One-pot sequential cross-metathesis/hydride reduction: highly stereoselective synthesis of primary (E)-allylic alcohols from terminal olefins

Article abstract of DOI:10.1016/j.tetlet.2008.03.132

Several di- and trisubstituted primary (E)-allylic alcohols have been prepared from the corresponding terminal olefins in a highly stereoselective manner (>20:1 E/Z) by sequencing olefin cross-metathesis (CM) with hydride reduction (DIBAL-H) in good yields utilizing only commercially available reagents in a one-pot fashion. The method is a reliable alternative to the direct CM of terminal olefins with allyl alcohol, which is not always stereoselective but rather highly substrate dependent.

Full text of DOI:10.1016/j.tetlet.2008.03.132

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3363–3367
One-pot sequential cross-metathesis/hydride reduction:
highly stereoselective synthesis of primary (E)-allylic
alcohols from terminal olefins
Tapas Paul, Gopal Sirasani, Rodrigo B. Andrade *
Temple University, Department of Chemistry, Philadelphia, PA 19122, United States
Received 12 February 2008; revised 24 March 2008; accepted 25 March 2008
Available online 29 March 2008
Abstract
Several di- and trisubstituted primary (E)-allylic alcohols have been prepared from the corresponding terminal olefins in a highly
stereoselective manner (>20:1 E/Z) by sequencing olefin cross-metathesis (CM) with hydride reduction (DIBAL-H) in good yields
utilizing only commercially available reagents in a one-pot fashion. The method is a reliable alternative to the direct CM of terminal
olefins with allyl alcohol, which is not always stereoselective but rather highly substrate dependent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: One-pot; Cross-metathesis; Synthesis; Primary (E)-allylic alcohol
1. Introduction
MesN NMes
Cl
Ru
O
Streamlining linear sequences of chemical reactions are
a routine tactic when carrying out an efficiency-driven syn-
thesis, be it toward the preparation of building blocks, a
natural product target/analogue, or a pharmaceutical inter-
mediate. One-pot and tandem reactions are excellent exam-
ples of such tactics, which both accelerate product
preparation and reduce cost by consolidating time-consum-
ing purification steps (i.e., chromatography).1 In the con-
text of sequencing CM with other transformations,
methodologies can be classified into those carried out in
a one-pot fashion and those that are not.2 We and others
have focused efforts on the former in order to maximize
efficiency.3 Olefin cross-metathesis is a powerful methodo-
logy for the elaboration of olefinic substrates, particularly
terminal alkenes, due largely to the advent of powerful
catalysts such as the Grubbs 2nd generation catalyst (1)
MesN NMes
Cl
Cl
Ru
Me
Ph
Cl
PCy3
Me
Grubbs II
Hoveyda-Grubbs II
(1)
(2)
Fig. 1. Structures of olefin CM catalysts Grubbs II (1) and Hoveyda–
Grubbs II (2).
and the Hoveyda–Grubbs 2nd generation catalyst (2)
(Fig. 1).4
We recently reported a sequential CM/phosphorus-
based olefination sequence for the rapid and stereoselective
preparation of either (2E,4E)- or (2Z,4E)-dienoates by (1)
performing a CM between a terminal olefin and crotonal-
dehyde (3) to stereoselectively afford an intermediary a,b-
enal (>20:1 E:Z); and (2) utilizing either the Wittig (one-
pot) or Horner–Wadsworth–Emmons reaction as the
second step.3g Continuing with our program directed at
*
Corresponding author. Tel.: +1 215 204 7155; fax: +1 215 204 9851.
E-mail address: randrade@temple.edu (R. B. Andrade).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.132

3364
T. Paul et al. / Tetrahedron Letters 49 (2008) 3363–3367
MesN NMes
Cl
Ru
Ph
Cl
PCy3
Grubbs II
R3
R3
(1)
DIBAL-H
or
+
R
R1
O
R
OH
R
O
R2
R2
R2
MesN NMes
Cl
trans
Ru
Cl
allylic OH
dr > 20:1
not isolated
R1, R2 = H or Me; R3 = H or OMe
O
i
-Pr
Hoveyda-
Grubbs II
(2)
Scheme 1. Generalized one-pot sequential CM/hydride reduction of terminal olefins.
sequencing CM with non-metathesis reactions, we report
our findings on the use of DIBAL-mediated reduction as
the second step, which afford primary (E)-allylic alcohols
in good yields and excellent stereoselectivities (>20:1 E:Z)
when either crotonaldehyde (3), methacrolein (4) or methyl
acrylate (5) are used as coupling partners (Scheme 1).
Primary (E)-allylic alcohols are excellent substrates for a
variety of transformations such as the Sharpless asymmet-
ric epoxidation reaction,5 which has been heavily utilized in
the iterative synthesis of polyketide-derived natural prod-
ucts.6,7 These substrates are typically prepared in the
three-step sequence due to the need for redox manipula-
tion: (1) oxidation of a primary alcohol or terminal olefin
to the aldehyde; (2) olefination of the resulting aldehyde
with a phosphorus-based reagent (e.g., phosphorane, phos-
phonate); and (3) 1,2-reduction of the enoate to the
By sequencing (1) the highly (E)-selective CM reaction
of an electron-rich terminal olefin and an electron-poor
olefin (i.e., acrolein, acrylate, etc.)8 with (2) a hydride
reduction step, the stereochemical fidelity of the product
is preserved. Table 1 shows a variety of terminal olefins
that were subjected to this one-pot method.9 Styrene (6)
and a series of TBS-protected a,x alkenols were treated
with 3 equiv of either crotonaldehyde (3) or methacrolein
(4) and 5 mol % Grubbs II (1) in refluxing CH2Cl2 for
3 h to afford intermediary a,b-enals in high yield and high
1
dr (>20:1 E/Z by H NMR).10 As these reactions proceed
cleanly and in high yield (a priori requirements for efficient
one-pot procedures), the reaction mixtures were sub-
sequently cooled to À78 °C and treated with excess
DIBAL-H (commercially available solution in hexanes),
affording exclusively primary (E)-allylic alcohols 10–15 in
synthetically useful yields (59–74%). The temperature
regime was necessary to avoid undesired 1,4 reduction.
The substitution of the double bond is controlled by choice
of coupling partner (3 or 4).
With these results in hand, we turned our attention to
more synthetically useful terminal olefins (Table 2).11 The
allylation and crotylation reaction of aldehydes represent
formidable alternatives to the acetate and propionate aldol
primary (E)-allylic alcohol (Scheme 2a).
A shorter
alternative route features a CM between a terminal olefin,
`
which can be likened to an aldehyde surrogate vis-a-vis tra-
ditional olefination chemistry, and allyl alcohol (Scheme
2b). While this short route is attractive, the stereoselectivity
of the transformation is highly dependent on the nature of
‘R’ such that an increase in steric bulk favors the (E)
geometric isomer.8
1,2-
R
R
OH
oxidation
olefination
reduction
CO2R'
(a)
(b)
or
R
R
R
OH
O
(E) only
CM
+
R
R
OH
OH
E/Z mixture
dr highly
dependent
on nature of R
Scheme 2. Routes to primary (E)-allylic alcohols: (a) traditional; (b) CM.

T. Paul et al. / Tetrahedron Letters 49 (2008) 3363–3367
3365
Table 1
One-pot sequential CM/hydride reduction method for the stereoselective synthesis of primary (E)-allylic alcohols with the Grubbs II catalyst (1)
Grubbs II (1)
DIBAL-H
(5 mol%)
CHO
CHO
+
R1
R
R
OH
R
CH2Cl2
CH2Cl2
R2
R2
not isolated
R2
reflux, 3 h
-78 °C, 2 h
3: R1=Me; R2=H
>20/1 E/Z
>20/1 E/Z
4: R1=H; R2=Me
Entry
1
Olefin
Coupling partner (3 equiv)
Product
Yielda (%) dr > 20:1 (E/Z)b
CHO
Me
OH
70
3
10
6
TBSO
TBSO
TBSO
OH
2
3
3
74
72
7
11
OH
TBSO
3
8
12
CHO
TBSO
TBSO
OH
TBSO
TBSO
4
5
56
69
Me
Me
8
13
4
OH
4
4
7
14
Me
TBSO
OH
TBSO
6
59
Me
9
15
a
Yields refer to the average of two runs.
Ratio determined by 1H NMR.
b
reactions, respectively. These methodologies have been lev-
eraged in the stereoselective total synthesis of natural prod-
ucts, particularly those of polyketide origin.12 As the
products of these reactions are terminal olefins, they repre-
sent excellent substrates for our methodology. Toward this
goal, a variety of protected homoallylic alcohols 16–21
were prepared using established procedures and subjected
to our method. For these substrates, we found that the
combination of 10 mol % Hoveyda–Grubbs II catalyst (2)
and 3 equiv of methyl acrylate (5) gave the best results.13
In addition, after the addition of DIBAL-H at À78 °C,
the reaction mixture was warmed À45 °C and stirred for
2 h. Of note are chemoselective CM entries 3 and 6, which
afford alcohols 24 and 27 due to the bulky TBS protecting
group that sterically shields the allylic site.14 Synthetically
useful yields (54–74%) were obtained for both allylated
(entries 1–4) and crotylated (entries 5–6) substrates.
In summary, we have developed a convenient one-pot
sequential CM/hydride reduction method for the rapid
synthesis of di- and trisubstituted primary (E)-allylic alco-
hols from terminal olefins in good yields as one geometric
isomer. The method utilizes only commercially available
reagents and should find utility in the elaboration of syn-
thetic intermediates. We will continue to probe the utility
and demonstrate the value sequencing CM with other
reactions and those results will be presented in due
course.
2. Experimental procedures
2.1. Representative procedure for CM/hydride reduction
sequence (Tables 1 and 2)
To a solution of olefin (0.48 mmol) and a,b-unsaturated
carbonyl partner (1.45 mmol) in deaerated CH2Cl2
(3.0 mL) was added catalyst 1 or 2 (5–10 mol %). The reac-
tion mixture was heated to 40 °C under an Ar atmosphere
and stirred for 3 h. The reaction mixture was cooled to
À78 °C, and DIBAL-H (1 M in hexanes, 1.8 mL,
1.80 mmol) was added dropwise. The reaction mixture
was stirred at À78 °C for 2 h and quenched by the slow
addition of MeOH (1.8 mL) followed by a saturated solu-
tion of Rochelle’s salt (1.8 mL). The reaction mixture was
warmed to room temperature and filtered through a cotton
plug. The residue was washed thoroughly with CH2Cl2
(3 Â 10 mL). The combined organic layers were washed
with brine (2 Â 10 mL), dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified
by flash column chromatography eluting with 20%
EtOAc/hexanes.

3366
T. Paul et al. / Tetrahedron Letters 49 (2008) 3363–3367
Table 2
One-pot sequential CM/hydride reduction method for the stereoselective synthesis of primary (E)-allylic alcohols with the Hoveyda–Grubbs II catalyst (2)
Hoveyda-
Grubbs II (2)
DIBAL-H
(10 mol%)
CO2Me
+
CO2Me
R
R
R
OH
CH2Cl2
-78 °C
CH2Cl2
5
not isolated
reflux, 3 h
(3 equiv.)
then -45 °C, 2 h
>20/1 E/Z
>20/1
E/Z
Entry
1
Olefin
Product
OBn
Me
Yielda (%) dr > 20:1 (E/Z)b
OBn
59
Me
OH
16
22
OTBS
OTBS
2
3
56
54
Ph
OH
Ph
17
23
OTBS
OTBS
18
Ph
OH
Ph
24
OTBS
OTBS
Me
Me
4
5
64
OH
25
OTBS
Me
Me
19
OTBS
57
74
Ph
OH
Ph
Ph
Me
OTBS
20
Me
OTBS
26
6
Ph
OH
Me
21
Me
27
a
Yields refer to the average of two runs.
Ratio determined by 1H NMR.
b
Tetrahedron Lett. 2007, 48, 5367. For
metathesis/non-metathesis processes, see: (h) Dragutan, V.; Drag-
utan, I. J. Organomet. Chem. 2006, 691, 5129.
a highlight of tandem
Acknowledgments
Financial support of this work by the Department
of Chemistry at Temple University is gratefully
acknowledged. We kindly thank Materia, Inc. for a gener-
ous donation of Grubbs II catalyst (1) and Hoveyda–
Grubbs II catalyst (2).
4. (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
and references cited therein; (b) Chatterjee, A. K.; Choi, T. L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
5. For a review of the SAE, see: Johnson, R. A.; Sharpless, K. B. Catal.
Asymmetric Synth. 2000, 231 (2nd ed.).
6. Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
7. For examples see: Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95,
2041.
References and notes
8. Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R.
A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
9. Spectral data (1H and 13C) were in agreement for the following
compounds: Compound 10: (a) Pospisil, J.; Marko, I. E. . Org. Lett.
2006, 8, 5983; Compound 11: (b) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330;
Compound 12: (c) Francesca, A.; Federico, C.; Paolo, C.; Cristina,
G.; Granco, M.; Mauro, P. Tetrahedron 1995, 51, 10601; Compound
13: (d) Wang, J.; Hsung, R. P.; Ghosh, S. K. Org. Lett. 2004, 6, 1939;
Compound 14: (e) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.;
Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321;
Compound 15: (f) Hayashi, Y.; Kanayama, J.; Yamaguchi, J.; Shoji,
M. J. Org. Chem. 2002, 67, 9443.
1. Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
2. (a) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891; (b)
Gebauer, J.; Dewi, P.; Blechert, S. Tetrahedron Lett. 2005, 46, 43; (c)
Edlin, C.; Faulkner, J.; Quayle, P. Tetrahedron Lett. 2006, 47, 1145;
(d) Mix, S.; Blechert, S. Adv. Synth. Catal. 2007, 349, 157.
3. (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312; (b) Goldberg, S.; Grubbs, R. H. Angew. Chem., Int.
Ed. 2002, 41, 807; (c) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert,
S. Angew. Chem., Int. Ed. 2006, 45, 1900; (d) Virolleaud, M.-A.; Piva,
O. Eur. J. Org. Chem. 2007, 1606; (e) Comins, D. L.; Dinsmore, J. M.;
Marks, L. R. Chem. Commun. 2007, 4170; (f) Murelli, R. P.; Snapper,
M. L. Org. Lett. 2007, 9, 1749; (g) Paul, T.; Andrade, R. B.

T. Paul et al. / Tetrahedron Letters 49 (2008) 3363–3367
3367
10. Enoate intermediates were isolated in separate experiments. Coupling
constants obtained from the 1H NMR (J = 15.6–16.0 Hz) confirm a
trans olefin geometry, which is retained in the subsequent reduction
(DIBAL-H) step.
11. Spectral data (1H and 13C) were in agreement for the following
compounds: Compound 25: Takano, S.; Sekiguchi, Y.; Shimazaki, Y.;
Ogasawara, K. Heterocycles 1992, 33, 713. Compound 16: Yadav, J.
S.; Rao, E. S.; Synth. Commun. 1988, 18, 2315. Compound 17: Hiebel,
M.-A.; Pelotier, B.; Piva, O. Tetrahedron 2007, 63, 7874. Compound
19: Masamune, S.; Kaiho, T.; Garvey, D. S. J. Am. Chem. Soc. 1982,
104, 5521.
Compound 23: 1H NMR (400 MHz, CDCl3): d 7.37–7.20 (m, 5H),
5.70–5.58 (m, 2H), 4.68 (dd, J = 7.0, 5.0 Hz, 1H), 4.05–4.04 (m, 2H),
2.50–2.35 (m, 2H), 1.39 (br s, 1H), 0.88 (s, 9H), 0.02 (s, 3H), 0.13 (s,
3H); 13C NMR (100 MHz, CDCl3): d 144.9, 131.5, 129.4, 128.0 (2C),
127.0, 125.8 (2C), 74.9, 63.7, 43.8, 25.8, 18.2, À4.7, À4.9; IR (neat):
3363, 2953, 2930, 2885, 2857, 1471, 1362, 1255, 1091, 1005, 909,
836 cmÀ1; HRMS (FAB) calcd for C17H28O2Si+Na 315.1756, found
315.1750.
Compound 24: 1H NMR (400 MHz, CDCl3): d 7.39–7.30 (m, 4H),
7.26–7.23 (m, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.20 (dd, J = 16.0,
6.4 Hz, 1H), 5.74–5.71 (m, 2H), 4.36 (q, J = 6.0 Hz, 1H), 4.16–4.12
(m, 2H), 2.38–2.35 (m, 2H), 1.50 (br s, 1H), 0.95 (s, 9H), 0.12 (s, 3H),
0.10 (s, 3H); 13C NMR (100 MHz, CDCl3): d 137.0, 132.7, 131.7,
129.3, 128.8, 128.5 (2C), 127.4, 126.4 (2C), 73.3, 63.6, 41.5, 25.9, 18.3,
À4.3, À4.7; IR (neat): 3356 cmÀ1; IR (neat): 3356, 2953, 2929, 2893,
Compound 18: 1H NMR (400 MHz, CDCl3): d 7.46–7.44 (m, 2H),
7.40–7.37 (m, 2H), 7.32–7.29 (m, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.31
(dd, J = 16.0, 6.0 Hz, 1H), 5.99–5.89 (m, 1H), 5.20–5.13 (m, 2H),
4.44–4.39 (m, 1H), 2.51–2.37 (m, 2H), 1.03 (s, 9H), 0.19 (s, 3H), 0.16
(s, 3H); 13C NMR (100 MHz, CDCl3): d 137.1, 134.8, 132.8, 129.2,
128.5, 127.3, 126.4, 117.0, 73.3, 43.2, 25.9, 18.3, À4.3, À4.7; IR (neat):
2955, 2930, 2895, 2856, 1472, 1361, 1254, 1071, 966, 910 cmÀ1; HRMS
(FAB) calcd for C18H28OSi–H+ 287.1831, found 287.1826.
Compound 20: 1H NMR (400 MHz, CDCl3): d 7.30–7.21 (m, 5H),
5.88–5.79 (m, 1H), 4.98–4.89 (m, 2H), 4.45 (d, J = 6.0 Hz, 2H), 2.43–
2.41 (m, 1H), 0.89 (s, 3H), 0.87 (s, 9H), À0.02 (s, 3H), À0.22 (s, 3H);
13C NMR (100 MHz, CDCl3): d 143.7, 141.1, 127.6, 126.9, 126.9,
114.4, 79.1, 46.4, 25.8, 18.2, 16.1, À4.6, À5.1; IR (neat): 2957, 2930,
2886, 2858, 1454, 1362, 1254, 1086, 1065, 910 cmÀ1; HRMS (FAB)
calcd for C17H28OSi–H+ 275.1831, found 275.1830.
2856, 1471, 1253, 1071, 968 cmÀ1
; HRMS (FAB) calcd for
C19H30O2Si+Na 341.1913, found 341.1904.
Compound 26: 1H NMR (400 MHz, CDCl3): d 7.29–7.21 (m, 5H),
5.72–5.50 (m, 2H), 4.43 (d, J = 6.0 Hz, 1H), 4.06 (br s, 2H), 2.45–2.40
(m, 1H), 1.16 (br s, 1H), 0.89 (d, J = 3.6 Hz, 3H), 0.87 (s, 9H), 0.01 (s,
3H), À0.22 (s, 3H); 13C NMR (100 MHz, CDCl3): d 143.6, 135.3,
129.2, 127.6, 127.0, 126.9, 126.8, 79.1, 63.9, 45.1, 25.8, 18.2, 16.5,
À4.6, À5.1; IR (neat): 3333, 2955, 2929, 2885, 2856, 1471, 1455, 1253,
1088, 1064 cmÀ1; HRMS (FAB) calcd for C18H30O2Si+Na 329.1913,
found 329.1923.
Compound 27: 1H NMR (400 MHz, CDCl3): d 7.42–7.34 (m, 4H),
7.30–7.26 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.19 (dd, J = 16.0,
6.8 Hz, 1H), 5.80–5.68 (m, 2H), 4.19–4.16 (m, 3H), 2.44–2.38 (m, 1H),
1.43 (br s, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H), 0.12 (s, 3H),
0.08(s, 3H); 13C NMR (100 MHz, CDCl3): d 137.1, 135.0, 131.4,
130.3, 129.3, 128.5 (2C), 127.4, 126.4 (2C), 77.3, 63.8, 43.6, 25.9, 18.2,
15.8, À4.2, À4.8; IR (neat): 3357, 2956, 2929, 2884, 2856, 1471, 1461,
Compound 21: 1H NMR (400 MHz, CDCl3): d 7.53–7.51 (m, 2H),
7.47–7.43 (m, 2H), 7.38–7.34 (m, 1H), 6.66 (d, J = 16.0 Hz, 1H), 6.33
(dd, J = 16.0, 6.5, 16 Hz, 1H), 6.07–5.99 (m, 1H), 5.23–5.18 (m, 2H),
4.19 (t, J = 5.2, 1.2 Hz, 1H), 2.53 (m, 1H), 1.20 (d, J = 6.8 Hz, 1H),
1.11 (s, 9H), 0.24 (s, 6H); 13C NMR (100 MHz, CDCl3): d 140.8,
137.2, 131.4, 130.2, 128.5, 127.3, 126.4, 114.6, 45.1, 25.9, 18.3, 15.4,
À4.1, À4.8; IR (neat): 2957, 2929, 2886, 2857, 1252, 1065, 967 cmÀ1
;
1362, 1253, 1070, 969, 909 cmÀ1; HRMS (FAB) calcd for C20H32
O2Si+Na 355.2069, found 355.2079.
-
HRMS (FAB) calcd for C19H30OSi–H+ 301.1989, found 301.1996.
Compound 22: 1H NMR (400 MHz, CDCl3): d 7.35–7.26 (m, 5H),
5.76–5.65 (m, 2H), 4.54, 4.52 (ABq, J = 12.0 Hz, 2H), 4.08 (br s, 2H),
3.41–3.35 (m, 1H), 2.33–2.30 (m, 2H) 1.59–1.55 (m, 3H), 0.93 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 138.9, 131.4, 129.0,
128.3 (2C), 127.7 (2C), 127.5, 79.8, 70.9, 63.6, 36.1, 26.4, 9.6; IR
(neat): 3384, 2964, 2932, 2872, 1454, 1349, 1090, 1064, 1027, 1005,
972, 910 cmÀ1; HRMS (FAB) calcd for C14H20O2+Na 243.1361,
found 243.1351.
12. For a review see: (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 1982,
21, 555; (b) Roush, W. R. In Comprehensive Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 1.
13. Cossy, J.; BouzBouz, S.; Hoveyda, A. J. Organomet. Chem. 2001, 624,
327.
14. BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6,
3465.