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DOI: 10.1055/s-0028-1087641
Asymmetric Pentenylation of Aldehydes: A New Benchmark for the Preparation of Ethyl-Substituted Homoallylic Alcohol
Publication History
Publication Date:
15 January 2009 (online)
Abstract
A highly diastereo- and enantioselective boron-mediated pentenylation reaction is presented. The chiral pentenylborane reagents, which are derived from pinene, undergo addition to various aldehydes to afford ethyl-substituted homoallylic alcohols in good yield and high stereoselectivity. The latter are then easily converted into the corresponding α,β-unsaturated δ-lactones using an acylation/ring-closing metathesis sequence. The relative and absolute stereochemistry is exclusively controlled by the reagent.
Key words
asymmetric pentenylation - α,β-unsaturated lactone - ring-closing metathesis
During the past two decades, carbonyl allylations and crotylations have become important tools in modern organic synthesis, especially for the construction of polyketide natural products. [¹] In this context, a plethora of effective protocols have been developed to provide excellent levels of diastereo- and enantioselection. The methods developed by Brown, [²] Roush [³] and Duthaler [4] are notable among them, as the absolute and relative configurations of the resulting homoallylic alcohols are mainly determined by the choice of the reagent. Interestingly, whereas all these methods allow an easy access to the propionate subunit, there were no general methods leading to the homologous butyrate subunit reported when we started this work. [5] Since then, Hatakeyama et al. reported one example in their synthesis of phoslactomycin B. [6] The need for developing such a method is especially felt when trying to synthesize molecules containing an α,β-unsaturated δ-lactone substituted at the γ-position by an ethyl group, as this motif is present in a number of natural products such as pironetin [7] (1) and leustroducsin B [8] (2), which exhibit interesting antifungal, antibacterial and antitumoral activities (Figure [¹] ).

Figure 1 Structure of pironetin (1) and leustroducsin B (2)
In this communication, we wish to report a highly stereoselective boron-mediated pentenylation reaction which allows a straightforward access to both syn- and anti-ethyl-substituted homoallylic alcohols in good yields (Scheme [¹] ). [9] The latter were further converted into the corresponding α,β-unsaturated δ-lactones through an acylation/ring-closing metathesis sequence. Our strategy to develop a reagent for the asymmetric pentenylation of aldehydes was based upon the crotylboron reagent developed by Brown and thus derived from diisopino-campheylborane and either (Z)- or (E)-2-pentene. Also, we expected that this new reagent would react in a similar fashion and therefore operate via a rigid chair-like Zimmerman-Traxler transition state, which should ensure a highly stereochemical transfer of the reagent’s olefinic geometry.

Scheme 1 Synthesis of syn- and anti-ethyl substituted homoallylic alcohols through boron-mediated asymmetric pentenylation
The chiral pentenylating reagent was generated in situ following Brown’s procedure [¹0] starting from (+)-methoxydiisopinocampheylborane and (Z)-2-pentene in the presence of the Schlosser base, [¹¹] and tested on 3-phenylpropionaldehyde (Table [¹] , entry 1). To our delight, the asymmetric pentenylation process gave rise to the corresponding homoallylic alcohol in high yield (71%), good diastereoselectivity (syn/anti = 15:1) and an excellent enantioselectivity of 91% as determined by chiral SFC analysis (see footnote d in Table [¹] ).
With these conditions in hand, a close examination of the reagent’s scope was undertaken with a set of aliphatic, aromatic and propargylic aldehydes. The results are reported in Table [¹] . As a general trend, the syn diastereoisomer was formed as the major product (dr >15:1). In addition, both the yields and the enantioselectivities were good ranging from 53% to 92% and from 64% to 92%, respectively. Finally, we were able to confirm the absolute stereochemistry of the products by performing ¹H NMR analyses on the corresponding mandelate derivatives. [¹²]
In order to show that the selectivity of this pentenylation process is solely dependant on the reagent, we successively applied the (+)- and the (-)-diisopinocampheylpentenylborane to aldehyde 3 bearing a substituent at the α-position (Scheme [²] ). With these two reagents, moderate yields (40-51%) and high selectivities were observed (4/5/6/7 = 10:1:0:0 and 4/5/6/7 = 1:10:0:0, respectively). More interestingly, the ratios obtained confirmed that the reaction was totally under reagent control in a similar fashion to Brown’s crotylation. [²]

Scheme 2 syn-Pentenylation of an α-branched aldehyde
Following these initial results, we turned our attention to the use of the analogous (E)-pentenylborane reagent which should lead to the anti-ethyl substituted homoallylic alcohols. As expected, under a slightly modified procedure, [¹³] the corresponding anti product could be isolated in high yield (78%) and reasonable enantioselectivity (76% ee; Scheme [³] ).

Scheme 3 anti-Pentenylation of 3-bromobenzaldehyde
Finally, the previously obtained homoallylic alcohols were efficiently converted into the corresponding α,β-unsaturated δ-lactones through a two-step sequence involving an acylation and a ring-closing metathesis (Table [²] ). [¹4]
In conclusion, we have developed two highly enantio- and diastereoselective reagents for the pentenylation of aldehydes, which offer a great alternative to the standard aldol processes. [¹5] While the (Z)-pentenylborane reagent allows access to syn-ethyl substituted homoallylic alcohols, the analogous (E)-pentenylborane analogue leads to the anti- stereoisomer. We have also prepared a variety of α,β-unsaturated δ-lactones in good yields thus illustrating the importance of this methodology in the synthesis of complex natural products with interesting biological activities.
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Entry | Substrate | Product | Yield (%)a | ||||||||||||||||
1 |
![]() |
![]() | 58 | ||||||||||||||||
2 |
![]() |
![]() | 55 | ||||||||||||||||
3 |
![]() |
![]() | 60 | ||||||||||||||||
4 |
![]() |
![]() | 71 | ||||||||||||||||
5 |
![]() |
![]() | 80 | ||||||||||||||||
6 |
![]() |
![]() | 80 | ||||||||||||||||
7 |
![]() |
![]() | 80 | ||||||||||||||||
8 |
![]() |
![]() | 77 | ||||||||||||||||
| |||||||||||||||||||
a Isolated
yield. |
- For recent reviews, see:
- 1a
Main
Group Metals in Organic Synthesis
Vol. 2:
Yamamoto H.Oshima K. Wiley-VCH; Weinheim: 2004. - 1b
Junzo O. Modern Carbonyl Chemistry Wiley-VCH; Weinheim: 2000. - 1c
Marshall JA. Chem. Rev. 2000, 100: 3163 - 1d
Marshall JA. Chem. Rev. 1996, 96: 31 - 1e
Yamamoto Y.Asao N. Chem. Rev. 1993, 93: 2207 - 1f
Nishigaichi Y.Takuwa A.Naruta Y.Maruyama K. Tetrahedron 1993, 49: 7395 - 1g
Roush WR. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I.Heathcock CH. Pergamon; Oxford: 1991. p.1-53 - 2
Brown HC.Bhat KS.Randad RS. J. Org. Chem. 1989, 54: 1570 - 3
Roush WR.Ando K.Powers DB.Palkowitz AD.Halterman RL. J. Am. Chem. Soc. 1990, 112: 6339 - 4
Hafner A.Duthaler RO.Marti R.Rihs G.Rhote-Streit P.Schwarzenbach F. J. Am. Chem. Soc. 1992, 114: 2321 - 5 A racemic pentenylation of aldehydes
was developed by Fujita and Schlosser. See:
Fujita K.Schlosser M. Helv. Chim. Acta 1982, 65: 1258 - 6
Shibahara S.Fujino M.Tashiro Y.Takahashi K.Ishihara J.Hatakeyama S. Org. Lett. 2008, 10: 2139 - 7a
Yoshida T,Koizumi K,Kawamura Y,Matsumoto K, andItazaki H. inventors; Jpn. Patent, 5310726. - 7b
Yoshida T,Koizumi K,Kawamura Y,Matsumoto K, andItazaki H. inventors; Eur. Patent 560389 A1. - 7c
Yasui K.Tamura Y.Nakatani T.Kawada K.Ohtani M. J. Org. Chem. 1995, 60: 7567 - 7d
Kobayashi S.Tsuchiya K.Harada T.Nishide M.Kurokawa T.Nakagawa T.Shimada N.Kobayashi K. J. Antibiot. 1994, 47: 697 - 7e
Kobayashi S.Tsuchiya K.Harada T.Nishide M.Kurokawa T.Nakagawa T.Shimada N.Iitaka T. J. Antibiot. 1994, 47: 703 - 7f
Bressy C.Vors J.-P.Hillebrand S.Arseniyadis S.Cossy J. Angew. Chem. Int. Ed. 2008, 52: 10137 - 8a
Kohama T.Enokita R.Okazaki T.Miyaoka H.Torikata A.Inukai M.Kaneko I.Kagasaki T.Sakaida Y.Satoh A.Shiraishi A. J. Antibiot. 1993, 46: 1503 - 8b
Kohama T.Nakamura T.Kinoshita T.Kaneko I.Shiraishi A. J. Antibiot. 1993, 46: 1512 - 8c
Matsuhashi H.Shimada K. Tetrahedron 2002, 58: 5619 - 8d
Moïse J.Sonawane RP.Corsi C.Wendeborn SV.Arseniyadis S.Cossy J. Synlett 2008, 2617 - Since the (Z)-crotyl potassium species are thermodynami-cally more stable than the corresponding E-isomer, pre-ferential access to syn-substituted homoallylic alcohols is observed with them. See:
- 11a
Schlosser A.Despond O.Lehmann R.Moret E.Rauchschwalbe G. Tetrahedron 1993, 49: 10175 - 11b
Schlosser A.Hartmann J. J. Am. Chem. Soc. 1976, 98: 4674 - 11c
Roush W.Adam M.Walts A.Harris D. J. Am. Chem. Soc. 1986, 108: 3422 - 12
Seco JM.Quiñoá E.Riguera R. Tetrahedron: Asymmetry 2001, 12: 2915 - 14a
Cossy J.Bauer D.Bellosta V. Tetrahedron Lett. 1999, 40: 4187 - 14b
Fürstner A.Langemann K. J. Am. Chem. Soc. 1997, 119: 9130 - 14c
Ghosh AK.Cappiello J.Shin D. Tetrahedron Lett. 1998, 39: 4651 - 14d
Boucard V.Broustal G.Campagne JM. Eur. J. Org. Chem. 2007, 225 - 15a
Heathcock CH. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I. Pergamon Press; Oxford: 1991. p.181 - 15b
Kim BM.Williams SF.Masamune S. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I. Pergamon Press; Oxford: 1991. p.239
References and Notes
It is noteworthy that optically active ethyl-substituted homoallylic alcohols are exclusively accessed through aldol chemistry.
10
General Procedure
for the syn-
Selective
Boron-Mediated Pentenylation Reaction: To a stirred suspension
of t-BuOK (1.1 equiv) and (Z)-2-pentene (2.2 equiv) in THF at -78 ˚C was
added n-BuLi (1.1 equiv) dropwise. After
complete addition, the reaction mixture was stirred for 5 min at
-50 ˚C.
The resulting orange solution was then cooled
to -78 ˚C
and to it, was added dropwise a solution of (+)-methoxydiisopinocampheylborane
in Et2O (1.35 equiv, 0.5 M in Et2O). After
stirring for 30 min at -78 ˚C, boron trifluoride
diethyl etherate (1.5 equiv) was added followed by the aldehyde
(1 equiv). The reaction mixture was then stirred for an extra 5
h at the same temperature before it was treated with a 3 M solution
of NaOH and H2O2 and refluxed for 1 h. The
reaction mixture was then extracted with EtOAc, washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on
silica gel using a gradient of eluents to afford the corresponding
homoallylic alcohol.
Same procedure as previously employed except that the temperature was not raised to -50 ˚C after the addition of n-BuLi.
- For recent reviews, see:
- 1a
Main
Group Metals in Organic Synthesis
Vol. 2:
Yamamoto H.Oshima K. Wiley-VCH; Weinheim: 2004. - 1b
Junzo O. Modern Carbonyl Chemistry Wiley-VCH; Weinheim: 2000. - 1c
Marshall JA. Chem. Rev. 2000, 100: 3163 - 1d
Marshall JA. Chem. Rev. 1996, 96: 31 - 1e
Yamamoto Y.Asao N. Chem. Rev. 1993, 93: 2207 - 1f
Nishigaichi Y.Takuwa A.Naruta Y.Maruyama K. Tetrahedron 1993, 49: 7395 - 1g
Roush WR. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I.Heathcock CH. Pergamon; Oxford: 1991. p.1-53 - 2
Brown HC.Bhat KS.Randad RS. J. Org. Chem. 1989, 54: 1570 - 3
Roush WR.Ando K.Powers DB.Palkowitz AD.Halterman RL. J. Am. Chem. Soc. 1990, 112: 6339 - 4
Hafner A.Duthaler RO.Marti R.Rihs G.Rhote-Streit P.Schwarzenbach F. J. Am. Chem. Soc. 1992, 114: 2321 - 5 A racemic pentenylation of aldehydes
was developed by Fujita and Schlosser. See:
Fujita K.Schlosser M. Helv. Chim. Acta 1982, 65: 1258 - 6
Shibahara S.Fujino M.Tashiro Y.Takahashi K.Ishihara J.Hatakeyama S. Org. Lett. 2008, 10: 2139 - 7a
Yoshida T,Koizumi K,Kawamura Y,Matsumoto K, andItazaki H. inventors; Jpn. Patent, 5310726. - 7b
Yoshida T,Koizumi K,Kawamura Y,Matsumoto K, andItazaki H. inventors; Eur. Patent 560389 A1. - 7c
Yasui K.Tamura Y.Nakatani T.Kawada K.Ohtani M. J. Org. Chem. 1995, 60: 7567 - 7d
Kobayashi S.Tsuchiya K.Harada T.Nishide M.Kurokawa T.Nakagawa T.Shimada N.Kobayashi K. J. Antibiot. 1994, 47: 697 - 7e
Kobayashi S.Tsuchiya K.Harada T.Nishide M.Kurokawa T.Nakagawa T.Shimada N.Iitaka T. J. Antibiot. 1994, 47: 703 - 7f
Bressy C.Vors J.-P.Hillebrand S.Arseniyadis S.Cossy J. Angew. Chem. Int. Ed. 2008, 52: 10137 - 8a
Kohama T.Enokita R.Okazaki T.Miyaoka H.Torikata A.Inukai M.Kaneko I.Kagasaki T.Sakaida Y.Satoh A.Shiraishi A. J. Antibiot. 1993, 46: 1503 - 8b
Kohama T.Nakamura T.Kinoshita T.Kaneko I.Shiraishi A. J. Antibiot. 1993, 46: 1512 - 8c
Matsuhashi H.Shimada K. Tetrahedron 2002, 58: 5619 - 8d
Moïse J.Sonawane RP.Corsi C.Wendeborn SV.Arseniyadis S.Cossy J. Synlett 2008, 2617 - Since the (Z)-crotyl potassium species are thermodynami-cally more stable than the corresponding E-isomer, pre-ferential access to syn-substituted homoallylic alcohols is observed with them. See:
- 11a
Schlosser A.Despond O.Lehmann R.Moret E.Rauchschwalbe G. Tetrahedron 1993, 49: 10175 - 11b
Schlosser A.Hartmann J. J. Am. Chem. Soc. 1976, 98: 4674 - 11c
Roush W.Adam M.Walts A.Harris D. J. Am. Chem. Soc. 1986, 108: 3422 - 12
Seco JM.Quiñoá E.Riguera R. Tetrahedron: Asymmetry 2001, 12: 2915 - 14a
Cossy J.Bauer D.Bellosta V. Tetrahedron Lett. 1999, 40: 4187 - 14b
Fürstner A.Langemann K. J. Am. Chem. Soc. 1997, 119: 9130 - 14c
Ghosh AK.Cappiello J.Shin D. Tetrahedron Lett. 1998, 39: 4651 - 14d
Boucard V.Broustal G.Campagne JM. Eur. J. Org. Chem. 2007, 225 - 15a
Heathcock CH. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I. Pergamon Press; Oxford: 1991. p.181 - 15b
Kim BM.Williams SF.Masamune S. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Fleming I. Pergamon Press; Oxford: 1991. p.239
References and Notes
It is noteworthy that optically active ethyl-substituted homoallylic alcohols are exclusively accessed through aldol chemistry.
10
General Procedure
for the syn-
Selective
Boron-Mediated Pentenylation Reaction: To a stirred suspension
of t-BuOK (1.1 equiv) and (Z)-2-pentene (2.2 equiv) in THF at -78 ˚C was
added n-BuLi (1.1 equiv) dropwise. After
complete addition, the reaction mixture was stirred for 5 min at
-50 ˚C.
The resulting orange solution was then cooled
to -78 ˚C
and to it, was added dropwise a solution of (+)-methoxydiisopinocampheylborane
in Et2O (1.35 equiv, 0.5 M in Et2O). After
stirring for 30 min at -78 ˚C, boron trifluoride
diethyl etherate (1.5 equiv) was added followed by the aldehyde
(1 equiv). The reaction mixture was then stirred for an extra 5
h at the same temperature before it was treated with a 3 M solution
of NaOH and H2O2 and refluxed for 1 h. The
reaction mixture was then extracted with EtOAc, washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on
silica gel using a gradient of eluents to afford the corresponding
homoallylic alcohol.
Same procedure as previously employed except that the temperature was not raised to -50 ˚C after the addition of n-BuLi.

Figure 1 Structure of pironetin (1) and leustroducsin B (2)

Scheme 1 Synthesis of syn- and anti-ethyl substituted homoallylic alcohols through boron-mediated asymmetric pentenylation


















Scheme 2 syn-Pentenylation of an α-branched aldehyde

Scheme 3 anti-Pentenylation of 3-bromobenzaldehyde
















