Asymmetric synthesis of α-substituted allyl boranes and their application in the synthesis of iso-agatharesinol

Article abstract of DOI:10.1002/anie.200603659

(Chemical Equation Presented) Use your borane: A stereocontrolled synthesis of allyl boranes from chiral sulfur ylides and their subsequent reaction with aldehydes to give homoallylic alcohols is described. The allyl boranes also could undergo a stereospe

Full text of DOI:10.1002/anie.200603659

Angewandte
Chemie
DOI: 10.1002/anie.200603659
Allyl boranes
Asymmetric Synthesis of a-Substituted Allyl Boranes and Their
Application in the Synthesis of Iso-agatharesinol**
Guang Yu Fang and Varinder K. Aggarwal*
The reaction of chiral allyl boron reagents with aldehydes has
played and continues to play a major role in the asymmetric
synthesis of complex natural products.[1] Despite the fact that
a-substituted allyl boron reagents often react with aldehydes
with almost complete stereoinduction, such reagents have not
enjoyed the same profile, possibly because their asymmetric
synthesis is less facile. Nevertheless, a number of methods
have been described for the synthesis of a-substituted allyl
borates in enantiomerically enriched form.[2–5] However, the
synthesis of the more reactive a-substituted allyl boranes has
proved elusive: the only examples that have been reported
are those derived from the asymmetric hydroboration of
cyclic 1,3-dienes.[6] Herein we describe a simple procedure for
the synthesis of a-substituted allyl boranes with very high
enantioselectivity and demonstrate their utility in synthesis.
Scheme 1. The reaction of B-hexenyl-9-BBN (2a)with sulfonium
benzylide 1.
We recently described the reaction of chiral sulfur ylides
with symmetrical boranes which after oxidation furnished
secondary alcohols with very high enantioselectivity.[7] This
study suggested to us a potential solution to the synthesis of a-
substituted allyl boranes: the reaction of chiral sulfur ylides
with vinyl boranes. Substituted vinyl 9-borabicyclo-
[3.3.1]nonanes (9-BBNs) are easily obtained by regioselective
trapping with benzaldehyde furnished another homoallylic
alcohol 6a with similarly high diastereoselectivity (proce-
dure B, Scheme 1).
We applied procedure A to a range of vinyl boranes using
hydroboration of terminal alkynes with 9-BBN. However, in the chiral sulfonium salt 7[11] (Table 1) that had previously
the reaction of nonsymmetrical boranes with sulfur ylides,
issues of migration ability of the different groups have to be
addressed.[8] Although the vinyl group is expected to be a
better migrating group than the boracycle,[9] the outcome was
not clear, as we had already experienced surprises in the
reaction of B-phenyl-9-BBNwith the ylide derived from 1, in
which we found competing migration of the boracycle.[10]
In the event, reaction of the ylide derived from 1 with
vinylborane 2a at À1008C followed by addition of PhCHO at
the same temperature furnished the homoallylic alcohol 5a in
96% yield as a single diastereomer with high Z selectivity
(procedure A, Scheme 1). The high yield obtained clearly
indicated that the vinyl group migrated exclusively. We also
found that warming allylborane 3a to 08C resulted in
isomerization to 4a, which upon recooling to À788C and
been used in highly enantioselective reactions between
boranes and sulfur ylides,[7] epoxidations,[12] and other related
reactions.[13] In all cases, we observed essentially complete
enantio- and diastereoselectivity with very high Z selectivity.
Table 1: Reactions of enantiopure benzylide 7 with 9-BBN derivatives 2.
Entry
R
Yield (9)
Z/E[b]
d.r. [%][b,c]
ee [%][c]
[%][a]
1
2
3
4
5
nBu a
Me b
79
81
15:1
40:1
>40:1
>40:1
>40:1
>95
>95
>95
>95
>95
>99
>99
>99
>99
>99
[*] Dr. G. Y. Fang, Prof. Dr. V. K. Aggarwal
School of Chemistry
H c
61[d]
61[f,g]
72[h]
TMSOCH2[e]
d
University of Bristol
Cantock’s Close, Bristol, BS81TS (UK)
Fax: (+44)117-929-8611
AcOCH2CH2 e
[a] Yield of isolated product. [b] The ratios were obtained by 1H NMR
spectroscopy. [c] Data for Z isomers only. [d] The product from boracycle
migration, 1-phenyl-1-(5-hydroxycyclooctyl)methanol, was also isolated
in 15% yield. [e] TMS=trimethylsilyl. [f] The product from boracycle
migration was also isolated in 20% yield. [g] The compound was isolated
as the corresponding diol. [h] The product from boracycle migration was
also isolated in 12% yield.
E-mail: v.aggarwal@bristol.ac.uk
[**] We thank the EPSRC for financial support and Dr. J. P. H. Charmant
for X-ray analyses. V.K.A. thanks the Royal Society for a Wolfson
Research Merit Award.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 359 –362
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Table 2: Stereocontrolled synthesis of the homoallylic alcohols by
procedure B.
Furthermore, the chiral sulfide 10 could be reisolated in
greater than 90% yield in all cases. The reaction was
compatible with substituted and unsubstituted vinyl boranes,
and tolerated both ether and ester functionalities. Interest-
ingly, with the less electron-rich vinyl groups (entries 3–5),
competing migration of the boracycle, which led to 1-phenyl-
1-(5-hydroxycyclooctyl)methanol was also observed, thereby
resulting in somewhat reduced yields of the homoallylic
alcohols 9c–e.
The absolute stereochemistry of allylborane 8 originates
from the established high level of control of ylide conforma-
tion and face selectivity, followed by stereospecific 1,2-
metalate rearrangement of 11 (Scheme 2).[7] The high selec-
tivity in the subsequent reaction with the aldehyde across all
three elements of stereogenicity is believed to arise from the
chair transition state 12 (which is favored over transition state
13, which leads to the minor E isomer 14 with opposite
absolute stereochemistry).[14] In transition state 12, the a
substituent occupies an axial position to minimize steric
interactions with the bulky and conformationally locked
9-BBNmoiety (Scheme 2).
Entry
R
Yield (15)
Z/E[b]
d.r. [%][b,c]
ee [%][c]
[%][a]
1
2
3
4
nBu a
Me b
TMSOCH2 d
AcOCH2CH2 e
81
76
10:1
30:1
>30:1
13:1
>95
>95
>95
>95
>99
>99
>99
>99
49[d,e]
56[f]
[a] Yield of isolated product. [b] The ratios were obtained by 1H NMR
spectroscopy. [c] Data for Z isomers only. [d] The product from boracycle
migration was also isolated in 19% yield. [e] The yield of the
corresponding diols. [f] The product from boracycle migration was also
isolated in 12% yield.
calculations have suggested that
the 1,3-borotropic rearrangement
occurs through a pseudopericyclic
transition state,[18] but as far as we
are aware, this study provides the
first experimental proof of the
complete stereoselectivity and
suprafacial nature of this rear-
rangement (Scheme 2).[19]
This stereocontrolled three-
component-coupling
reaction
was applied to a short synthesis
of iso-agatharesinol, isolated
Scheme 2. Rationale for the observed stereochemistry.
from the roots of asparagus gobi-
cus.[20] Members of this family of
nor-lignans show potent cytotox-
Procedure B was also applied to the same range of vinyl
boranes and chiral sulfonium salt 7 (Table 2). Again, essen-
tially complete enantio- and diastereoselectivity was observed
with high Z selectivity. Since procedures A and B share
common borate intermediates 11, the competing migration of
the boracycle, previously seen with less electron-rich vinyl
boranes, was again observed (Table 2, entries 3 and 4). The
relative and absolute stereochemistry of 9b and 15a were
determined by transformation into known diols (see the
Supporting Information).[4]
icity against human ovarian carcinoma and human hepa-
toma.[18] However, the relative and absolute stereochemistry
of one member of this family, iso-agatharesinol, has not yet
been established (Scheme 4).[20] To determine the structure of
the natural product, we set about synthesizing both diaste-
reomers of iso-agatharesinol with the 3S configuration
because this absolute stereochemistry had been established
in related compounds such as nyasol.[21]
The complete selectivity observed following procedure B
is consistent with the 1,3-borotropic rearrangement being a
highly stereoselective, intramolecular process which leads to
4’ rather than 4’’ (Scheme 3). The preferred formation of 4’
over 4’’ results from minimization of the A1,3 strain[15] in the
conformations required (3’ and 3’’) for the borotropic
rearrangement to occur. Crotyl borane reagents are known
to rapidly isomerize,[16] and racemization of allyl boranes has
also been noted,[17] but such observations do not provide any
information on the nature of the rearrangement. Theoretical
Scheme 3. Proposed [1,3]-borotropic rearrangement.
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Scheme 4. Structures of iso-agatharesinol and nyasol.
We initially explored the racemic synthesis of iso-agatha-
resinol using the achiral sulfonium salt 16a (Scheme 5). Thus,
treatment of sulfonium salt 16a with base followed by
reaction with vinylborane 17a and subsequent addition of
the required aldehyde furnished the homoallylic alcohol
18aa, but in only 42% yield. Product 18aa was also
accompanied by 49% of the eight-membered-ring diol 19a,
which resulted from migration of the boracycle followed by
oxidation. We believe that the competing migration of the
Scheme 6. Racemic synthesis of both possible diastereomers of
iso-agatharesinol. DEAD=diethylazodicarboxylate, TBAF=
tetra-n-butylammonium fluoride.
reported data for the natural product
most closely matched polyol 20. In par-
ticular, the diastereotopic methylene pro-
tons in 20 appeared close together as a
1
multiplet in the H NMR spectrum (sim-
ilar to that reported) whereas in 21 they
were widely separated in a classic ABX
system.[23]
Having established the relative ste-
reochemistry of iso-agatharesinol, the
asymmetric synthesis was carried out
beginning with the chiral sulfonium salt
22 (Scheme 7). The key ylide addition,
1,2-metalate rearrangement,[24] and trap-
ping with the aldehyde occurred in 72%
yield and with greater than 99% ee, and
without migration of the boracycle.
Deprotection furnished iso-agatharesinol
whose data ([a]2D0 = + 50.7 (c = 0.75, ace-
tone)) corresponded with those reported
([a]2D0 =+ 49.7 (c = 5.40, acetone)).[20] We
Scheme 5. Establishment of suitable protecting groups on the phenol function.
TBS=tert-butyldimethylsilyl.
boracycle originates from the rearrangement process becom-
ing more facile when the ylidic carbon atom is substituted
with an electron-rich aromatic group (which helps expel the
sulfide leaving group) and so the benefit of the higher
migratory ability of the vinyl group on the borane is
attenuated.[10] As the methoxy groups were also difficult to
remove without destroying the sensitive cis olefin, we
substituted the strongly electron-donating methoxy group
on the ylide for the much weaker pivalate (Piv) group 16b.
This time, reaction of ylide 16b with vinylborane 17b
followed by the aldehyde gave homoallylic alcohol 18bb in
78% yield (Z/E 10:1), with no migration of the boracycle
observed (Scheme 5).
Deprotection of 18bb gave the required polyol 20 in 81%
yield (Scheme 6). The other diastereomer 21 was prepared by
Mitsunobu inversion[22] of alcohol 18bb followed by depro-
tection as before (Scheme 6). Of the two isomers, the
Scheme 7. Synthesis of (+)-iso-agatharesinol.
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361

Communications
[7] V. K. Aggarwal, G. Y. Fang, A. T. Schmidt, J. Am. Chem. Soc.
2005, 127, 1642.
[8] V. K. Aggarval, G. Y. Fang, X. Ginesta, D. M. Howells, M. Zaja,
Pure Appl. Chem. 2006, 78, 215.
[9] M.-Z. Deng, N.-S. Li, Y.-Z. Huang, J. Org. Chem. 1982, 47, 4017.
[10] R. Robiette, G. Y. Fang, J. N. Harvey, V. K. Aggarwal, Chem.
Commun. 2006, 741.
[11] V. K. Aggarwal, E. Alonso, G. Hynd, K. M. Lydon, M. J. Palmer,
M. Porcelloni, J. R. Studly, Angew. Chem. 2001, 113, 1479;
Angew. Chem. Int. Ed. 2001, 40, 1430.
[12] a) V. K. Aggarwal, E. Alonso, I. Bae, G. Hynd, K. M. Lydon,
M. J. Palmer, M. Patel, M. Porcelloni, J. Richardson, R. A.
Stenson, J. R. Studley, J.-L. Vasse, C. L. Winn, J. Am. Chem. Soc.
2003, 125, 10926; b) V. K. Aggarwal, I. Bae, H.-Y. Lee, D. T.
Williams, Angew. Chem. 2003, 115, 3396; Angew. Chem. Int. Ed.
2003, 42, 3274. .
have thus established the relative and confirmed the absolute
stereochemistry of isoagatharesinol.
In conclusion, we have described a new method for the
stereocontrolled synthesis of allyl boranes and their subse-
quent reactions with aldehydes which occur with almost
complete selectivity over the three elements of stereogenicity
created. Furthermore, we have shown that the allyl boranes
also undergo a stereospecific 1,3-borotropic rearrangement
leading to new allyl boranes which also show almost complete
selectivity in reactions with aldehydes. The efficiency of this
process has been demonstrated by a short synthesis of the nor-
lignan, iso-agatharesinol, which also confirmed its structure.
Received: September 7, 2006
Published online: December 5, 2006
[13] V. K. Aggarwal, C. L. Winn, Acc. Chem. Res. 2004, 37, 611.
[14] R. W. Hoffmann, U. Weidmann, J. Organomet. Chem. 1980, 195,
137.
[15] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841.
[16] a) H. C. Brown, R. Liotta, G. W. Kramer, J. Am. Chem. Soc.
1979, 101, 2966; b) H. C. Brown, P. K. Jadhav, K. S. Bhat, J. Am.
Chem. Soc. 1985, 107, 2564; c) K.K. Wang, Y. G. Gu, C. Liu, J.
Am. Chem. Soc. 1990, 112, 4424.
[17] H. C. Brown, K. S. Bhat, P. K. Jadhav, J. Chem. Soc. Perkin Trans.
1 1991, 2633.
[18] U. Henriksen, J. P. Snyder, T. A. Halgren, J. Org. Chem. 1981, 46,
3767.
[19] This experiment provides indirect proof of the stereochemical
course of the 1,3-borotropic rearrangement. Attempts to provide
more direct evidence through oxidation of the two allyl boranes
were not successful because of rapid isomerization of borane 8 to
its allylic isomer.
[20] C.-X. Yang, S.-S. Huang, X.-P. Yang, Z.-J. Jia, Planta Med. 2004,
70, 446.
[21] G. B. Marini-Bettolo, M. Nicoletti, I. Messana, Tetrahedron
1985, 41, 665.
Keywords: asymmetric synthesis · boranes ·
.
homoallylic alcohols · sulfur · ylides
[1] For reviews on allyl boranes, see: a) Y. Yamamoto, N. Asao,
Chem. Rev. 1993, 93, 2207; b) W. R. Roush, in Methoden der
Organischen Chemie (Houben-Weyl), Vol. 3 E21 (Eds: G.
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, 1996, pp. 1410 – 1486; c) Y. Bubnov in Science
of Synthesis, Vol. 6 (Eds.: D. E. Kaufmann, D. S. Matteson),
Thieme, Stuttgart, 2004, pp. 945 – 1072; For recent develop-
ments, see: d) J. W. Kennedy, D. G. Hall, J. Am. Chem. Soc. 2002,
124, 11586; e) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006,
128, 9646; f) E. Canales, K. G. Prasad, J. A. Soderquist, J. Am.
Chem. Soc. 2005, 127, 11572; g) P. V. Ramachandran, T. E.
Burghardt, M. V. R. Reddy, J. Org. Chem. 2005, 70, 2329.
[2] a) R. W. Hoffmann, S. Dresely, Chem. Ber. 1989, 122, 903;
b) R. W. Hoffmann, K. Ditrich, G. Köster, R. Stürmer, Chem.
Ber. 1989, 122, 1783; c) R. W. Hoffmann, S. Dresely, J. W. Lanz,
Chem. Ber. 1988, 121, 1501.
[22] S. F. Martin, J. A. Dodge, Tetrahedron Lett. 1991, 32, 3017.
[23] We thank Prof. Jia for sending us the 1H and 13C NMR spectra of
an authentic sample of iso-agatharesinol.
[24] a) D. S. Matteson, D. Majumdar, J. Am. Chem. Soc. 1980, 102,
7588; b) P. Kocienski, C. Barber, Pure Appl. Chem. 1990, 62,
1933.
[3] E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644.
[4] J. Pietruszka, N. Schöne, Eur. J. Org. Chem. 2004, 5011.
[5] D. S. Matteson, D. J. S. Tsai, Organometallics 1983, 2, 236.
[6] H. C. Brown, P. K. Jadhav, K. S. Bhat, J. Am. Chem. Soc. 1985,
107, 2564.
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