Stereodivergent addition of 4-silyloxy-1,2-allenes to aldehydes by hydroboration

Article abstract of DOI:10.1002/chem.201001563

All-ene one! Three out of four stereoisomers of 2-vinyl-1,3-diols can be obtained from a single allene. A simple variation of the reaction conditions modifies the stereochemical outcome of the addition of an allene to an aldehyde via hydroboration. Stereocontrol is dependent upon the order in which the reagents are mixed (leading to E or Z boron species) and the type of aldehyde (aliphatic or aromatic) used.

Full text of DOI:10.1002/chem.201001563

COMMUNICATION
DOI: 10.1002/chem.201001563
Stereodivergent Addition of 4-Silyloxy-1,2-Allenes to Aldehydes by
Hydroboration
Carolina Sꢀnchez, Xavier Ariza,* Josep Cornellꢁ, Jaume Farrꢁs, Jordi Garcia,* and
Jordi Ortiz[a]
Dedicated to Professor Pelayo Camps on the occasion of his 65th birthday
Chiral allyl- and crotylboron reagents have demonstrated
their value for the stereoselective conversion of aldehydes
into homoallylic alcohols.[1] Asymmetric induction is usually
controlled by terpene[1,2] and tartrate[1,3] ligands linked to
boron or by using chiral aldehydes, or by both methods.
However, the use of chiral allyl or crotyl moieties has been
less explored.[1,4] A careful analysis of the chair-like transi-
tion state involved in such additions (Scheme 1) shows that
the d position of the crotyl group can have a direct effect on
crotylboron reagents, particularly when they are highly func-
tionalized. In many cases, preparation involves the use of 2-
alkenyl metal reagents that are incompatible with some
functionalities.[1d] The hydroboration of allenes[5] might be a
versatile alternative to the preparation of crotylborane I
since it obviates the use of transient reactive organometal-
lics.[1d,6] In our search for new methods for the preparation
of polyols,[7] we anticipated that the hydroboration of allene
II, which has a stereocentre next to the allenyl moiety, fol-
lowed by the addition to an aldehyde would afford 1,3 diols
with high stereoselectivity (Scheme 2).
À
the stereoselectivity since it is near to the new C C bond. In
fact, this position (R* in Scheme 1) is as close to the new
À
C C bond as the a carbon of the aldehyde (R’). Since R’
can exert a pivotal role in the stereoselectivity of the reac-
tion in chiral aldehydes,[1] we anticipated that the unex-
plored use of crotylboron reagents (I) with a stereocenter at
the d position would also provide satisfactory stereoselectiv-
ity.
Scheme 2. Allene hydroboration followed by an aldehyde addition.
Our initial proposal for allene II was (S)-nonan-1,2-dien-
3-ol protected as tert-butyldimethylsilyl ether ((S)-1), which
is easily obtained from commercially available (S)-3-octin-1-
ol in two steps.[8] Thus, allene (S)-1, was hydroborated with
dicyclohexylborane (1.1 equiv) in CH2Cl2 at RT for two
hours (Scheme 3) and then isobutyraldehyde (1.4 equiv) was
added at À788C. Pleasingly, the reaction afforded the ex-
pected 1,3-diol as a major isolable syn,syn-3a stereoisomer
(>99:1 e.r.)[9] in good yields. In addition to the major
syn,syn isomer, a small amount of a 7:3 mixture of anti,syn
and anti,anti was also isolated.
The observed syn,syn and anti,syn relative configurations
for the major isomer of 3a agree with those expected for
the addition of thermodynamically favoured 2-alkenylbor-
ane (E)-2 to both faces of the aldehyde through a chair-like
transition state (Scheme 1), whereas the anti,anti isomer
could have arisen in a similar way from (Z)-2.[10,11] Thus, we
Scheme 1. Crotylboron addition to aldehydes.
A serious challenge in the allylboration of aldehydes
arises from the stereoselective preparation of the required
[a] C. Sꢀnchez, Dr. X. Ariza, J. Cornellꢁ, Dr. J. Farrꢁs, Dr. J. Garcia,
Dr. J. Ortiz
Departament de Quꢂmica Orgꢁnica, Fac. de Quꢂmica
Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona
C/Martꢂ i Franquꢃs 1-11, 08028 Barcelona (Spain)
Fax : (+34)933397878
E-mail: xariza@ub.edu
jordigarciagomez@ub.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001563.
Chem. Eur. J. 2010, 16, 11535 – 11538
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11535

Table 1. Hydroboration of 1 followed by addition of aldehydes.
Entry
R’
(aldehyde)
Major
product
Facial
E/Z[b]
Yield
[%]
G
selectivity[a]
1
2
3
4
ethyl
syn,syn-3b
syn,syn-3c
syn,syn-3d
syn,syn-3e
91:9
89:11
95:5
93:7
93:7
96:4
95:5
97:3
59
65
71
95
n-pentyl
phenyl
2-furyl
[a] syn,syn/anti,syn ratio. [b] Ratio of (syn,syn
syn,anti) isomers.
+ anti,syn)/(anti,anti +
leads to the observed syn,syn adduct, while the transition
state that leads to the anti,syn isomer (TS2) is 1.4 kcalmolÀ1
higher, in qualitative agreement with the experimental data.
These results indicate that the preference for syn,syn ad-
ducts can be attributed to the ability of TS1 to minimize the
interactions of the chain of the aldehyde and the substitu-
ents at the chiral center of crotylboron reagent.
In an effort to improve our control of the Z/E ratio of the
2-alkenyl borane intermediate, alternative hydroborating
agents were considered. Thus, 9-BBN under the conditions
Scheme 3. Hydroboration of 1 followed by the addition of isobutyralde-
hyde.
concluded that although the Z isomer is probably formed
faster in the hydroboration step for steric reasons, it under-
goes extensive isomerization to its E isomer at RT by a
known boratropic allylic rearrangement.[12] According to the
data, the facial selectivity of the crotyl reagent (E)-2 gener-
ated in situ in the addition was 93:7 (ratio syn,syn/anti,syn).
We explored the scope of this reaction with a set of repre-
sentative aldehydes (Table 1). Satisfactory yields of isolable
syn,syn-3 were consistently obtained for both aliphatic and
aromatic aldehydes, again showing the high facial selectivity
(ratio syn,syn/anti,syn) of the transient E crotyl reagent gen-
erated by hydroboration (E/Z ratio ~95:5).[13]
The effect of the protecting group in the allene was also
examined. When TBS was replaced by TBDPS in allene 1
similar yields and selectivities were observed in the addition
to benzaldehyde. The corresponding homoallylic alcohol
was obtained in 77% yield with a 95:5 syn,syn/anti,syn dia-
stereomeric ratio. Other O-protecting groups on nonan-1,2-
dien-3-ol such as acetyl or benzyl or even the unprotected
allenol did not afford the expected products.
Major syn,syn isomer could be also isolated in good yield
when we extended our protocol to the addition of other rac-
emic allenes (R=Me, iPr and Ph) to a variety of aliphatic,
a,b-unsaturated and aromatic aldehydes. As shown in
Table 2, in all the cases the
facial selectivity of the major E
crotyl reagent (E/Z ratio
~95:5) was at least 92:8.[13]
Scheme 4. Reaction of model crotylboron reagent 10 with acetaldehyde.
Table 2. Hydroboration of allenes 4–6 followed by addition of aldehydes.
In an attempt to explain the
high facial selectivity of the
chiral boron reagent, the reac-
tion of model crotylboron re-
agent 10 with acetaldehyde was
modelled using the Gaussi-
an03[14] series of programs. As
Entry
R
R’
(aldehyde)
Major
product
Facial
E/Z[b]
Yield
[%]
A
G
selectivity[a]
1
2
3
4
5
6
7
8
methyl (4)
methyl (4)
methyl (4)
isopropyl (5)
isopropyl (5)
isopropyl (5)
phenyl (6)
phenyl (6)
ethyl
isopropyl
2-furyl
n-pentyl
phenyl
1-nonenyl
n-pentyl
isopropyl
syn,syn-7a
syn,syn-7b
syn,syn-7c
syn,syn-8a
syn,syn-8b
syn,syn-8c
syn,syn-9a
syn,syn-9b
93:7
93:7
93:7
95:5
96:4
98:2
92:8
95:5
95:5
96:4
96:4
96:4
96:4
96:4
96:4
95:5
54
65
81
60
65
83
88
79
shown
in
Scheme 4
and
Figure 1, at the RHF/6-31G**
level of theory, the lowest-
energy transition state (TS1)
[a] syn,syn/anti,syn ratio. [b] Ratio of (syn,syn + anti,syn)/(anti,anti + syn,anti) isomers.
11536
www.chemeurj.org
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11535 – 11538

Stereodivergent Addition of Allenes to Aldehydes
COMMUNICATION
hydes and ketones, this process is slow at low tempera-
tures.[19] Thus, we envisaged that the hydroboration of the
allene might be possible in the presence of the aldehyde. We
hypothesized that when the allene was hydroborated to
form the kinetic Z boron reagent it would be immediately
trapped by the aldehyde. Therefore, the unprecedented idea
of hydroborating the allene in the presence of the aldehyde
should allow us to isolate anti,anti-3 or syn,anti-3 as major
isomers rather than the syn,syn-3. As expected, when dicy-
clohexylborane (1.1 eq) was added to a mixture of allene 1
and ethanal in CH2Cl2 at 08C anti,anti-3b (entry 1, Table 3)
was isolated as major isomer at RT. The analysis of the
minor stereoisomers revealed a notable 6:94 facial diaste-
reoselectivity (syn,anti/anti,anti ratio) in the addition of the
Z alkenyl borane intermediate to the aldehyde.[20] The main
minor isomer detected was syn,syn-3b possibly resulting
from the partial isomerization of (Z)-2 to (E)-2 (Z/E ratio
86:14). The same behavior was observed for the addition of
a number of racemic allenes to aliphatic, aromatic and het-
eroaromatic aldehydes (Table 3).[13]
Remarkably, the facial stereoselectivity in the addition to
aromatic aldehydes was very good (up to >99:1) but with
opposite facial bias (syn,anti products) to that noted for the
aliphatic ones (anti,anti products). This behavior is observed
for both electron-rich (p-methoxybenzaldehyde or furfural)
and electrondeficient aldehydes (p-nitrobenzaldehyde). This
unexpected effect could be explained by assuming a twist-
boat transition state that can overcome the more usual
chair-like arrangement in such cases. In fact, this situation
has been suggested for the reaction of (Z)-2-alkenyl metals
with hindered aldehydes.[21,22]
Figure 1. Calculated transition state for adduct syn,syn-11.
of Scheme 3 gave the same major stereoisomer (syn,syn-3a)
but in lower yield and diasteromeric ratio (83:17). Interest-
ingly, when (S)-1 was hydroborated at RT with (À)-Ipc2BH
the anti,anti-3a isomer, presumably arising from the (Z)-2
borane intermediate, was obtained (d.r. 85:15)[15] in 54%
yield. The diastereomeric ratio was improved to 91:9 when
the same reaction was performed at À258C (55% yield).
The mismatch reaction with (+)-Ipc2BH at RT yielded a dis-
appointing mixture (40 (anti,anti): 40 (syn,anti): 20 (anti,
syn)). On the other hand, we also explored the effect of the
temperature on the selectivity of the hydroboration. Surpris-
ingly, when the hydroboration of 1 with dicyclohexylborane
was performed at lower temperature (À408C) the stereose-
lectivity switched to the anti,anti-3a isomer (d.r. 88:12)[11]
but in low yield (17%) probably due to the fact that the hy-
droboration was incomplete under these conditions.
In conclusion, we have established a new stereodivergent
approach to 2-vinyl-1,3-diols based on a hydroboration of
These experiments suggest that when dicyclohexylborane
or 9-BBN was used, (Z)-2 was
first formed in the hydrobora-
Table 3. Hydroboration–addition to aldehydes by “one-pot” protocol.
tion step (probably between
À40 and À208C) but it easily
isomerized at RT to the more
stable isomer (E)-2. However,
at lower temperatures or when
a more hindered hydroborating
agent is involved (Ipc2BH), the
Z/E isomerization could be
slow enough to achieve the ad-
dition of (Z)-2 to the alde-
hyde.[1d,16]
Nevertheless, none of these
attempts to control the Z/E
configuration of the boron in-
termediate during the hydrobo-
ration step was completely sat-
isfactory. Neither the change of
the temperature[17] nor the use
of other hydroborating agent[18]
was successful.
Entry
R (allene)
R’ (aldehyde)
Major
product
Facial
Z/E[b]
Yield
[%]
selectivity[a]
1
2
3
4
5
6
7
8
n-pentyl (1)
n-pentyl (1)
n-pentyl (1)
n-pentyl (1)
methyl (4)
ethyl
phenyl
2-furyl
anti,anti-3b
syn,anti-3d
syn,anti-3e
syn,anti-3 f
anti,anti-7b
syn,anti-7c
anti,anti-8a
syn,anti-8b
syn,anti-8d
syn,anti-8e
anti,anti-9a
anti,anti-9b
6:94
92:8
>99:1
>99:1
9:91
86:14
88:12
84:16
93:7
84:16
80:20
80:20
91:9
80:20
84:16
85:15
85:15
65
70
90
58
87
66
86
65
67
56
53
60
p-MeO-C6H4
isopropyl
2-furyl
n-pentyl
phenyl
p-MeO-C6H4
p-NO2-C6H4
n-pentyl
isopropyl
methyl (4)
97:3
isopropyl (5)
isopropyl (5)
isopropyl (5)
isopropyl (5)
phenyl (6)
15:85
>99:1
98:2
99:1
11:89
11:89
9
10
11
12
phenyl (6)
Although borane or alkylbor-
ane species can reduce alde- [a] syn,anti/anti,anti ratio. [b] Ratio of (anti,anti + syn,anti)/(syn,syn + anti,syn) isomers.
Chem. Eur. J. 2010, 16, 11535 – 11538
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11537

J. Garcia, X. Ariza et al.
[7] a) Y. Georges, Y. Allenbach, X. Ariza, J.-M. Campagne, J. Garcia, J.
Org. Chem. 2004, 69, 7387–7390; b) X. Ariza, J. Garcia, Y. Georges,
M. Vicente, Org. Lett. 2006, 8, 4501–4504.
[8] a) S. Searles, Y. Li, B. Nassim, M.-T. Robert Lopes, P. T. Tran, P.
Crabbꢆ, J. Chem. Soc. Perkin Trans. 1 1984, 747–751; b) S. Ma, H.
Hou, S. Zhao, G. Wang, Synthesis 2002, 1643–1645.
[9] The enantiomer of syn,syn-3a was also prepared from allene (R)-1.
The enantiomeric purity was >99:1 as determined by HPLC analy-
sis of the corresponding benzoates using a Chiralpak IA column
(see the Supporting Information).
[10] An analogous cyclic transition state for (Z)-2 was assumed to ac-
count the formation of anti,anti- and syn,anti-3a.
allene/addition of aldehyde tandem process. The stereocen-
ter present next to the allenyl moiety (C1) in the starting
allene effectively determines the configuration of the new
formed carbinol (C3) whereas the relative configuration of
C2 and C3 is determined by the configuration (E/Z) of the
transient 2-alkenylborane intermediate. It should be noted
that the order of mixing of the reagents and the kind of al-
dehyde used allowed us to obtain three out of the four pos-
sible diastereomers of the 1,3-diol.
[11] For the relative configurational assignments, see the Supporting In-
formation.
Acknowledgements
[12] For a discussion on the configurational stability of allylmetal com-
pounds, see: a) R. W. Hoffmann, Angew. Chem. 1982, 94, 569–580;
Angew. Chem. Int. Ed. Engl. 1982, 21, 555–566. See also: b) K. K.
Wang, Y. G. Gu, C. Liu, J. Am. Chem. Soc. 1990, 112, 4424–4431;
c) D. H. Ess, J. Kister, M. Chen, W. R. Roush, Org. Lett. 2009, 11,
5538–5541.
This work has been supported by the Ministerio de Educaciꢅn y Ciencia
(CTQ2006-13249 and CTQ2009-09692). We thank the Generalitat de
Catalunya for a doctorate studentship to C.S. and J.O.
[13] Detailed data of the isomeric product composition of crude mixtures
are given in the Supporting Information.
Keywords: aldehydes · allenes · asymmetric synthesis ·
hydroboration
[14] Gaussian 03, Revision E.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
ery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004.
[1] a) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207–2293; b) D.
Hoppe in Stereoselective Synthesis Methods of Organic Chemistry
(Houben–Weyl), E21b, Vol. 3 (Eds.: G. Helmchen, R. W. Hoffmann,
J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1996, pp. 1357–1486;
c) W. R. Roush in Stereoselective Synthesis Methods of Organic
Chemistry (Houben–Weyl), E21b, Vol. 3 (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1996,
pp. 1410–1486; d) M. V. Perkins in Science of Synthesis, Vol. 36
(Ed.: J. Clayden), Thieme, Stuttgart, 2008, pp. 667–753; e) Y.
Bubnov in Science of Synthesis, Vol. 36 (Ed.: J. Clayden), Thieme,
Stuttgart, 2008, pp. 945–1064.
[2] a) H. C. Brown, P. K. Jadhav, J. Am. Chem. Soc. 1983, 105, 2092–
2093; b) P. K. Jadhav, K. S. Bhat, P. T. Perumal, H. C. Brown, J. Org.
Chem. 1986, 51, 432–439; c) H. C. Brown, K. S. Bhat, R. S. Randad,
J. Org. Chem. 1989, 54, 1570–1576; d) P. V. Ramachandran, Aldri-
chimica Acta 2002, 35, 23–35.
[15] The main minor isomer was syn,syn-3a.
[16] The sterically hindered disiamylborane gave also anti,anti-3a (d.r.
80:9:11 anti,anti/syn,syn/anti,syn) as the major isomer.
[17] For a successful control of the E/Z configuration by changing the
temperature, see: reference [6g].
[18] For the stereoselective formation of (Z)-boron intermediates by hy-
droboration, see: references [6d,f].
[3] a) W. R. Roush, A. E. Walts, L. K. Hoong, J. Am. Chem. Soc. 1985,
107, 8186–8190; b) W. R. Roush, R. L. Halterman, J. Am. Chem.
Soc. 1986, 108, 294–296; c) W. R. Roush, K. Ando, D. B. Powers,
A. D. Palkowitz, R. L Halterman, J. Am. Chem. Soc. 1990, 112,
6339–6348.
[4] R. W. Hoffmann, Pure Appl. Chem. 1988, 60, 123–130.
[5] For a review on allene chemistry, see: a) Modern Allene Chemistry
(Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004;
b) S. Ma, Aldrichimica Acta 2007, 40, 91–102; c) H. H. A. M.
Hassan, Curr. Org. Synth. 2007, 4, 413–439; d) H. Kim, L. J. Wil-
liams, Curr. Opin. Drug Discovery Dev. 2008, 11, 870–894.
[6] a) H. C. Brown, G. Narla, J. Org. Chem. 1995, 60, 4686–4687; b) G.
Narla, H. C. Brown, Tetrahedron Lett. 1997, 38, 219–222. For some
recent examples of the use of functionalized alkenyl boranes pre-
pared by hydroboration, see: c) Y. Yamamoto, R. Fujikawa, A.
Yamada, N. Miyaura, Chem. Lett. 1999, 1069–1070; d) R. Pragani,
W. R. Roush, Org. Lett. 2008, 10, 4613–4616; e) A. Z. Gonzꢀlez,
J. G. Romꢀn, E. Alicea, E. Canales, J. A. Soderquist, J. Am. Chem.
Soc. 2009, 131, 1269–1273; f) J. Kister, A. C. DeBaillie, R. Lira,
W. R. Roush, J. Am. Chem. Soc. 2009, 131, 14174–14175; g) M.
Chen, M. Handa, W. R. Roush, J. Am. Chem. Soc. 2009, 131, 14602–
14603; h) F. Li, W. R. Roush, Org. Lett. 2009, 11, 2932–2935; i) X.
Ariza, J. Cornellꢁ, J. Garcia, J. Ortiz, C. Sꢀnchez, M. Font-Bardia,
X. Solans, Angew. Chem. 2009, 121, 4266–4269; Angew. Chem. Int.
Ed. 2009, 48, 4202–4205.
[19] A. Pelter, K, Smith in Comprehensive Organic Chemistry, Vol. 3
(Eds.: D. H. R. Barton, W. D. Ollis), Pergamon, Oxford 1979,
pp. 689–940.
[20] Major anti,anti and syn,anti products of Table 3 were easily separat-
ed from the mixture of the rest of minor isomers by flash chroma-
tography. The same applies for the syn,syn major compounds in
Tables 1 and 2.
[21] Reference [1b], pp. 1361–1364.
[22] In contrast with the performed ab initio calculations for the addition
of (E)-2-alkenylboranes to aldehydes in which the chair-like transi-
tion states are predicted to dominate over boat-like arrangements,
the situation is less clear for the (Z)-2-alkenyl boranes where differ-
ent transition states of similar energy could be found.
Received: June 3, 2010
Revised: August 3, 2010
Published online: August 30, 2010
11538
www.chemeurj.org
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11535 – 11538