the europium complex. The upper and lower
1H NMR spectra in the Figure 1 correspond to the
mixture of allenes 2g and 3g in the presence and absence
of the shift reagent, respectively. Apparently in the upper
spectrum, peaks of the two diastereomers could be
resolved completely in the presence of 0.3 molar amount
of Eu(fod)3. Further, signals corresponding to the 3-exo
and 3-endo protons of 2g are discernible in the spectrum.

1310 J . Org. Chem., Vol. 67, No. 4, 2002
Hung et al.
F igu r e 6. The ∆δ of 3-exo and 3-endo protons of 12d vs the
equivalents of Eu(fod)3.
F igu r e 4. The ∆δ of 3-exo and 3-endo protons of 3g vs the
equivalents of Eu(fod)3.
To test the scope and limitation of diastereoselectivity
on the camphor-based chiral allenes 2, we have conducted
the hydroboration-oxidation reactions with them. When
the less-substituted double bond of the allene reacts with
9-BBN, the facial selectivity would depend on the steric
bulk of the substituents of the other double bond. As the
re face of the less-substituted double bond is blocked by
the bridgehead methyl group, 9-BBN is expected to
approach selectively from the si face (Scheme 2). Treat-
ment of allenes 2 with 9-BBN in THF at room temper-
ature followed by oxidative workup with basic hydrogen
peroxide produced a mixture of allylic alcohols 4 and 5
with good diastereoselectivity (Table 1). Chiral alcohol 4
was the major product and selectivity varied from 6:1 to
18:1 depending on the substituent. The stereochemistry
of the trisubstituted double bond of compound 4 was
established by NOE studies. For example, irradiation of
the bridgehead methyl signal of 4d produced 12.7% peak
enhancement in the olefinic proton signal. On the other
hand, irradiation of the methine signal of the carbinol
produced peak enhancement for both exo and endo C3
protons. These observations suggested that the olefinic
proton is spatially closer to the bridgehead methyl group
as expected for E-isomer 4d . Allyl alcohol 5d was
characterized as the E-isomer by a similar NOE experi-
ment. To confirm that compounds 4 and 5 are C2′
diastereomers, 4d was oxidized with PCC to enone 6 and
then reduced with NaBH4 in the presence of CeCl3‚
7H2O.11 Two products were obtained in a ratio of 1 to 1.7
and their spectral data was identical with that of
compounds 4d and 5d , respectively. The formation of the
major product 4 in the hydroboration-oxidation of allene
2 can be explained by two different reaction pathways.
First, the addition of 9-BBN to the si face of allene 2
produces allyborane 9 as an intermediate, and its sub-
sequent oxidation gives allyl alcohol 4. Alternatively,
9-BBN may add to the re face of allene 2 to produce
allyborane 7 which suffers from an A1,3-strain. Allyl-
borane rearrangement of allylborane 712 from the less-
hindered face to borane 8, followed by its C1′-C2 bond
rotation and subsequent repetition of allylborane re-
arrangement results in allylborane 9. However, allyl-
borane rearrangement was ruled out from the tempera-
F igu r e 5. The ∆δ of C8, C9, and C10 protons of 3g vs the
equivalents of Eu(fod)3.
Chemical correlation was done to assign the stereo-
chemistry of other chiral allenes. Treatment of the
mixture of 2g and 3g with MsCl/Et3N followed by LiAlH4
reduction produced a mixture of two diastereomers. The
1H NMR spectrum of the major compound was identical
with that of allene 2b, indicating that the ethyl group of
2b is syn to the C10 protons. Since allenes 2a , 2b, 2c, 2d ,
and 2e with an alkyl substituent have close structural
similarity, logically they should have the same stereo-
chemistry in the allene moiety. Mixture of 2g and 3g was
benzylated with benzyl bromide to give a major product
1
whose H NMR spectrum was identical with that of 2h ,
indicating that CH2CH2OBn group is syn to the C10
protons in 2h . Allenes 2h and 2f have similar ethereal
functionality and are expected to have the same stereo-
chemistry.
Propargyl alcohols 1a -h undergo reductive elimina-
tion through an anti mode (Scheme 1) contrary to the
observation of Claesson and co-workers1c who reported
the syn mode of reaction of AlH3 with propargyl alcohols.
The reason for this discrepancy is presumably due to the
steric effect of the C8 protons that prevents the alignment
of propargyl ate complex for an intramolecular syn-
hydride delivery. Thus, preparation of chiral allenes 2
could be achieved with high diastereoselectivity when
there is no second hydroxyl group in the intermediate
propargyl alcohols.
1
ture variation 1H NMR experiments. H NMR spectra
Earlier Brown and co-workers have studied the hydro-
boration reactions of allenes and demonstrated that
9-BBN is one of the most useful hydroboration reagents
exhibiting a high degree of regio- and stereospecificity
and is remarkably sensitive to the structure of allenes.10
(10) Brown, H. C.; Liotta, R.; Kramer, G. W. J . Am. Chem. Soc. 1979,
101, 2966.
(11) Luche, J . L.; Gemal, A. L. J . Am. Chem. Soc. 1981, 103, 5454.
(12) Brown, H. C.; Kramer, G. W. J . Organomet. Chem. 1977, 132,
9.

Synthesis of (1R)-(+)-Camphor-Based Chiral Allenes
J . Org. Chem., Vol. 67, No. 4, 2002 1311
Sch em e 1
Sch em e 2
were recorded for a sample containing allene 2 and
9-BBN over a range of temperature from -60 °C to room
temperature. The spectral data obtained from all these
experiments was identical, indicating that rearrange-
ment did not take place. Apparently, the reaction may
be proceeding with the addition of 9-BBN to 2 through
the si face. On the other hand, formation of the minor
product 5 is unusual and could not be rationalized at this
moment. It might have resulted from the epimerisation
of either allyl alcohol 4 or allylborane 9 during the course
of the reaction, though such phenomena were not re-
ported earlier.
The absolute configuration at the carbinol carbon of
compounds 4c-e was established by a two steps conver-

1312 J . Org. Chem., Vol. 67, No. 4, 2002
Hung et al.
Sch em e 3
sion of 4 to the corresponding (R)-1,2-hexanediol 1113
(Scheme 3). Acetylation of 4d with acetyl chloride in the
presence of pyridine provided allyl acetate 10d . Ozonoly-
sis of 10d followed by reductive workup by stirring with
NaBH4 for 2 h at room temperature yielded a mixture of
(R)-1,2-hexanediol 11d , epoxides 12d and 13d , and
borneol 14 in 53%, 34%, 6%, and 42% yields, respectively.
Diol 11d was characterized by its 1H and 13C NMR
spectra. Optical rotation of 11d , [R]32 +19.2 (c 1.65,
D
EtOH) was similar to the reported value of R isomer (lit.
[R]22 +15.2 (c 13.14, EtOH))13 indicating its R configu-
D
ration. Optical purity of 11d was further confirmed from
the comparison of 19F spectra (Figure 7) of its bis-R-
methoxy-R-trifluoromethyl-R-phenyl acetate14 and the
corresponding derivative of its racemic mixture. Mosher
esters from racemic diol showed two 19F resonances,
where as, the Mosher ester 15d prepared from 11d has
exhibited only one 19F resonance confirming that com-
pounds 11d and 15d are >95% ee. The stereochemistry
of 12d was established by NOE experiment. Irradiation
of carbinol proton signal produced larger peak enhance-
ment for exo proton (3.9%) when compared to that of endo
proton (1.7%), indicating the configurational proximity
of exo and carbinol protons. This was further corroborated
by the lanthanide shift studies. The variation of chemical
shift of 3-exo and 3-endo protons with the amount of
Eu(fod)3 was shown in Figure 6. The shift for 3-exo proton
is more prominent confirming its proximity to hydroxyl
group. This experimental data suggests that epoxide
oxygen of 12d is in the R face. Stereochemistry of epoxide
13d was demonstrated to be identical with that of 12d
from the conversion of 13d into 12d by saponification.
Acetylation of allyl alcohols 4c and 4e under similar
experimental conditions afforded corresponding allyl
acetates 10c and 10e. By reducing the reaction temper-
ature and time during reductive workup with NaBH4
after ozonolysis, 10c and 10e furnished a mixture of only
F igu r e 7. (a) 19F NMR spectrum of (()-1,2-hexanediol bis-
Mosher ester. (b) 19F NMR spectrum of (+)-1,2-hexanediol bis-
Mosher ester 15d .
three compounds 11, 13, and 14, presumably due to the
prevention of ester hydrolysis of 13 under the relatively
mild reaction conditions. Diols 11c and 11e were con-
verted into the corresponding Mosher esters 15c and 15e,
respectively, in >95% ee, vide 19F NMR.
In summary, a general and highly stereoselective
procedure is developed for the synthesis of camphor-
based chiral allenes. Hydroboration-oxidation reactions
of these chiral allenes proceeded with moderate to high
diastereoselectivity.
(13) Mukaiyama, T.; Asami, M. Chem. Lett. 1983, 93.
(14) Mosher, H. S.; Dale, J . A.; Dull, D. L. J . Org. Chem. 1969, 34,
2543.

Synthesis of (1R)-(+)-Camphor-Based Chiral Allenes
J . Org. Chem., Vol. 67, No. 4, 2002 1313
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
experimental procedures for all the new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. The authors thank Professor
Reinhard W. Haffmann for his kind discussion of allyl
borane rearrangement and the National Science Council
of the Republic of China for the financial support of this
research work.
J O016201I